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PHYSIOLOGICAL REVIEWS
Vol. 79, No. 3, July 1999
Printed in U.S.A.
Central Control of the Cardiovascular and Respiratory Systems
and Their Interactions in Vertebrates
EDWIN W. TAYLOR, DAVID JORDAN, AND JOHN H. COOTE
School of Biological Sciences and Department of Physiology, The University of Birmingham, Edgbaston,
Birmingham; and Department of Physiology, Royal Free and University College Medical School,
Hampstead, London, United Kingdom
I. Introduction
II. Patterns of Ventilation and Central Respiratory Pattern Generation
A. Mammals
B. Cyclostomes
C. Fish
D. Air-breathing fish
E. Amphibians
F. Reptiles
G. Birds
III. Afferent Innervation of the Circulatory and Respiratory Systems
A. Mammals
B. Fish
C. Air-breathing fish
D. Amphibians
E. Reptiles
F. Birds
IV. Cranial Autonomic Innervation of the Cardiorespiratory System
A. Mammals
B. Cyclostomes
C. Elasmobranch fish
D. Teleost fish
E. Air-breathing fish
F. Amphibians
G. Reptiles
H. Birds
V. Sympathetic Innervation of the Cardiorespiratory System
A. Mammals
B. Cyclostomes
C. Elasmobranch fish
D. Teleost fish
E. Amphibians
F. Reptiles
G. Birds
VI. Central Control of Cardiorespiratory Interactions
A. Mammals
B. Fish
C. Air-breathing fish
D. Amphibians
E. Reptiles
F. Birds
VII. Concluding Comments
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Taylor, Edwin W., David Jordan, and John H. Coote. Central Control of the Cardiovascular and Respiratory
Systems and Their Interactions in Vertebrates. Physiol. Rev 79: 855–916, 1999.—This review explores the fundamental neuranatomical and functional bases for integration of the respiratory and cardiovascular systems in
0031-9333/99 $15.00 Copyright © 1999 the American Physiological Society
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Volume 79
vertebrates and traces their evolution through the vertebrate groups, from primarily water-breathing fish and larval
amphibians to facultative air-breathers such as lungfish and some adult amphibians and finally obligate air-breathers
among the reptiles, birds, and mammals. A comparative account of respiratory rhythm generation leads to consideration of the changing roles in cardiorespiratory integration for central and peripheral chemoreceptors and
mechanoreceptors and their central projections. We review evidence of a developing role in the control of
cardiorespiratory interactions for the partial relocation from the dorsal motor nucleus of the vagus into the nucleus
ambiguus of vagal preganglionic neurons, and in particular those innervating the heart, and for the existence of a
functional topography of specific groups of sympathetic preganglionic neurons in the spinal cord. Finally, we
consider the mechanisms generating temporal modulation of heart rate, vasomotor tone, and control of the airways
in mammals; cardiorespiratory synchrony in fish; and integration of the cardiorespiratory system during intermittent
breathing in amphibians, reptiles, and diving birds. Concluding comments suggest areas for further productive
research.
I. INTRODUCTION
This review explores the mechanisms of central control and coordination of the respiratory and cardiovascular systems in vertebrates. Animals have evolved sophisticated control mechanisms enabling them to match their
rates of oxygen uptake to their rates of aerobic metabolism. As the relative effectiveness of respiratory gas exchange over lungs or gills is determined not only by their
physical dimensions but also by the rates and patterns of
their ventilation and perfusion, it is essential that these
latter components are controlled, both individually and in
relation to one another. It has long been recognized that
the overall rates of flow of air or water and of blood over
the respiratory surfaces are matched according to their
respective capacities for oxygen so that the ventilationto-perfusion ratio varies from ;1 in air-breathers to 10 or
more in water-breathers, with the bimodal, air/waterbreathers among the lungfishes and amphibians showing
variable ratios (286, 498). However, these overall ratios
ignore the pulsatile and sometimes intermittent nature of
both ventilation and perfusion. Careful study of respiratory and cardiac rhythms often shows them to be temporally related in ways that may optimize respiratory gas
exchange. Control of these cardiorespiratory interactions
resides in the central nervous system that integrates afferent inputs from a range of central and peripheral receptors and coordinates central interactions between
pools of neurons generating the respiratory rhythm and
determining heart rate variability. Thus, although the absence of a heart beat signifies death, a high and unvarying
heart rate can indicate incipient brain death.
Many aspects of the brain circuitry of this remarkably
sensitive system seem to have been highly conserved
throughout evolution. Thus the regulatory mechanisms
that operate in the central nervous systems of lower
chordates such as the elasmobranch fishes show a remarkable degree of homology with those that operate in
mammals, including humans (606). Homology literally
means “of the same essential nature” having affinity of
structure and origin. In this review, we examine apparent
homologies in the cardiorespiratory control system of
vertebrates, in terms of the location and phenotype of the
neuronal substrate, the pattern of central nervous system
(CNS) connections, the development and conservation of
fundamental rhythms of nerve discharge, and neuroeffector mechanisms. Of course, we are aware that a strictly
phylogenetic approach to comparative physiology is inappropriate, since parallel evolution can result in clear homologies of structure and function in distantly related
species. Accordingly, we have emphasized the topographical similarities and their apparent evolution and treated
the functional role of central nervous connections separately, while drawing parallels with their structural bases.
We have not attempted to draw a phylogenetic tree for
control of cardiorespiratory function; rather, we have
explored its evolutionary roots. We show that there are
considerable similarities in the topography and functional
characteristics between groups of neurons in the hindbrain and spinal cord of the different vertebrate groups.
However, there are also significant differences, the problem then being to know when it is reasonable to generalize and when not.
There are important differences in the construction
of the respiratory and cardiovascular systems in vertebrates, related to their modes of respiration. Fish typically
propel water unidirectionally over the gills, using ventilatory muscles that operate around the jaws and skeletal
elements in the gill arches lining the pharynx. Adult amphibians, which lack a diaphragm, retain the buccal force
pump for tidal lung ventilation; their larvae are aquatic
gill-breathers. Thus, in fish and amphibians, the major
respiratory muscles are cranial muscles, innervated by
motoneurons with their cell bodies in the brain stem.
Reptiles retain an elaborate buccal, hyoidean force pump,
but ventilate the lungs primarily with a thoracic aspiratory
pump, although they typically lack a diaphragm. Mammals have aspiratory lungs, and ventilation is accomplished by coordinated contractions of diaphragmatic,
intercostal and/or abdominal muscles innervated from the
spinal cord, with only some accessory respiratory muscles (e.g., for control of the glottis) innervated by cranial
nerves. Consequently, medullary respiratory neurons
send axons down the spinal cord to innervate spinal
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motoneurons. The respiratory system in birds resembles
that of mammals, except that they lack a diaphragm and
the lungs are ventilated by volume changes in the air sacs.
The cardiovascular system is undivided in a typical
fish, with the heart delivering blood into the branchial
vasculature and an arterioarterial respiratory route conducting blood directly from the gills to the systemic circuit. A parallel arteriovenous route through the branchial
circulation is probably nutritive, rather than constituting a
functional shunt past the respiratory route. In contrast,
mammals and birds have a completely divided circulatory
system, with separate pulmonary and systemic circuits.
Air-breathing fish, amphibians, and most reptiles have
more or less incompletely divided circulatory systems,
allowing differential perfusion of the pulmonary circuit.
This ability may be an essential component of their intermittent patterns of ventilation, often associated with periods of submersion. Amphibians may, in addition, utilize
bimodal respiration. Larval amphibians possess gills, often in combination with developing lungs, while adult
amphibians can switch between cutaneous and lung
breathing (e.g., during graded hypoxia or submersion) so
that the distributing effect of vascular mechanisms are of
paramount importance.
Despite these major differences in the construction
and mode of operation of their respiratory and cardiovascular systems, evidence is accumulating that the vertebrates share some important similarities in the mechanisms of central generation of the respiratory rhythm,
control of the cardiovascular system and, more specifically in the present context, in the central nervous and
reflex generation of cardiorespiratory interactions. The
central theme of this review is the evolution of the mechanisms of integration and coordination that match blood
flow to ventilatory movements, a relationship probably
fundamental to the success of vertebrates. Accordingly,
we address such questions as the origin and nature of
tonic nervous activity to the heart, to blood vessels, and to
the airways. It may be that our review of the evolutionary
relationships between cardiorespiratory control systems
in vertebrates will illuminate our current inadequate understanding of the fundamental mechanisms underlying
the observed interrelationships between respiratory control and cardiac control.
Knowledge of this complex area is of course dominated by the results of medically oriented research on
mammals. To thoroughly review the mammalian literature is beyond the scope and length constraints of the
current account. Instead, reference will be made in the
relevant sections to recent extensive reviews. Readers
requiring a more detailed account of the mammalian literature thus have points of access to that debate, without
unduly lengthening the current review, or unbalancing it
in relation to the available information from “lower” vertebrates. Each aspect of the review, therefore, begins with
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a summary of our current understanding of the extensive
mammalian literature. This then underpins the subsequent comparative survey of the other vertebrate groups,
considered in turn from fish, through amphibians and
reptiles to birds, in relation to our more thorough understanding of the mammalian pattern. The treatment of each
group is necessarily uneven because of the limitations on
our knowledge so that the sections on “fish” are sometimes divided between elasmobranchs and teleosts and
sometimes not. It must be emphasized here that, unlike
the mammals and birds, the so-called “lower vertebrate”
groups have a complex phylogeny; that is to say that fish,
amphibian, or reptile is an umbrella term describing very
diverse groups of animals, some relatively little studied.
Because the respiratory and cardiovascular systems and
their innervation in the lower vertebrates are less well
known than those of mammals, some brief descriptions of
selected examples are included to illuminate the account
of the mechanisms of their control.
Some consideration of the mechanisms of ventilation
and of the generation of the respiratory rhythm in the CNS
is a necessary prelude to a review of the control of
cardiorespiratory interactions. Consequently, a very brief
overview of this area in mammals leads to a comparative
account of our more limited understanding of the mechanisms in lower vertebrates, which includes descriptions
of their patterns of ventilation and their origins in the
brain stem, plus a consideration of the factors determining the onset and frequency of bouts of intermittent
breathing in air-breathing fish, amphibians, and reptiles.
We then describe the innervation of the reflexogenic
areas supplying the cardiovascular and respiratory systems and implicated in the generation of cardiorespiratory interactions, including central and peripheral chemoreceptors, arterial baroreceptors, and mechanoreceptors
supplying the respiratory system. There follows a review
of the evidence for functional chemoreceptors and mechanoreceptors in fish, including air-breathing fish, and in
amphibians, which considers the developing roles for
central chemoreceptors, lung stretch receptors, and arterial baroreceptors as the vertebrates evolved from primarily water-breathing to facultative and then to obligate
air-breathing forms.
A review of the efferent innervation of the cardiovascular and respiratory systems is initiated by consideration
of the cranial autonomic outflow. Beginning with a detailed description of the central locations of vagal preganglionic neurons (VPN) in mammals, which emphasizes the
importance of the nucleus ambiguus (nA), a comparative
account of the central origins of vagal efferents innervating the cardiovascular and respiratory systems in lower
vertebrates follows. This considers evidence of a developing role in the control of cardiorespiratory interactions
for neurons relocated from the dorsal motor nucleus of
the vagus (DVN) into the nA. Description of the sympa-
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thetic innervation of the cardiorespiratory system explores evidence for the existence of functionally organized specific groups of cells, including the possible
functional importance of the arrangement of their dendritic fields, in the control of heart rate, vasomotor control, and the control of airway resistance.
The review culminates in a consideration of the central control of cardiorespiratory interactions in mammals,
with a necessarily less detailed comparison of the mechanisms in lower vertebrates. This account begins with a
consideration of control of the heart then progresses to a
review of the role of central interactions and reflex inputs
in the generation of cardiorespiratory modulation of heart
rate, vasomotor tone, and control of the airways in mammals. Discussion of the role of neurons and their connections within the nucleus of the solitary tract (NTS) and the
ventrolateral medulla in the generation of cardiorespiratory interactions is followed by a consideration of the
generation of respiratory oscillations in sympathetic cardiovascular neurons. A comparative account of the central and peripheral interactions resulting in cardiorespiratory synchrony in fish is followed by consideration of the
interactions responsible for control of the cardiorespiratory responses of intermittent breathers among the amphibians, reptiles, and diving birds.
We conclude the review with a summary of the apparent evolutionary changes in the control systems described in lower vertebrates, toward the more fully investigated systems in mammals, which attempts to identify
areas that merit the urgent attention of comparative physiologists. The identification of these areas is made in the
knowledge that comparative studies are becoming ever
harder to fund from the agencies that support academic
research. It is our task to emphasize that such studies are
not only of great intrinsic interest but can further illuminate our understanding of mammalian, and therefore human, systems.
II. PATTERNS OF VENTILATION AND CENTRAL
RESPIRATORY PATTERN GENERATION
Mammals characteristically display continuous,
rhythmic, aspiratory breathing to maintain their relatively
high rates of oxygen uptake and carbon dioxide excretion. Exceptions are the fetus and neonate which often
show intermittent cycles of breathing related to sleep
states (260) and diving or hibernating mammals which
suspend or markedly reduce breathing and heart rates for
varying periods but otherwise show typical cardiorespiratory control mechanisms. Patterns of ventilatory mechanics are defined solely in terms of the time spent in
inspiration and expiration and the rate of air flow. Combinations of these variables produce the more familiar
components of breathing, namely, frequency, tidal vol-
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ume, and minute ventilation. From neurophysiological
data, the mammalian ventilatory cycle has been divided
into three distinct neural phases in which each phase
reflects a “state” of the oscillating network rather than a
particular configuration of the motor output. In other
words, a cycle phase in this context means a recurring
episode when one or more groups of neurons in the
network discharge a characteristic pattern of action potentials (528, 529). These phases have been defined as
inspiration, postinspiration (passive expiration), and expiration (active expiration). The postinspiratory phase is
a period of inspiratory braking, which is also referred to
as the first stage of expiration (EI) (364, 528).
Pattern is more complex in arrhythmic or episodic
breathers, such as the amphibians and reptiles, where the
components of breathing frequency also include number
of breaths per episode and an apneic or nonventilatory
period of variable duration. Kogo and Remmers (364)
have recently discussed the similarity of the respiratory
phases between amphibians and mammals. Their intraand extracellular recordings of respiratory neurons in
bullfrogs provide solid evidence to argue that lower vertebrates also have a three-phase respiratory cycle. According to their analysis, the first phase is expiration, and
it occurs when the glottis is first opened. This is then
followed by inspiration, which is produced by the brisk
activation of the buccal levators to push air back into the
lungs. The last phase is a period of breath holding, during
which neurons other than those involved in the production of the two other phases were shown to be active. This
phase corresponds to the postinspiratory phase described
previously for mammals. They conclude their discussion
by stating that this analysis is consistent with that of Pack
et al. (487), who suggest that lungfish, which also have a
buccal force pump, have a postinspiratory phase.
The mechanisms underlying respiratory rhythmogenesis in mammals are only now being resolved (67, 529,
585), and even less is known about respiratory rhythmogenesis in nonmammalian species. Recordings from isolated brain stem-spinal cord preparations in lamprey
(539), bullfrog (427), and turtle (178) have shown rhythmic respiratory-related discharges in spinal and cranial
motoneurons. Because these preparations can produce a
respiratory rhythm in the absence of afferent feedback
(with the possible exception of input from central oxygen
chemoreceptors, when present) it would appear that a
central respiratory pattern generator is present in all vertebrates. At the same time, because it is possible to eliminate breathing by artificially meeting the convective requirements of an animal (e.g., external membrane lung,
unidirectional gill or lung ventilation; for review, see Ref.
440), it would appear that the CPG requires some external
stimulus to trigger respiratory events.
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A. Mammals
The neural substrate responsible for respiratory
rhythm generation and mediation of respiratory reflexes
lies within the brain stem of mammals. Groups of respiratory premotoneurons and neurons innervating upper
airway muscles are found in the caudal medulla near the
nA and the Bötzinger complexes. In addition, at least one
site of respiratory rhythmogenesis has been identified, in
neonatal mammals, in the “pre-Bötzinger” complex which
is situated in the reticular formation of the rostral medulla, at the level of the hypoglossal nuclei (585). These
outflows probably derive, in an evolutionary sense, from
the branchial motoneurons of more primitive, gill-breathing vertebrates that retain their primary roles in respiratory rhythm generation in present-day fish and larval amphibians. Accordingly, the reticular formation is thought
to be the site both of the primary respiratory rhythm
generator in fish and amphibians and of the respiratory
and suckling rhythms in neonatal mammals.
Because the detailed organization of central respiratory control in mammals has been exceedingly well reviewed recently (67, 200, 529), a brief synopsis, for comparison with nonmammalian vertebrates, will be
sufficient here. Two models have been proposed to try to
explain respiratory rhythmogenesis in mammals. One proposes that the central respiratory rhythm generator consists of burster or pacemaker neurons, which show spontaneous rhythmic oscillations in membrane potential in
the absence of synaptic inputs or alternatively require a
tonic excitatory input before they exhibit rhythmic oscillatory activity. The second postulates that respiratory
rhythm is produced by neural networks that exhibit oscillatory behavior due to synaptic interactions alone. Indeed, although pacemaker-like neurons have been identified in the pre-Bötzinger region in neonatal mammals in
vitro, when sensory input was removed (585), most recently Richter (529) has argued for a hybrid of these two
in vivo, whereby under normal conditions of sensory
input, the synaptic interactions between respiratory neurons override the effects of pacemaker inputs. In their
recent review of the literature on the central control of
breathing in mammals, Bianchi et al. (67) have proposed
that respiratory rhythm is not generated by a single conditional pacemaker process. Their argument was based
on the assumption that brain stem respiratory activity
results from the sequential activation of many populations of neurons to produce a three-phase motor act
(breathing) in which each process is conditioned by the
previous one and initiates the next. An alternate view
would be that the coordination of the groups of respiratory neurons would be performed by a different entity.
This entity would be responsible for processing the relevant sensory signals and would ensure precise spatial and
temporal pattern of muscle activation during each breath
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so that the respiratory system meets the demand of the
organism. It is to help understand the relationship between respiratory rhythm and pattern that the concept of
a central respiratory pattern generator has emerged (203,
439). Because the mechanisms underlying the generation
of central respiratory rhythms are not the prime subject of
this review, central pattern generation will be referred to
nonspecifically and the generator designated as the CPG.
B. Cyclostomes
This group of vertebrates is composed of the myxinoids (e.g., Myxine, the hagfish) and the petromyzontes
(e.g., Lampetra, the lamprey). They are jawless fishes,
possibly related to the primitive, extinct agnathans, but
with highly specialized life-styles. In the hagfishes, water
is drawn in through the nostrils by the action of a muscular membrane known as the velum and exits from a
series of gill pouches via a single external opening. The
ammocoete larva of the lamprey has a series of finely
divided gill slits which it ventilates unidirectionally by
means of the velum. Water flow is utilized both for gas
exchange and filter-feeding. Adult lampreys are ectoparasites and have powerful suckers around the mouth with
which they attach themselves to their fish hosts. The gills
are enclosed in a series of pouches that are ventilated
with tidal flow of water in and out of the small external
openings of each pouch. Expiration is the active phase
with muscles in the walls of the pouches contracting
against the elastic recoil of the branchial basket.
Spontaneous bursts of respiration-related activity
have been recorded from the isolated brain stem of the
lamprey. Recording sites included respiratory motor nuclei in the caudal half of the medulla, innervating the
VIIth, IXth and Xth cranial nerves and sites near the
trigeminal (Vth) motor nuclei, in the rostral half of the
medulla (538, 541, 622). Periodic bursts of small spikes
recorded from the rostral medulla, at the levels of the V
motor nuclei, continued after isolation of the isthmictrigeminal region by transections and occurred before
bursts recorded from the IX and X cranial nerve roots.
Electrical stimulation of this area excited respiratory motoneurons monosynaptically and could entrain or reset
the respiratory rhythm. These observations suggest that
the motor pattern for respiration is at least partly generated and coordinated in the rostral half of the medulla in
the lamprey and is transmitted to respiratory motoneurons through descending pathways (539).
C. Fish
Water contains less oxygen per unit volume than air
and yet is considerably more dense and viscous. Consequently, fish have to work relatively hard to extract suf-
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TAYLOR, JORDAN, AND COOTE
Volume 79
FIG. 1. Diagram of distribution of components
of cranial nerves involved in control of ventilation
in a shark (Squalus). Roman numerals refer to cranial nerves: V1, ophthalmic ramus of trigeminal
nerve; V2, maxillary division; V3, mandibular division of trigeminal; VII Pal, palatine ramus of facial
nerve; X, vagus nerve supplying branchial branches
to gill arches 2–5, cardiac and visceral branches;
XII, trunk of conjoined occipital and anterior spinal
nerves to form hypobranchial nerve innervating
ventral muscles inserted on pectoral column and
used in feeding and forced ventilation; hm, hyomandibular; lat, lateral line trunk; occ n, occipital
nerves; s op, superficial ophthalmic; S, position of
spiracle; sp n, anterior spinal nerves; 1–5, position
of gill slits. [From Taylor et al. (613).]
ficient oxygen from water and normally exhibit continuous rhythmical breathing movements of the buccal and
septal or opercular pumps. Fish use cranial muscles for
gill ventilation. These are innervated by a dorsal group of
cranial nerves exiting from the brain stem and termed the
branchial nerves (536). This series of nerves contains
sensory fibers and in most cases visceral motor components (Fig. 1). The nerves innervating respiratory muscles
include the trigeminal Vth which provides the major innervation to the mouth region of all vertebrates, including
the maxillary branch to the upper jaw and mandibular
branch to the lower jaw, responsible for motor control of
the jaw-closing muscles. Jaw opening is passive in routine
aquatic ventilation (31, 285). The facial VIIth nerve provides the hyomandibular branch to the branchial muscles
in the hyoid arch, including the levator hyoidei and, in
teleosts, the opercular muscles. The glossopharyngeal
IXth and the vagal Xth cranial nerves innervate the gill
arches and in particular provide afferent innervation of
the mechanoreceptors and chemoreceptors important in
ventilatory control and efferent innervation to intrinsic
respiratory muscles in the gill arches. These branchial
nerves have their efferent cell bodies and afferent sensory
projections located dorsomedially in the brain stem, close
to the fourth ventricle, in a rostrocaudally sequential series (607; Fig. 2).
Rhythmic ventilatory movements continue in fish after brain transection to isolate the medulla oblongata,
although changes in pattern indicate that there are influences from higher centers (563). Central recording and
marking techniques have identified a longitudinal strip of
neurons with spontaneous respiration-related bursting activity, extending dorsolaterally throughout the whole extent of the medulla (36, 564, 565, 636). These neurons
make up elements of the trigeminal Vth, facial VIIth,
glossopharyngeal IXth, and vagal Xth motor nuclei, which
drive the respiratory muscles, together with the descending trigeminal nucleus and the reticular formation (Fig. 1).
All the motor nuclei are interconnected, and each receives an afferent projection from the descending trigem-
inal nucleus and has efferent and afferent projections to
and from the reticular formation (29). The intermediate
facial nucleus, which receives vagal afferents from the gill
arches that innervate a range of tonically and physically
active mechanoreceptors (164) as well as chemoreceptors (607), projects to the motor nuclei (34). Finally, areas
in the midbrain such as the mesencephalic tegmentum
have efferent and afferent connections with the reticular
formation (33, 335). The respiratory rhythm apparently
originates in a diffuse respiratory pattern generator in the
reticular formation, and this remains functional under
anesthesia (29).
Some fish will exhibit episodic breathing patterns
when exposed to particular environmental conditions
such as hyperoxia. Carp were shown to possess a group
of neurons with phase-switching properties, situated in
the dorsal tegmentum at the level of the caudal midbrain.
This group of respiratory rhythmic neurons (termed type
A neurons) do not sustain continuous respiration but
appear to play a key role in the control of episodic breathing. Indeed, type A neurons fire just before the onset of a
breathing bout during intermittent respiration. Furthermore, stimulation of this area of the brain stem, during a
ventilatory pause, brings forward the onset of the next
breathing bout (334).
Central recordings from the medulla oblongata of the
carp suggested that adjacent neurons have different firing
patterns (30). These authors identified the target muscle
for individual motoneurons by simultaneous recordings
of neuronal activity and electromyograms (EMG) from
the respiratory muscles. In contrast, retrograde intra-axonal transport of horseradish peroxidase (HRP) along
nerves that innervate the respiratory muscles revealed
that in the brain stem of elasmobranchs the neurons in the
various motor nuclei are distributed in a sequential series
(607). Recordings of efferent activity from the central cut
ends of the nerves innervating the respiratory muscles of
the dogfish Scyliorhinus canicula (52) and the ray Raia
clavata (E. W. Taylor and J. J. Levings, unpublished data)
have revealed that the branches of the Vth, VIIth, IXth,
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
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FIG. 2. Right: schematic diagram of a dorsal view of hindbrain of dogfish, Scyliorhinus canicula, to show
distribution of motonuclei (indicated by hatched areas) supplying efferent axons to cranial nerves innervating respiratory muscles and heart. These are adductor mandibulae nucleus of cranial nerve V, supplying closing muscles in jaw;
facial motor nucleus of VII, supplying muscles of jaw and spiracle; glossopharyngeal nucleus of IX, supplying first gill
arch; dorsal motor nucleus of vagus Xm, which is divided rostrocaudally into separate subnuclei innervating branchial
arches 2– 4 (Xm 1–3), branchial arch 5 plus branchial cardiac nerve (Xm4), and heart plus anterior regions of gut (X vis).
Lateral nucleus of vagus (Xl) supplies axons solely to branchial cardiac nerve. Hypobranchial nucleus (hy) supplies
axons to feeding muscles via occipital nerve XI and anterior spinal nerves (not shown). Other labels indicate cerebellum
that overhangs medulla and is outlined by heavy line, a cerebellar auricle (aur) octavus nerve (VIII) and spinal canal
(spc). Obex marks position where roof of 4th ventricle is devoid of nervous tissue rostrally and covered by choroid
plexus. Left: a diagrammatic transverse section (T.S.) taken at obex; through medulla of dogfish (indicated by divided
line on right panel) to show vertical and horizontal disposition of vagal and hypobranchial nuclei. Labels indicate a vagal
rootlet (X), dorsal motor nucleus of vagus (Xm), lateral vagal nucleus (Xl), vagal sensory nucleus (Xs), hypobranchial
nucleus (hy) and sulci in 4th ventricle (4th V), namely, sulcus medianus inferior (smi), sulcus intermedius ventralis (siv),
and sulcus limitans of His (slH). [From Taylor (608).]
and Xth cranial nerves fire sequentially in the order of the
sequential rostrocaudal distribution of their motonuclei in
the brain stem and rostral spinal cord. The resultant
coordinated contractions of the appropriate respiratory
muscles may relate to their original segmental arrangement before cephalization, an arrangement which is retained in the hindbrain of the fish in the sequential topographical arrangement of the motor nuclei, including the
subdivisions of the vagal motonucleus (Fig. 2). This traditional view of the origin of the jaws and visceral arches
and their innervation (161) has recently been questioned
on the basis of developmental studies of the role of neural
crest cells (215). These suggest a separate origin for the
jaws as feeding structures, independent of the visceral
arches, which combined ventilation with filter-feeding, a
view supported by study of marker genes (586). A possible evolutionary antecedent of the jaws may be the velum
of filter feeding protochordates or larval cyclostomes
(M. A. Smith, personal communication).
Both elasmobranchs and teleosts can recruit an additional group of muscles into the respiratory cycle to
provide active jaw occlusion. These are derived phylogenetically from the forward migration of four anterior myotomes (the hypaxial muscles) to form a complex ventral
sheet of muscle, inserted between the pectoral girdle, the
lower jaw, and the ventral processes of the hyoid and
branchial skeleton. They are associated primarily with
suction feeding and ingestion in water-breathing fishes
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(285) but can be recruited into the respiratory cycle during periods of vigorous, forced ventilation such as may
occur following exercise or deep hypoxia (32, 285). These
muscles are innervated by the hypobranchial nerve,
which contains elements of the occipital nerves and the
anterior spinal nerves (Figs. 1 and 2). The hypobranchial
nerve in fish is the morphological equivalent of the hypoglossal nerve that innervates the muscles of the tongue in
reptiles, birds, and mammals. These muscles are utilized
in suckling by infant mammals, an activity likely to require its own central oscillator, which is thought to reside
in the reticular formation.
In the dogfish and ray, rhythmic opening and closing
of the mouth occurs during ingestion of food, implying the
central generation of a feeding rhythm (391). The neural
mechanisms operative in the control of masticatory
rhythms in fish remain unexplored, although it has been
argued that the respiratory and feeding rhythms in fish are
generated by separate groups of interneurons (32). It is
now well established that in mammals the masticatory
rhythm is generated in the hindbrain, in the reticular
formation (481), and the same has been suggested for
birds (181). It is interesting, in this regard, that the CPG in
fish is thought to reside in the reticular formation (29).
Preliminary studies on dogfish, in which simultaneous
recordings were made of efferent activity in the central cut
end of a branchial branch of the vagus and of a branch of the
hypobranchial nerve in decerebrate, paralyzed fish, confirmed that the hypobranchial nerve is inactive during normal fictive ventilation (Taylor and Levings, unpublished
data). Short sequences of bursting activity were elicited in
the silent hypobranchial nerve by activation of tongue mechanoreceptors and skin stretch receptors on the jaw (stimuli
associated with feeding). Periods of spontaneous, respiration-related bursting activity could be elicited by stimulation
of gill proprioreceptors and chemoreceptors (this latter response to experimental oxygen deprivation) and by intravenous injection of norepinephrine, which increases ventilation in dogfish, possibly due to central stimulation of
respiratory neurons (517, 615). The mechanisms involved in
recruitment of hypobranchial motoneurons into the respiratory rhythm have not been studied.
D. Air-Breathing Fish
Air-breathing fish retain gills, ventilated by cranial
muscles, for the uptake of a variable proportion of their
oxygen requirements, dependent on species and conditions, and excretion of most of their carbon dioxide.
Gulping of air is achieved through the action of the same
muscles in all air-breathing fish. These are elements of the
jaw musculature, innervated by cranial nerve V, together
with hypobranchial musculature, identified by Liem (396,
397) such as the geniohyoideus and sternohyoideus mus-
Volume 79
cles. The combined action of jaw and hypobranchial muscles in the generation of feeding or air-gulping, independently of the visceral arches, may derive from their
separate embryological and evolutionary origins (586).
Liem (397) described the sequence of events associated
with air-breathing in the primitive actinopterygian, the
bowfin (Amia calva), a fish that utilizes a well-vascularized swimbladder as an air-breathing organ (ABO), and
suggested that the action of air-breathing would require
little change in the pattern of neural control required for
suction feeding and/or coughing, with the exception of
control over glottal opening. Brainerd (82) has suggested
separate origins for air-pumping mechanisms in actinopterygian fishes (derived from the suction feeding/
coughing pumps) and sarcoptergian lung fish and amphibians (the branchial irrigation pump). However, both
pumps utilize the same sets of muscles and possibly the
same central oscillators. In the bowfin, there appear to be
two types of air breath, one that involves exhalation
followed by inhalation (designated “type I” air breaths by
the authors) and one that simply involves inhalation
(“type II” air breaths), and it is suggested that type I
breaths are respiratory in nature, whereas type II breaths
have a buoyancy-regulating function (266).
Reorganization of the CNS associated with the evolution of air-breathing has been poorly studied in fish. It has
been suggested that the African lungfish (Protopterus aethiopicus) possesses two separate central rhythm generators, one for gill ventilation and the other for air-breathing
(205). With regard to actinopterygian, air-breathing fishes,
there is probably a CPG for gill ventilation located in the
reticular formation of the hindbrain, similar to that of waterbreathing fish (29). In the bowfin, catecholamine infusion
stimulates gill ventilation, apparently via a central mechanism, but has no effect on air-breathing in normoxia or
hypoxia (422, 423), indicating that central sites controlling
gill ventilation and air-breathing are pharmacologically and
possibly spatially different. The central sites responsible for
control of air-breathing reflexes in fish are still unknown.
Some authors have suggested that air-breathing is critically
dependent on afferent feedback (568, 575, 577) and, as
stated above, is simply a reorganization of coughing and
suction-feeding movements requiring relatively little neural
reorganization (397, 575, 577). In the bowfin, spectral analysis indicates that there is an inherent rhythmicity to type I
(i.e., respiratory-related) air-breathing, both in normoxia and
hypoxia (267). These authors suggest, however, that this
periodicity may be driven by changes in blood oxygen status
that occur during the interbreath interval, rather than by a
CPG for air-breathing.
E. Amphibians
Amphibian tadpole larvae have gills ventilated by
activity in cranial muscles, with branchial performance
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
comparable to teleost fish, but carry out a large proportion (60%) of respiratory gas exchange over their permeable skin. As development proceeds, the lungs assume
increasing importance in oxygen uptake, although the
skin remains the major exchange surface until metamorphosis is nearly complete (91). In adult amphibians, most
oxygen is taken up from the lungs, ventilated by the
buccal cavity, but the skin retains a predominant role in
the excretion of carbon dioxide (80%, r 5 7.5).
The sequence of air flow in the breathing cycle of
lungfish and amphibians such as bullfrogs is similar. Unlike air-breathing fish, which must open their mouth to
aspirate ambient air into their buccal cavity at the onset of
the breathing cycle, frogs aspirate air via nostrils. Even
though this modification imposes a slight resistance to gas
flow, it eliminates the energy expenditure associated with
gulping air at the water surface (213, 214). Lung ventilation usually occurs episodically in bullfrogs. A breathing
cycle begins by activation of the buccal depressor muscles that brings buccal pressure below ambient, and air is
aspired into the buccal cavity via the nostrils. The laryngeal dilator muscles then contract to open the glottis, and
this allows outflow of pulmonary gas that exits by the
nostrils. Subsequent closure of the nostrils coincides with
a brisk contraction of the buccal levators, which pushes
the bolus of gas through the glottis and into the lungs. The
glottis then closes, and the inflated lung is held at a
positive pressure. Lung inflation cycles, in which a series
of inhalations occur without an intervening expiratory
phase, are associated with experimental hypoxia or hypercapnia (640).
Typically, after a bout of lung breathing, there follows a series of elevations and depressions of the floor of
the buccal cavity, called buccal oscillations. These smallamplitude, low-pressure buccal movements may help
flush the buccal cavity from the previous expiration, before the next air breath (166, 168, 213, 214, 648), although
their primary role may be olfaction (650). It has been
suggested that they may be remnants of the mechanisms
of gill ventilation used by the premetamorphic tadpole
stages, and homologous to gill ventilations in fish, and
that their rhythm may reflect vestiges of the central
rhythm generator for gill ventilation (209, 395, 487, 576).
Buccal oscillations and lung ventilations are produced by
the same muscles. The primary difference between these
two events is the force of the contraction and the positions of the glottis and nares. Lung ventilations are associated with more forceful contractions with the glottis
open and nares closed; buccal oscillations are associated
with less forceful contractions with the nares open and
the glottis closed. In resting animals, buccal oscillations
occur more or less continuously and are interrupted by
periodic lung ventilations, which normally occur at a time
when another buccal oscillation would have been initiated. Regardless of the level of respiratory drive, there
863
appears to be an intrinsic rhythm to lung inflation events,
increasing respiratory drive simply appears to result in
this rhythm being expressed a greater percentage of the
time.
These observations suggest at least two possible scenarios. The first is that there is a single central rhythm
generator whose output is integrated with inputs from
higher centers and peripheral feedback (mechano- and
chemoreceptors) at two distinct pattern generators. At
low levels of respiratory drive, only output from the pattern generator driving buccal oscillations is produced, but
as respiratory drive increases, output is generated from
the pattern generator driving lung inflation, which leads to
the increase in the force of buccal contraction and the
switch in the state of the nares and glottis. The other
possibility is that there are two distinct rhythm generators, with expression of the lung rhythm being conditional
upon a higher level of central and/or peripheral receptor
input. However, the fact that lung ventilation always occurs at a time when a buccal oscillation would otherwise
have occurred suggests that if there are separate rhythm
generators, they are entrained to a large degree. Kinkead
(354) has described some circumstantial evidence for the
existence of two central respiratory rhythm generators in
the bullfrog. Hypercapnia had no effect on the frequency
of lung inflations but reduced both the occurrence of
buccal oscillations and their instantaneous frequency
when they did occur. This might suggest that there are
separate rhythms for lung inflation and buccal oscillation,
which can be uncoupled.
Recently, a number of investigators have used in
vitro preparations of the larval or adult anuran brain stem
to examine the mechanisms of respiratory rhythmogenesis (209, 427– 429, 491). Recordings of fictive breathing in
isolated brain stem preparations revealed spontaneous
neural output from the roots of cranial nerves V, VII, X,
and XII. However, these bursts were synchronous, implying that the spatiotemporal relationships between bursts
of activity in these nerves in the intact animal rely on
feedback from peripheral receptors. Microinjections of
glutamate into rostral areas of the bullfrog brain stem,
near the VII motor nucleus, caused a brief excitation of
fictive breathing (427). Interestingly, this area corresponds to the pre-Bötzinger area of the reticular formation in the mammalian brain stem, considered to be the
primary site for respiratory rhythmogenesis in the neonate (e.g., Ref. 523). The CPG in fish is thought to reside
in the reticular formation (29). Other pharmacological
investigations support the suggestion that the neural networks associated with respiratory rhythmogenesis may
be well conserved during vertebrate evolution (640).
Extracellular recording from in vitro brain stem as
well as spinal cord preparations of Rana catesbeiana
tadpoles and adults revealed that it is possible to manipulate the two types of neural activity associated with
864
TAYLOR, JORDAN, AND COOTE
buccal or lung breathing independently, using pharmacological agents (209, 428, 487, 585, 637). Superfusion of an
in vitro brain stem-spinal cord preparation from the bullfrog tadpole with chloride-free saline eliminated the
rhythmic bursts associated with gill ventilation while augmenting lung bursts, indicating that the former arise from
a GABAergic, network-type rhythm generator, whereas
lung ventilatory rhythms arise from pacemaker cells
(209). This apparent discrimination is of interest in comparison to the situation described in fish, where gill ventilation may depend on pacemaker cells located in the
reticular formation, and in adult mammals, where lung
ventilation may be dependent on activity in neural networks. The evolution/development of air-breathing
rhythms may have required a new motor pattern in the
CNS rather than one that evolved from progressive modification of the branchial rhythm generator (354, 577).
This may have evolved from the generator for the feeding
rhythm that can be recruited by the respiratory CPG
during forced ventilation in fish or when air-breathing fish
gulp air at the water surface, as described above.
A recent report by Brainerd and Monroy (83) described activity in hypaxial muscles during exhalation in
salamanders, possibly representing a primitive condition,
intermediate between the buccal force pump of fish and
the thoracic/abdominal aspiration pump of reptiles, birds,
and mammals. Although similar data are not available for
anuran amphibians, which may have lost this function,
these data raise important considerations regarding the
evolution of the control of ventilation in amphibians,
which imply that descending fibers from the brain stem,
innervating spinal motoneurons can have important roles
in some species, anticipating their roles in the supposedly
more advanced tetrapods.
Amphibians often breathe intermittently, with bouts
of ventilation interrupted by quiescent periods or, in
aquatic species or stages, submersion. Intermittent
breathing patterns are common in lower vertebrates, such
as reptiles and amphibians, and contrast with the continuous breathing patterns of nondiving birds and mammals
in their apparent lack of constancy and intrinsic rhythm.
Many researchers have ascribed the genesis of breathing
episodes in amphibians and reptiles to the inherent oscillations of blood oxygen and/or CO2/pH levels associated
with intermittent breathing, rather than to the action of a
“mammalian-type” central control mechanism. In this
model, lung ventilations are induced when a certain arterial PO2 (PaO2) or arterial PCO2 (PaCO2) threshold is
reached and breathing ceases when the blood gas values
have been brought back within a certain range (79, 568,
649). The observation that breathing is completely suppressed when convective requirements are met by unidirectional ventilation (354, 357, 580, 649) indicates that
lung ventilation is conditional upon a minimal stimulatory
input (439, 576, 580, 649). However, these experiments
Volume 79
were conducted with some degree of lung inflation, which
may have overridden peripheral chemoreceptor drive.
Preliminary evidence from experiments on decerebrate,
paralyzed, and unilaterally ventilated toads suggests that
pulmonary stretch receptor inputs may be important in
the initiation of breathing. When fictive ventilation had
been suppressed by unilateral ventilation, it was induced
by lung deflation (640). Clearly, chemoreceptor and lung
mechanoreceptor inputs influence the respiratory CPG,
but their central interactions are unknown.
Several studies suggest that episodic breathing does
not necessarily reflect the phasic nature of afferent chemoreceptor or mechanoreceptor inputs. Unidirectionally
ventilated toads (580, 640, 649) can still display episodic
breathing or fictive ventilation, although this experimental procedure has been assumed to maintain blood gases
constant, and in paralyzed animals, lung distension constant, and thus produces only tonic chemoreceptor and
mechanoreceptor input. These data imply that the mechanisms underlying episodic breathing may be an intrinsic
property of the central respiratory control system, a view
which seems confirmed by the observation that the motor
output from a brain stem-spinal cord preparation of the
bullfrog was episodic, in the absence of any possible
feedback from the periphery (354). The central generation
of these episodic breathing patterns has been localized to
the nucleus isthmi in the brain stem of the bullfrog (354,
356). This mesencephalic structure is the neuranatomical
equivalent of the pons in mammals, which contributes to
the control of breathing pattern (202).
Whether episodic air-breathing is generated by central or peripheral mechanisms, it is vulnerable to inputs
from centers higher in the CNS. In their recent review,
Burggren and Infantino (90) described how adult male
newts reduced air-breathing frequency to maximize time
for courtship behavior toward females during the breeding season. Foraging or searching for prey can impact on
surfacing behavior in amphibians. Larval salamanders
supplied with benthic food showed reductions in buoyancy (which reflects degree of lung inflation) and frequency of air breaths compared with plankton feeders.
These larvae also reduced air-breathing frequency during
daylight hours, presumably to reduce the risk of aerial
predation. A similar interpretation was placed on the very
different periods of surface breathing between day and
night in Xenopus laevis (288).
F. Reptiles
Reptiles are typically committed air-breathers, having dry scaly skin and well-developed lungs. They are an
ancient and highly polyphyletic class of vertebrates. Extant members show diverse respiratory and cardiovascular mechanisms, including some they share with the am-
July 1999
CARDIORESPIRATORY CONTROL IN VERTEBRATES
865
FIG. 3. Patterns of ventilation in lightly anesthetised agamid lizard, Uromastyx microlepis. Animal was inserted into
a whole body plethysmograph to record lung volume changes. Activity in thoracic and gular pumps were recorded as
electromyograms (EMG) from appropriate muscles. Recordings from intercostal muscles in thorax included electrocardiogram (ECG). Blood pressure was recorded from a cannulated femoral artery. Traces were from below: 1) lung
ventilation recorded as pressure changes in plethysmograph (increased pressure signifies lung inflation); 2) EMG from
intercostal muscles, together with ECG; 3) EMG from geniohyoid muscle; 4) EMG from sphincter colli muscle; 5) blood
pressure. A series of thoracic aspiratory pumping movements, which inflated lungs, terminated in a bout of gular
pumping, which also resulted in lung inflation. A second bout of gular pumping was seemingly initiated by a single
thoracic breathing movement. Heart rate appeared unaffected, and variations in blood pressure did not appear to refer
to breathing movements. (From M. Al-Ghamdi J. F. X. Jones, and E. W. Taylor, unpublished data.)
phibians, such as an incompletely divided circulatory
system and periodic ventilation, often combined with periods of submersion. Accordingly, generalizations regarding the topography and control of their cardiorespiratory
systems must be avoided. The anapsids or turtles and
tortoises are the most primitive extant group of reptiles.
However, their ventilatory mechanisms are highly specialized to account for their shell. This incorporates their
vertebrae and ribs so that the lungs cannot be ventilated
by movements of the thoracic cage as in other tetrapod
vertebrates, and lung ventilation is greatly restricted
when the animal retreats into its shell. In the tortoise,
Testudo, the forelimbs move in and out as the animal
breathes; the turtles have sheets of muscle wrapped
around the viscera or under the skin at the anterior and
posterior openings of the shell, which contract alternately
to ventilate the lungs. Thus the respiratory muscles are
elements of the limb or body wall musculature, innervated by spinal nerves. Many of the freshwater turtles are
extremely tolerant of anoxia, experienced when denied
access to air by submersion under ice in frozen ponds. In
the crocodilians, which have a divided circulatory system
and may be more closely related to the birds rather than
other reptiles, breathing movements are driven by muscles of the body wall moving the liver, which is attached
to a transverse connective tissue sheet resembling a mammalian diaphragm.
Lizards, in common with all other reptiles (except
some crocodilians), lack a diaphragm. However, unlike
modern amphibians, they do have ribs, and lung ventilation has long been considered to be generated by intercostal muscles acting on the rib cage, with a primitive
buccopharyngeal or gular pump, like that described in
amphibians, utilized primarily for olfaction. As lizards run
in a serpentine manner, employing segmental muscles
from the body wall, it was asserted by some investigators
that they are unable to breathe while running. Recently
these views have been questioned. Whole animal plethysmography, together with recordings of EMG from respiratory muscles, in the agamid lizard, Uromastyx microlepis, revealed that the prevailing mode of ventilation in
the lightly anesthetized animal involved the intercostal
muscles in triphasic lung inflation and deflation, with both
passive and active expiratory stages, interrupted by periods of breath-hold (7). However, an alternative mode of
ventilation involved a gular pump that alternated with the
costal pump. After a short passive expiration, a bout of
buccal pumping caused a progressive increase in lung
volume, followed by breath-hold (Fig. 3). Gular pumping
commenced as lightly anesthetized lizards were warmed
from 30 to 35°C, as part of their normal daily cycle of
temperature variation, and could be induced by tactile
stimulation of conscious lizards. A parallel study, using
X-ray imaging of varanid lizards, Varanus exanthemati-
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TAYLOR, JORDAN, AND COOTE
cus, has revealed that when at rest they rarely used an
accessory gular pump. However, during recovery from
exercise, all animals used gular pumping in addition to a
costal pump, with between one and five gular pumping
movements following costal inspiration. These clearly
caused lung inflation, with caudal translation of the visceral mass (84). More recently, these lizards have been
shown to employ gular pumping when walking, thus overcoming the supposed mechanical constraint on active
lung ventilation during exercise (486).
The existence of anatomically and functionally separate thoracic and gular respiratory pumps in lizards would
seem to require separate sites of central respiratory
rhythm generation. However, this interesting possibility
remains unexplored. Putative sites of respiratory pattern
generation, having similarities in neural organization and
activation to those extensively documented for mammals,
have been described for turtles (603). However, the direct
contribution of these populations of neurons and their
potential integration of sensory information in determining the generation of respiratory movements remain unclear (439). In turtles, the basic output of the CPG is
episodic, even under experimental conditions when all
sensory feedback appears tonic (178). Experiments performed on reptiles demonstrated that mild anesthesia and
brain stem section at the level of the rostral rhombencephalon (metencephalon) abolish these breathing episodes, i.e., the animals now breathe in an uninterrupted
fashion (461– 463). Vagotomy also affects the breathing
pattern by reducing the number of breaths per episode in
crocodilians (461– 463). It is interesting to note, however,
that vagotomy had no effect on the breathing pattern
when it was performed after episodic breathing had been
abolished by a caudal midbrain transection (463).
As in amphibians, it has been suggested that the
initiation of bouts of discontinuous breathing may owe
more to thresholds for stimulation of central and peripheral chemoreceptors than to patterns dictated by a central
rhythm generator (439). This may enable the flexibility of
response essential for an ectothermic vertebrate, since
the thresholds for stimulation will vary with temperature,
in accordance with the animal’s oxygen demand. However, unidirectionally ventilated alligators display episodic breathing (179) so that centrally generated rhythmicity may have a role in its initiation.
G. Birds
Birds, like their endothermic relatives the mammals,
typically breath continuously and rhythmically, to supply
their high demand for oxygen, thus sustaining their high
metabolic rate. In both groups, ventilation is cyclic, with
air sucked into the lungs during inspiration and expelled
at expiration. However, birds do not have a diaphragm,
Volume 79
and lung volume appears to vary little over the respiratory
cycle. Instead, tidal volume is taken up by thin-walled,
highly extensible air sacs. Respiratory gas exchange takes
place over the walls of the well-vascularized parabronchi
in the lung, which, because of the unique structure of the
respiratory apparatus, are ventilated unidirectionally. The
walls of the parabronchi bear air capillaries, the functional equivalent of mammalian alveoli, which are in intimate contact with blood capillaries, providing highly effective exchange conditions between blood and air,
described as cross-current flow (553).
The respiratory rhythm in birds is assumed to arise
from a CPG, evidenced by the virtually constant periods
of inspiration and expiration recorded from birds at various levels of ventilatory output (440). Other respiratory
variables, such as tidal volume and interbreath interval,
do vary, presumably under the influence of inputs from
central and peripheral receptors. Breathing hyperoxic gas
mixtures reduces ventilation in birds, implying a chemoreceptive drive to ventilation in normoxia (553). Diving
birds can show prolonged apneas, associated particularly
with forced submersion or extended “escape” dives, during which stimulation of water receptors in the airways
overrides respiratory drive. Control of the complex suite
of reflex cardiorespiratory responses shown by diving
birds to forcible submersion in the laboratory (apnea,
profound bradycardia, and marked increase in peripheral
resistance) and their very different responses during telemetered natural dives have been comprehensively reviewed (98, 589).
The pools of neurons in the medulla that generate the
patterned activity driving the respiratory muscles in birds
appear to resemble those described in mammals (153). A
pneumotaxic center, similar in location and functional
characteristics to that previously described in mammals,
has been postulated to exist in dorsal mesencephalic
regions of the brain (553). Sections caudal to this region
abolish rhythmic respiratory activity that can, however,
be reinstated by rhythmic electrical stimulation of the
vagus nerves. The normal respiratory period in birds may
be set by cyclical changes in lung CO2 levels. In a unidirectionally ventilated bird preparation, when insufflated
CO2 levels were raised to stimulate spontaneous breathing cycles, then periodically varied around this level, the
respiratory movements of the bird were found to lock
onto the imposed fluctuations in CO2 (553).
It has long been recognized that lung ventilation may
be coordinated with wing beat in birds. Compressive
effects of wing upstroke and expansive effects of downstroke may assist airflow through the lung, in coordination with activity in respiratory muscles. The correspondence between the two rhythms varies from a ratio of 1:1
in crows and pigeons up to 5:1 (wing beats per breath) in
ducks and pheasants (95). Bats, as flying mammals, show
similar patterns of coordination and also share a relatively
July 1999
CARDIORESPIRATORY CONTROL IN VERTEBRATES
large heart and increased blood oxygen capacity with
their flying cousins, the birds. Respiratory frequency increases immediately upon take off in pigeons, indicating
that a combination of central and peripheral nervous
mechanisms, as well as mechanical considerations, is
likely to be influencing the relationship. Stimulation of
ventilation with CO2 during flight did not alter the phasic
coordination patterns between respiratory and wingbeat
cycles in either pigeons or magpies (77), suggesting that
neural interactions between control centers in the CNS
are important. A potent influence of locomotor centers in
the brain stem upon respiratory center motor output (or
vice versa) in geese and ducks has been demonstrated by
Funk et al. (207, 208). Their studies on decerebrate geese
indicated that, in the absence of feedback from flapping
wings, there was a predominantly 1:1 ratio between the
two motor outputs, implying direct recruitment of one by
the other. The various patterns of coordination seen in
free-flying birds clearly require feedback from peripheral
receptors.
III. AFFERENT INNERVATION OF THE
CIRCULATORY AND RESPIRATORY
SYSTEMS
A. Mammals
The activity of the different types of sensory receptors in the cardiovascular system and the airways of
mammals has been described in several reviews (123, 489,
490, 544). In addition, the cardiovascular and respiratory
responses evoked in mammals by stimulation of arterial
chemoreceptors have been reviewed very recently (138,
415). Accordingly, the well-known characteristics of these
mammalian sensors and the responses they engender are
not described here but are referred to, for comparison, in
the descriptions of their equivalents in nonmammalian
vertebrates, in which their roles are still not yet fully
understood.
The central projections from the various reflexogenic
sites in the mammalian cardiorespiratory system are,
however, of direct relevance to the current account. A
wide variety of afferent fibers transmitting sensory information arises from the heart, vascular, and ventilatory
systems of mammals. Arterial baroreceptors are located
in the walls of the carotid sinus and aortic arch while
arterial chemoreceptor afferents are located in the carotid
and aortic bodies, and probably elsewhere in the circulation. Both the atria and ventricles of the heart contain
mechano- and chemoreceptive afferents in their walls.
Within the respiratory system there is a wide variety of
sensory afferents (both mechano- and chemosensitive)
throughout the respiratory tract, from the nasal cavity to
the alveolar walls. These circulatory and respiratory af-
867
ferents include both myelinated and unmyelinated nerve
fibers and are located mainly in the trigeminal, glossopharyngeal, and vagus nerves. In addition, activity in several
types of somatic afferent can have actions on either or
both the respiratory and cardiovascular systems. In general, in both systems, the different afferents can be split
into those involved in homeostasis, which monitor ongoing activity, whereas others, involved in defensive type
reflexes, are only activated by more aversive types of
stimuli (120, 121).
Afferents from receptors in the cardiorespiratory system, travelling in the cranial nerves, terminate in the brain
stem, in the NTS, and, to some extent, in the trigeminal
nucleus. These make multiple synapses in distinct regions
of the NTS and show a large amount of overlap in their
terminal fields. This allows convergence of input onto
postsynaptic neurons in the NTS and may form part of the
neural substrate by which various afferent inputs are
integrated into physiological response patterns, since it is
well known from reflex studies that simultaneous activation of several afferent inputs may interact in either a
positive or negative manner (see Ref. 121). At least some
of these interactions occur as the afferent information
arrives at the CNS. There is some evidence for polysynaptic convergence and interactions of afferent inputs on
postsynaptic NTS neurons, but the extent of these interactions is still a matter of debate and has been discussed
in detail previously (121, 328).
The topography of these central terminations has
been studied by a variety of techniques. The earliest studies have been summarized and discussed previously
(328). More detailed information has now become available and will form the basis of this description. Histological studies employing degeneration (129), or more recently anterograde axonal transport of neuronal markers
(337), have demonstrated that vagal afferents terminate
predominantly in the caudal two-thirds of the NTS,
whereas glossopharyngeal afferents terminate in the rostral two-thirds, overlapping in the region around obex. In
addition, there was a certain degree of topography of
termination within the different subnuclei of the NTS,
based on organ of innervation (118, 204, 337). Although
there are different degrees of input to the different subnuclei of the NTS, there is no clear anatomical separation
between the terminations of afferent fibers from the respiratory or circulatory systems.
These histological studies give little information
about the function of the visualized afferents, a major
restraint since both the vagus and glossopharyngeal nerve
contain a large number of functionally different afferent
fibers. Electrophysiological techniques have been used to
map terminations of afferents, whose function had been
identified (Fig. 4). This antidromic mapping technique has
been used to delineate the terminal fields of slowly adapting (176) and rapidly adapting (156) pulmonary stretch
868
TAYLOR, JORDAN, AND COOTE
FIG. 4. Summary of major regions of termination within nucleus
tractus solitarius (NTS) of cat cardiovascular and pulmonary afferents
as determined by antidromic mapping studies. Relative density of ipsilateral (●) and contralateral (E) regions of termination is denoted by
number of dots, and most extensive regions of termination are shaded.
[Modified from Jordan (321).]
receptor afferents, arterial baroreceptor and chemoreceptor afferents (174), and bronchial and pulmonary C-fiber
afferents (370). Slowly adapting pulmonary stretch receptor afferents terminate rostral to obex, mainly in the
ipsilateral medial subnucleus with some innervation of
the lateral and ventrolateral subnuclei. This latter region
is the location of the dorsal respiratory group (67, 188,
189). In contrast, rapidly adapting pulmonary stretch receptor afferents terminate more caudally, rostral and caudal to obex, mainly in the ipsilateral commissural nucleus,
with less dense innervation of the medial and ventrolateral subnuclei and the contralateral commissural nucleus.
Bronchial and pulmonary C-fiber afferents only project to
medial regions of the NTS spanning the obex region.
Unlike myelinated pulmonary afferents, there are no terminations in the lateral, ventrolateral, or ventral subnuclei of the NTS. Caudal to obex, the terminal fields are
localized to the dorsal part of the commissural nucleus.
This projection of C-fiber afferents is not dissimilar to that
of arterial chemoreceptor afferent fibers that terminate in
the medial and dorsomedial NTS and in the commissural
nucleus (320).
Although antidromic activation can delineate the terminal regions of functionally identified afferent fibers,
there are limitations when the question of the fine
Volume 79
branches is addressed. The organization of preterminal
processes and distribution of synaptic boutons for single
pulmonary stretch receptor afferents (both slowly and
rapidly adapting) has been described (338, 339) by microinjecting an HRP conjugate into axons impaled in the
solitary tract, allowing direct visualization of the terminal
fields of the labeled afferents. The intermediate, ventral,
ventrolateral, and interstitial nuclei were the only regions
of the NTS receiving terminals of slowly adapting receptor afferents, whereas rapidly adapting receptor afferents
terminated in the intermediate, dorsal, and dorsolateral
subnuclei more caudally. Similar studies (55, 557) have
shown that laryngeal afferents terminate mainly in the
ventral and ventrolateral NTS, with some projections to
the interstitial, dorsolateral, medial, and dorsomedial nuclei.
Little is known about the postsynaptic neurons activated by stimulation of bronchial or pulmonary C-fiber
afferents, although neurons in the commissural and caudal part of the medial NTS can be activated by stimulation
of C fibers in pulmonary branches of the vagus (58).
Although some of these neurons also received input from
nonmyelinated afferents arising in the heart, they never
received input from myelinated afferents, from either the
heart or lungs (58). In recent studies we have confirmed
that some neurons with these same properties are indeed
activated when phenylbiguanide is injected into the right
atrium (315, 317), whereas inspiratory neurons in the
ventrolateral NTS are inhibited by this stimulus (314).
Finally, arterial baroreceptor terminals are restricted to
the ipsilateral NTS, rostral to the obex. The dorsolateral
and dorsomedial subnuclei are the most often innervated,
and the commissural nucleus also received some innervation (318). The central terminations of afferents arising
in the heart have not been studied in such detail, but type
A atrial receptor afferents have been shown to terminate
in the dorsolateral and ventrolateral subnuclei (S. Donoghue and D. Jordan, unpublished observations).
In many species, activation of receptors in different
parts of the upper respiratory tract evokes similar cardiorespiratory responses (see Ref. 135). In dogs, cats, and
monkeys, stimulation of afferents in the superior laryngeal nerve (SLN) or nasal mucosa results in apnea, bradycardia, and vasoconstriction. The trigeminal nucleus is
one site where convergence of such afferent information
may take place, since it receives afferent input from some
vagal and glossopharyngeal fibers (351, 626) and SLN
(258, 599). Indeed, some SLN fibers bifurcate, one branch
terminating in the NTS and the other in the rostral trigeminal nucleus (114). Neurons in both the rostral and caudal
sensory trigeminal nuclei have been reported to receive a
convergent visceral and somatic inputs from stimulation
of the SLN, glossopharyngeal nerves, tooth pulp, and
cutaneous facial mechanoreceptors (282, 561). In addition, Jordan and Wood (332) reported a group of neurons
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
in the rostral trigeminal nucleus that were activated by
SLN stimulation and mechanical stimulation of the nasal
mucosa but were unaffected by tactile stimulation of
other parts of the face. Finally, stimulation of trigeminal
afferents has been shown to evoke a short latency response in vagal nerves (238).
Clearly, the neurons of the NTS and trigeminal nucleus are not simple relay stations. Integration between
different afferent inputs can occur here, and there is some
degree of functional organization within these nuclei. Unfortunately, such detailed information is not available
from the other vertebrate groups, where similar studies
have yet to be performed.
B. Fish
1. Chemoreceptors
Oxygen-sensitive chemoreceptors exert dominant
control over cardiorespiratory reflexes in fish. The typical
response to ambient hypoxia is a reflex bradycardia and
increased ventilatory effort (607). Many studies support
the existence of peripheral oxygen receptors on or near
the gills of fish, and these were recently reviewed (93).
However, the precise anatomical sites and functional
properties of these peripheral chemoreceptors in fish remain uncertain. Saunders and Sutterlin (551) observed an
increase in “breathing amplitude” in the sea raven when
the dorsal aorta was perfused with hypoxic blood, and
also when perfusing the dorsal aorta with normoxic blood
during ambient hypoxia, which they regarded as evidence
for both central and peripheral sites of oxygen receptor
activity. In the sturgeon, cyanide stimulated ventilation,
both when added to inspired water and when injected
intra-arterially, indicating the presence of oxygen receptors sensitive to both internal and external milieu (425). In
contrast, Eclancher and Dejours (182) observed a ventilatory and cardiac response only to an intravascular injection of cyanide; no response was evident to cyanide in
the ventilatory water stream of teleosts, indicating that
the PO2 receptors are located internally. Daxboeck and
Holeton (159) found that irrigation of the anterior region
of the respiratory tract of the trout with hypoxic water
caused a reflex bradycardia but no change in ventilation,
whereas McKenzie et al. (425) found that cyanide added
to the water stimulated a transient bradycardia in the
sturgeon, whereas intra-arterial infusion was without effect on heart rate, implying that different receptors are
involved in the induction of the two overt responses to
hypoxic exposure. Ventilation rate in trout varied inversely with blood oxygen content, independently of partial pressure, indicating that arterial receptors respond to
rate of delivery of oxygen to the receptor site (511). There
is some evidence for receptor sites outside the branchial
apparatus, including the proposed existence of venous
869
oxygen receptors in fish (50, 617). Alternatively, Bamford
(36) concluded that the most important site of oxygen
detection in the trout is the brain.
The gill arches in fishes are innervated by cranial
nerves IX and X, and it is these nerves that innervate the
carotid and aortic bodies of mammals. Bilateral section of
IX and X abolished the hypoxic bradycardia in the trout
(584) but did not in elasmobranchs (547). Butler et al.
(103) found it necessary to bilaterally section cranial
nerves V, VII, IX, and X to abolish the hypoxic bradycardia
in the dogfish and concluded that the oxygen receptors
are distributed diffusely in the orobranchial and parabranchial cavities. Laurent et al. (384) recorded oxygen
chemoreceptor activity from branches of cranial nerve IX
innervating the pseudobranch in the tench. This organ is
derived from the spiracle, which is open in elasmobranchs, and because it receives arterialized blood flowing from the gills, it is ideally suited to monitor blood
oxygen levels. Although Smith and Davie (583) concluded
that oxygen receptors were innervated by the IXth cranial
nerve in the salmon, bilateral denervation of the pseudobranch in the trout had no effect on the changes in
ventilation volume after exposure to hypoxia and hyperoxia (514). Afferent activity has been recorded from the
branchial branch of the vagus innervating the first gill
arch of tuna and trout (93, 443). Receptors that increased
their rate of discharge in response to a decrease in the
rate of perfusion or oxygen level of the perfusate also
responded to ambient hypoxia. Fibers responding to hypoxic water showed an exponential increase in rate of
discharge to decreasing external oxygen partial pressure,
with a sensitivity similar to that exhibited by mammalian
carotid body chemoreceptors (93).
Although fish have been shown to respond to hypercapnia, there is no clear evidence of a role for central
chemoreceptors in the control of ventilation in fish (93,
232, 512). Although hypercapnic acidosis stimulated ventilation in channel catfish, Ictalurus punctatus (92), the
response was abolished by branchial denervation, indicating that it resulted from stimulation of peripheral chemoreceptors, innervated by cranial nerves IX and X. These
may be the same receptors that respond to oxygen. Mammalian carotid and aortic receptors respond both to oxygen and CO2/pH (571).
Similarly, there is no evidence that chemoreceptor
stimulation produces behavioral arousal in fish similar to
the visceral alerting response that accompanies the stimulation of carotid chemoreceptors in mammals (415, 416).
In fact, the unrestrained dogfish responds to environmental hypoxia with a reduction in activity, which remains
suppressed throughout the hypoxic period, despite an
increase in circulating catecholamines (431). This is analogous to the “playing dead” response shown by many
animals, including some mammals (see Ref. 319), and
would seem to be the opposite of a defense or alerting
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TAYLOR, JORDAN, AND COOTE
response. The absence of clear visceral alerting or baroreceptor responses in dogfish (see sect. IIIB2) precludes
their interference in chemoreceptor-induced changes in
ventilation or heart rate.
2. Mechanoreceptors
The respiratory muscles in fish contain length and
tension receptors, in common with other vertebrate muscles, and the gill arches bear a number of mechanoreceptors with various functional characteristics. Satchell and
Way (550) characterized mechanoreceptors on the
branchial processes of the dogfish, and Sutterlin and
Saunders (598) described receptors on the gill filaments
and gill rakers of the sea raven. De Graaf and Ballintinjn
(163, 164) described slowly adapting position receptors
on the gill arches and phasic receptors on the gill filaments and rakers of the carp. They interpreted their function as maintenance of the gill sieve and detection of and
protection from clogging or damaging material. Mechanical stimulation of the gill arches is known to elicit the
“cough” reflex in fish (e.g., Ref. 547) and a reflex bradycardia (430, 604). These mechanoreceptors will be stimulated by the ventilatory movements of the gill arches and
filaments, but there is no direct evidence that they contribute to respiratory control on a breath-by-breath basis
(93). Stimulation of branchial mechanoreceptors by increasing rates of water flow may be the trigger for the
cessation of active ventilatory movements during “ram
ventilation” in fish (306, 511).
Despite the early recordings of apparent pressoreceptor responses in elasmobranch fish (e.g., Ref. 293),
evidence for the involvement of baroreceptors in vasomotor control in fish remains contentious. The evolution of a
role for baroreceptor afferents and for vasomotor control,
exercised via the sympathetic nervous system, in control
of the cardiovascular system, may be associated with the
evolution of air-breathing. The gills of fish are supported
by their neutral buoyancy in water. Ventilation of the gills
generates hydrostatic pressures that fluctuate around, but
predominantly above, ambient. Arterial blood pressures
in the branchial circulation of fish and the pressure difference across the gill epithelia are relatively low, despite
the fact that the highest systolic pressures are generated
in the ventral aorta, which leaves the heart to supply the
afferent branchial arteries. Consequently, the need for
functional baroreceptors in fish is not clear.
Increased arterial pressure has been shown to induce a
bradycardia in both elasmobranchs (409, 410) and teleosts
(457). However, in both cases, the increase in pressure
required to cause a significant reduction in heart rate was
relatively high (10–30 mmHg), and dogfish seem not to
control arterial pressure after withdrawal of blood (50, 595).
In teleosts, injection of epinephrine, which raised arterial
pressure, caused a bradycardia, abolished by atropine (516),
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whereas low-frequency oscillations in blood pressure, similar to the Mayer waves in mammals, were abolished by
injection of the a-adrenoreceptor antagonist yohimbine
(659). These data imply active regulation of vasomotor tone,
and the balance of evidence indicates that functional arterial
baroreceptors may exist in the branchial circulation of
teleost fishes (24, 93).
The branchial branches of cranial nerves IX and X
provide the afferent arm for the reflex changes in ventilation and heart rate after stimulation of the gill arches or
increases in arterial pressure. Central stimulation of
branchial nerves in both elasmobranchs (409, 668) and
teleosts (456) caused a bradycardia. However, this could
have stimulated mechanoreceptor and/or chemoreceptor
afferents (see above). Afferent information reaching the
brain in the IXth and Xth cranial nerves is also known to
influence the respiratory rhythm, with fictive breathing
rate slowing in teleosts and increasing in elasmobranchs
after transection of the branchial nerves or paralysis of
the ventilatory muscles (29, 52, 306). Central stimulation
of branchial branches of the vagus in the dogfish with
bursts of electrical pulses entrained the efferent activity
in neighboring branchial and cardiac branches (607). The
entrained activity in the cardiac vagus drove the heart at
rates either slower or faster than its intrinsic rate (see
sect. VIB).
The branchial branches of cranial nerves IXth and
Xth supplying the gill arches of fish project to the sensory
nuclei lying dorsally and laterally above the sulcus limitans of His immediately above the equivalent motor nuclei
in the medulla. These have an overlapping, sequential
rostrocaudal distribution in the brain stem. Other than
this generalization, the central projections of the sensory
afferents contributing to cardioventilatory control in fish
have not been identified (93).
C. Air-Breathing Fish
It has generally been considered that hypoxia, consequent upon stagnation of tropical freshwater habitats,
was the environmental spur for the evolution, in the Devonian era, of the ABO of air-breathing fishes. A contrary
view proposes that lungs evolved in vertebrates primarily
to supply oxygen to the heart, before the evolution of the
coronary vessels (193). Stimuli for air-breathing in fish
include hypoxia and hypercapnia, both modulated by increased temperature and exercise, which increase oxygen
demand and CO2 production (306, 513, 575, 577). It is not
yet established whether the increases in air-breathing
observed under these circumstances are stimulated by
changes in oxygen availability, delivery, or demand or
whether there are also responses to changes in blood pH
or PCO2. However, in the bowfin Amia calva, there is
evidence that air-breathing is only stimulated by changes
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
in water or blood oxygen status, not by changes in plasma
acid-base status (422), and further evidence suggests that
bowfin do not possess any central chemosensitivity controlling gill ventilation or air-breathing (265).
Application of the oxygen chemoreceptor stimulant
sodium cyanide (NaCN) into the ventilatory water stream
of longnose gar (Lepisosteus osseus) inhibits gill ventilation and elicits air breathing, whereas NaCN given into
the bloodstream (dorsal aorta) stimulates both gill ventilation and air-breathing (579). In the bowfin, only externally applied NaCN elicits air-breathing, whereas both
external and internal NaCN stimulate gill ventilation
(423). Both gar and bowfin utilize a well-vascularized
swimbladder as an ABO, and there are, to date, very few
studies on the distribution of receptors stimulating airbreathing in fish that use other types of ABO. In the
obligate air-breather the African lungfish, there are airbreathing responses to both internally and externally applied NaCN (376), whereas in the facultative air-breather
Ancistrus, which possesses suprabranchial chambers,
hypoxia stimulates air-breathing but increased temperature and exercise do not (231).
The sites and afferent innervation of oxygen-sensitive chemoreceptors that stimulate gill ventilation and
air-breathing have been studied in various species of gar
and in the bowfin. They are found diffusely distributed in
the gills and pseudobranch, innervated by cranial nerves
VII, IX, and X (423, 574, 579). In gar and bowfin, gill
denervation (with pseudobranch ablation in the latter
case) almost completely abolished air-breathing in normoxia and abolished responses to hypoxia and NaCN
(423, 574), indicating that such responses are indeed dependent on afferent (oxygen chemoreceptor) feedback
(568, 575, 577). Smatresk et al. (579) suggested that in gar
there is central integration of input from internally and
externally oriented receptors whereby internal receptors
set the level of hypoxic drive and external receptors set
the balance between air-breathing and gill ventilation.
Air-breathing can also be stimulated by other factors,
such as water-borne irritants (576) and stretch receptors
in the ABO (221, 266, 578). Stretch receptors in the swimbladder of another primitive actinopterygian, the spotted
gar (Lepisosteus oculatus), exhibit sensitivity to CO2
(578).
There is no experimental evidence for baroreceptor
responses in air-breathing fish. Most air-breathing fish
supply their various ABO from the systemic circulation.
Lungfish and all of the tetrapods have distinct pulmonary
arteries and veins in association with true lungs, having
highly permeable surfaces; the lungfish Protopterus has a
diffusion distance of 0.5 mm over the ABO, which is
similar to the mammalian lung (458). However, possibly
because they retain gills, lungfish have similar, relatively
low blood pressures in the respiratory and systemic circuits and may as a consequence not have a functional
871
requirement for baroreceptor responses to protect their
lungs against edema, resulting from hypertension. It could
of course be argued that control of blood pressure in a
relatively low pressure system requires sensitive pressoreception. This remains to be demonstrated.
D. Amphibians
1. Chemoreceptors
In their detailed review (650), West and Van Vliet
considered the roles of peripheral chemoreceptors and
baroreceptors in cardiorespiratory control in amphibians,
while the factors influencing the progressive transition
from water to air-breathing during amphibian metamorphosis were reviewed by Burggren and Infantino (90).
Although chemoreceptive responses have been described
previously, the specific role of peripheral oxygen receptors in the regulation of breathing in amphibians has only
recently been identified (79). Jia and Burggren (304) measured the time course of reflex changes in ventilation in
unanesthetized larval bullfrogs at various developmental
stages. Inspiration of hypoxic water or NaCN caused
rapid increases in the rate of gill ventilation, whereas
hyperoxic water reduced ventilation. These rapid responses to hypoxia were eliminated by ablation of the
first gill arches, suggesting that they are the site of the
oxygen-sensitive chemoreceptors (305). A residual slow
response was interpreted as stimulation of a second population of receptors, possibly monitoring the cerebrospinal fluid (CSF). The rapid responses to hypoxia are
blunted in later stage bullfrog larvae, in which the lungs
are developing and the gills degenerating (304). In an
earlier study of the bimodally breathing bullfrog tadpole,
mild aquatic hypoxia was found to increase gill ventilation, but more severe hypoxia promoted high frequencies
of lung ventilation and a suppression of gill ventilation
(645), which was in response both to lung inflation per se
and the resulting increase in PO2 (646).
In the neotenous, gill-bearing axolotl, Ambystoma
mexicanum, both gill ventilation and air-breathing were
stimulated by cyanide, infused either into the ventilatory
water stream or into the bloodstream (424). Cardiac responses were complex with an initial bradycardia, presumably in response to stimulation of peripheral chemoreceptors, followed by a tachycardia at the first air breath,
possibly in response to stimulation of lung stretch receptors, a situation comparable to the mammalian response
to hypoxia (144, 145). Heart rate in the bullfrog tadpole
did not change during aquatic hypoxia, with access to air
(645).
Although their larvae may retain functional oxygen
receptors on the gill arches, the carotid labyrinths are
putative sites for oxygen receptors in adult amphibians.
They are situated at the bifurcation of the internal and
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TAYLOR, JORDAN, AND COOTE
external carotid arteries and innervated by branches of
the glossopharyngeal nerve, which projects its afferent
fibers to the NTS in the brain stem (594). These receptors
are functionally similar to the mammalian carotid bodies,
as they also respond to hypercapnia, and their discharge
can be modulated by sympathetic stimulation (294, 295).
More recent studies have also shown that the receptors
are sensitive to oxygen partial pressure, rather than content (650), a finding consistent with the results of whole
animal study of the stimulus modality of the hypoxic
ventilatory response in toads (639). Elevated arterial levels of CO2/H1 increase discharge rate from the carotid
labyrinth of toads (650).
Although carotid labyrinth denervation caused a significant reduction of resting ventilatory activity, in comparison
with sham-denervated animals, it had no significant effect on
the ventilatory response to hypoxia in Xenopus laevis or
Bufo marinus (190, 649). These findings indicate that the
carotid labyrinth influences respiratory drive but is not essential for the control of ventilation during hypoxia in anurans. Given that hypoxia is a poor ventilatory stimulant in
frogs, it is not surprising that the current consensus, from
studies performed on whole conscious animals, tends to
minimize the importance initially accorded to the carotid
labyrinth in the regulation of ventilation. However, blood gas
levels in adult amphibians are not determined solely by rates
of lung ventilation; instead, the degree of shunting of blood
through the pulmonary circuit and/or the cutaneous vessels
may have a major role in determining oxygen and CO2 levels.
The degree of shunting is likely to be referred to input from
peripheral chemoreceptors. In the adult bullfrog, more
blood is directed toward the lungs during aquatic hypoxia,
while aerial hypoxia elicits an increase in cutaneous perfusion (80). The return of blood to the right side of the heart
from the cutaneous circulation may specifically serve to
improve oxygen supply to the myocardium, which in amphibians is devoid of a coronary circulation (193).
Other putative oxygen-chemosensitive areas associated with the aortic trunk have been identified in toads
(294, 631). Furthermore, it appears that the pulmocutaneous arteries of anurans may also be the site of an intraarterial chemoreceptive zone. Injection of NaCN into the
pulmocutaneous arches of anesthetized bullfrogs and
conscious toads stimulated ventilation (398, 631). In the
absence of recordings from pulmocutaneous chemoreceptors, however, the role of the pulmocutaneous artery
as a chemoreceptive site in amphibians is conjecture
(650). The relative contribution of the latter two chemoreceptive sites to the hypoxic ventilatory or cardiovascular responses in amphibians is yet to be investigated.
2. CO2/H1 receptors
Perfusion of the brain in anesthetized toads with
artificial CSF having low pH/high CO2 significantly in-
Volume 79
creased ventilation in normoxia (580). A similar response
was recorded from the in vitro preparation of the bullfrog
brain stem (355, 451). It appears that, as in most vertebrates (other than some fish) investigated thus far, toads
have central chemoreceptors, probably located on the
ventral surface of the medulla, which respond to acidic/
hypercapnic challenge. Repeating these experiments in
unanesthetized animals (85) indicated that the contribution of peripheral receptors to respiratory drive was secondary to the role of central chemoreceptors that contributed ;80% of the total hypercapnic respiratory drive in
the toad, a similar proportion to that observed in mammals.
This dominant role for central chemoreceptors in the
generation of respiratory drive in amphibians appears at
metamorphosis. An in vitro preparation of the isolated
brain stem from the bullfrog tadpole displayed coordinated, rhythmic bursting activity in cranial nerves V, VII,
and X, which could be characterized as representing fictive gill or lung ventilation. In early stage larvae, variations in pH of the superfusate were without effect on gill
or lung burst frequency. Later stage larvae showed an
increasing predominance of neural lung burst activity,
which markedly increased in acid pH (625). The onset of
episodic breathing patterns during metamorphosis was
coincident with developmental changes in the nucleus
isthmi in the bullfrog, and it seems possible that this
region of the brain stem is involved in integration of
central chemoreceptor information (354).
3. Pulmonary stretch receptors
Pulmonary stretch receptors (PSR) constitute another important source of feedback, contributing to the
control of breathing in amphibians. There are three different types of PSR in amphibians responding to 1) the
degree of lung inflation, 2) the rate at which lung volume
changes, or 3) both stimuli (312, 444). These receptors are
innervated by afferent fibers in the pulmonary vagii (312,
444) that project to the solitary tract in the brain stem
(594). The receptors are mostly slowly adapting, and their
firing rates decrease when the intrapulmonary CO2 concentration is increased (371, 444). Although pure chemoreceptors sensitive to CO2 have not been identified in the
lungs of frogs, the discharge of stretch receptors is sufficiently modulated by CO2 to have noticeable effects on
the breathing pattern. Vagotomy abolished the increase in
breathing frequency that anuran amphibians usually exhibit during hypercarbia (85, 580, 649), suggesting that
pulmonary vagal input is necessary for the production of
normal respiratory chemoreflexes.
Pulmonary afferent fibers play a key role in the termination of lung inflation in the adult and inhibition of
buccal oscillation in the premetamorphic tadpoles. The
evidence is that pulmonary deafferentation by vagotomy
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
in Xenopus results in an increase in the number of inspirations in a ventilatory period and overinflation of the
lungs (190). Sectioning the pulmonary branch of the vagus
nerve leads to an increase in the amplitude and frequency
of resting ventilation in the bullfrog (358, 359), indicating
that PSR feedback modulates breathing pattern; however,
these data also suggest that PSR feedback is not responsible for the onset/termination of the breathing episodes.
This matter remains unresolved as recent studies of decerebrate, paralyzed anurans showed that lung inflation
inhibited fictive breathing (364, 640), as would be predicted from work on mammals, while another study, of a
similar preparation, indicated that lung inflation stimulated fictive breathing (359).
Amphibians that breath discontinuously, often in association with periods of submersion, typically display
large increases in heart rate and pulmonary blood flow at
the onset of bouts of lung ventilation. However, the contribution of lung stretch receptors to this response is not
resolved (650). Whereas artificial lung inflation increased
heart rate in anesthetized toads, in conscious Xenopus
laevis, denervation of PSR did not abolish the increase in
heart rate associated with lung inflation (190), and in
lightly anesthetized animals, artificial lung inflation did
not affect heart rate, though pulmocutaneous blood flow
increased, presumably due to shunting (186). A similar
response was demonstrated in Bufo marinus (647).
E. Reptiles
1. Peripheral oxygen receptors
Scattered groups of glomus cells have been identified
in the connective tissue surrounding the main and collateral branches of the carotid arteries in lizards. This area is
profusely innervated by the superior laryngeal branch of
the vagus nerve (535) and possibly the glossopharyngeal
nerve (4). Although activity in these putative receptors
has not been recorded, denervation of this area abolished
the increase in ventilation shown by lizards when hypoxic
or hypercapnic blood was injected into the carotid arch
(130). In turtles, chemoreceptive tissue has been located
on the aortic arch innervated by the superior and inferior
branches of the vagus nerve (295). The former nerve is
thought to correspond to the aortic nerve of mammals,
whereas the latter arises from the ganglion trunci of the
vagus. The inferior branch also innervates chemoreceptors located on the pulmocutaneous artery of the turtle (3,
298). These receptor groups have been shown to respond
to changes in oxygen level, but their roles in establishing
resting ventilatory drive or in reflex responses to hypoxia
are unknown (440). All primary afferent fibers of the
glossopharyngeal and the majority of vagal afferent fibers
enter the NTS in the monitor lizard (38).
Oxygen uptake in reptiles is dependent on PO2 down
873
to a critical level, below which aerobic metabolism is
depressed (439). This critical PO2 varies with temperature
and can be correlated with changes in the relative affinity
for oxygen (measured as P50) of the animal’s hemoglobin
(568). Species having hemoglobin with a relatively high
affinity for oxygen, such as the turtle Chrysemys picta
(229), have greater hypoxic tolerance, and therefore a
lower threshold, but often show a more marked ventilatory response at threshold than species having lower
affinity hemoglobin, such as the lizard Lacerta viridis
(466). Current theory suggests a role for heme protein in
the functioning of peripheral chemoreceptors (442).
These data suggest that the peripheral oxygen receptors
respond to a reduction in oxygen content (i.e., hypoxemia) or to rate of delivery of oxygen to the receptor,
which includes blood flow, rather than to systemic hypoxia (i.e., a reduction in PO2). Similar characteristics have
been attributed to arterial chemoreceptors in fish (511,
512) and in birds and mammals (440).
Reptiles, in common with some air-breathing fish and
amphibians, have pulmonary and systemic circulations
that are incompletely separated so that some systemic
venous blood can bypass the lungs to reenter the systemic
circulation, while some arterialized blood can reenter the
pulmonary circulation. Consequently, arterial blood gas
composition is affected by the degree of admixture of
oxygenated arterialized blood and oxygen-depleted venous blood, rather than lung gas composition alone, as it
is in mammals. This presents the intriguing possibility
that regulation of these central vascular shunts, with reference to peripheral chemoreceptors, may play an important role in control of arterial blood gas composition in
reptiles, independent of ventilatory control (88, 640).
2. CO2/H1 receptors
The hypercapnic ventilatory response is well developed in reptiles, and changes in PaCO2 rather than PaO2
provide the dominant drive to breathe (439, 441). Central
chemical control of ventilation in an ectothermic, airbreathing vertebrate was first demonstrated in the unanesthetized turtle, Pseudemys scripta elegans (271). Perfusion of the lateral and fourth cerebral ventricles with
artificial CSF caused an increase in ventilation to four
times control, following a calculated pH change of only
0.02 units. Inhalation of gas mixtures enriched with CO2
stimulates ventilation and affects pulmonary vagal activity in crocodilians (441, 503). It causes ventilation volume
to rise, decreases periods of breath hold, and increases
the number of breaths in each breathing episode. Snakes
and lizards may respond to environmental hypercarbia,
which stimulates lung receptors, with decreased ventilation but show a marked increase in response to venous
CO2 loading (441).
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F. Birds
1. Peripheral oxygen receptors
In birds, chemoreceptive tissue is concentrated
around the common carotid arteries, close to the thyroid
glands, and is innervated by vagal branches from the
nodose ganglion (1). These receptors are thought to be
homologous to the carotid bodies of mammals (459).
Glomus tissue, which may be homologous to the aortic
bodies of mammals, has been described within the aortic
walls of birds (618), and a recording from a putative aortic
chemoreceptor in a duck has been reported (483). All
receptors respond to changes in PO2, but in some birds,
the threshold for a hypoxic ventilatory response is more
strongly correlated with blood oxygen content (78). The
carotid chemoreceptors contribute to resting ventilatory
drive and may be solely responsible for reflex responses
to hypoxia or hyperoxia (81). Hypoxia stimulates breathing in conscious, anesthetized, or decerebrate birds (553).
There are species differences in oxygen chemosensitivity.
For example, Pekin ducks showed a much higher cardiac
chronotropic sensitivity to hypoxia during forcible submergence than Canada geese (590).
2. CO2/pH
In birds, as in reptiles and mammals, the reflex effects of central chemoreceptor stimulation, following
changes in PaCO2 or arterial pH, appear to predominate
over all other receptor inputs. Cerebral perfusion and/or
denervation of peripheral receptors in ducks indicated
that central chemoreceptors are primarily responsible for
resting respiratory drive as well as reflex responses to
hypercapnia and acidosis (445). As in mammals, the glomus tissue associated with oxygen chemoreception is
also sensitive to changes in CO2 or pH. In addition, birds
possess intrapulmonary chemoreceptors that show discharge rates inversely proportional to the level of CO2 in
inhaled gas mixtures (553). They are located within the
lung, innervated by the vagus nerve and to some extent by
the cardiac sympathetic nerve (187). These receptors are
silenced by high levels of CO2 in the airway but are
insensitive to changing PO2, and their responses to
changes in lung volume or pressure are not significant
within physiological limits (198, 199, 553). Thus, unlike
mammals, lung stretch receptor inputs are not important
in the regulation of breathing or cardiorespiratory interactions in birds. This relates to the fundamental morphological and functional characteristics of the compact bird
lung, which is ventilated unidirectionally by volume
changes in the air sacs and is not itself stretched (553).
Because some birds, like the bar-headed goose,
Anser indicus, fly to extremely high altitudes, they regularly undertake exercise in hypobaric hypoxia (97). Their
adaptations to this environment include increased heart
Volume 79
size and blood oxygen affinity, compared with other birds
or with mammals. They have been found to maintain
arterialized blood PO2 very close to inspired levels in
hypoxia, by effective hyperventilation, with an associated
reduction in blood PCO2 and a respiratory alkalosis. This is
achieved without the reduction in cerebral blood flow
typically associated with hypocapnia in mammals, and
indeed, hypoxia causes a greater increase in cerebral
blood flow than is observed in mammals so that blood
flow to the brain may be maintained at high altitude. A
critical difference between these high-flying birds and
other birds or mammals appears to be their greater tolerance of hypocapnia, which is likely to reside at the level of
their central chemoreceptors in the brain.
IV. CRANIAL AUTONOMIC INNERVATION
OF THE CARDIORESPIRATORY SYSTEM
A. Mammals
1. Topography of the vagal motor column
The central origin of the motor fibers innervating the
heart and airways in mammals has been well documented
by localizing the retrograde labeling following application
of HRP or a conjugate to either the whole vagus nerve, its
individual branches, or directly into the relevant targets.
Neurons with vagally projecting axons are found predominantly ipsilaterally in both vagal motor nuclei, the DVN
and the nA, and in the region joining these two, the
intermediate zone.
The nA, as its name implies, is a diffuse region extending throughout the ventrolateral medulla, from the
level of the facial nucleus to the first cervical segment of
the spinal column. It has been described by several authors, and the terminology used was somewhat confusing
until a study in the rat (68) resulted in a description which
is beginning to be used by other authors and will be used
here. The nuclear regions of the nA are defined on the
basis of the location of neurons projecting in the glossopharyngeal and vagal nerves and their branches. There
are two major longitudinal divisions of the nucleus. The
dorsal division has three subdivisions, the compact, semicompact, and loose divisions (rostral to caudal, respectively), and comprises the somatomotor innervation of
the pharyngeal and thoracic viscera. The ventral external
formation comprises parasympathetic preganglionic neurons. The different subdivisions can be discerned by the
size of the neurons, their dendritic organization, and the
projection of their axons. There is less distinction in the
subregions of the DVN (206), but some differences do
exist, and there are suggestions of a topographical localization of DVN neurons, based on target organ. Even if
such an organization exists, the dendritic fields of many
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
DVN neurons are very extensive, often projecting into
adjacent DVN subnuclei or other medullary nuclei such as
the NTS (206, 562).
Vagal-projecting neurons are found throughout the
dorsal nA and in the external division ventrolateral to the
principal column. They are densest in the DVN and extend
lateral to its boundaries into the region bordering the NTS
and the reticular formation between it and the nA. A
similar distribution of vagal-projecting neurons has been
described in rats (126, 340), cats (336), dogs (116), ferrets
and mink (522), neonatal pigs (276), and Old and New
World monkeys (257). The central distribution of vagal
motoneurons includes those innervating both intrathoracic and abdominal organs, but there is no certainty that
individual organs are represented at all sites. More specific studies have examined the possibility that there is a
topographic organization based on the organ of innervation. Although the overall pattern of labeling is similar, the
detailed organization of the innervations do differ between species.
2. Innervation of the heart
In a number of studies, tracers have been applied to
the cardiac vagal branches or to the heart itself. Although
some neurons in the DVN and intermediate zone were
labeled, it is clear that the region of the nA provided the
major cardiac innervation in most mammals. In rats (298,
446, 479, 480, 593), cats (59, 117, 222, 223, 330, 337, 449,
596), dogs (59, 274, 275, 500), and neonatal pigs (276), the
majority of labeled neurons were located in the external
subnucleus of the nA. Neurons within the compact region
of the nA, if labeled, were always in the minority. When
the DVN was labeled, it was usually the lateral and dorsal
regions that contained the majority of labeled cells. The
relative contribution of DVN and nA to the cardiac vagi
seems to vary between species. The DVN contains relatively more cardiac-projecting neurons in rats, and least in
pigs and dogs, with cats lying somewhere in between. In
the cat (59, 330), cardiac VPN (CVPN) are found predominantly in the nA, with up to 78% of cardiac neurons found
in this location. This compares with 45% of CVPN located
ventrolaterally in the dogfish and ;30% in Xenopus, indicating that in mammals, compared with lower vertebrates, a greater proportion of cardiac vagal motoneurons
originate in this division. However, the ventrolateral
group of vagal perganglionic neurons in the dogfish are all
CVPN (see sect. IVC). Only one set of studies in cats (623,
624) denied the role of the nA in cardiac control, but this
has not been confirmed.
875
only a summary is provided here. In rats, Bieger and
Hopkins (68) demonstrated that the compact region of the
nA contained esophageal motoneurons, whereas pharyngeal motoneurons were located in both the more caudal
semicompact formation and in a group of neurons rostral
to the compact group and overlying the facial nucleus.
Glossopharyngeal motoneurons were also found at this
latter site and in the external formation where laryngeal
motoneurons were also localized in addition to rostral
part of the semicompact formation and the dorsal part of
the caudal compact formation. The external and dorsal
divisions differ in that the latter innervates striated muscles of the esophagus, larynx, and pharynx, whereas the
former is the origin of parasympathetic preganglionic
neurons. A similar localization of motoneurons innervating the rat esophagus, pharynx, and cricothyroid muscle
has been demonstrated (10). Preganglionic neurons innervating the trachea are located in the compact formation,
in the area ventral to it, and in the rostral part of the
medial NTS, but not in the DVN (263). This description of
the nuclear arrangement of the rat nA is similar to that
described in rabbits (296, 385, 386) and cats (242, 336, 337,
478, 479). The ambigual origin of the laryngeal motor
innervation was confirmed, with some cells also being
labeled in the rostral DVN. Neurons innervating the trachea overlapped those innervating the larynx in the rostral nA. In addition, cells in the nucleus retroambigualis
caudal to the obex also provided an innervation of the
extrathoracic trachea, whereas the DVN at around obex
level provided some innervation of the intrathoracic trachea. Bronchial motoneurons were found mainly in the
DVN, with limited numbers in the rostral nA, whereas
those labeled following injections into lung tissue were
located in both DVN and nA. This was partly confirmed
when tracer was applied to the individual pulmonary
branches of the vagus in cats (59, 330). Labeled neurons in
the nA were found over a 10-mm distance spanning the
obex in the external formation, but there was a trough in
the distribution of the cells projecting to the pulmonary
branches between 1 and 3 mm rostral to obex, where
neurons projecting to the cardiac branches were located
(Fig. 5). These pulmonary neurons outnumbered those
labeled in the lateral DVN. Thus, in the cat, both pulmonary (68%) and cardiac (78%) VPN are found predominantly in the nA (330). The labeling seen in dogs, following tracers applied to the superior or recurrent laryngeal
nerves (638) or pulmonary branches of the vagus (57,
261), is not unlike that described in cats.
B. Cyclostomes
3. Innervation of the airways
Similar anatomical studies have delineated the motor
innervation of the airways in air-breathing mammals. Because these have been described in detail recently (322),
The heart of myxinoids is aneural, that is, it is not
innervated by the vagus or the sympathetic nervous system (115, 237), whereas the heart of the lamprey (al-
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TAYLOR, JORDAN, AND COOTE
Volume 79
FIG. 5. Rostrocaudal distribution, with respect to
obex, of vagal preganglionic motoneurons in medulla
oblongata of cat. Neurons were retrogradely labeled
with horseradish peroxidase applied to cardiac or pulmonary branches of right vagus. Majority of labeled
neurons are located ventrolaterally in region of nucleus
ambiguus, with the remainder located medially in the
dorsal motor nucleus of the vagus.
though similarly devoid of a sympathetic supply) is innervated by the vagus (19, 521). The cardiac fibers leave the
thin nonmyelinated epibranchial trunk of the vagus and
run to the median jugular vein. In the wall of this vein, the
nerve fibers form a loose network with one or two main
bundles (192).
The main effect of vagal stimulation in lampetroids is
an acceleration of the heart with an accompanying decrease in the force of contraction (191). Acetylcholine
induces an acceleration of the heart, a response unique
among vertebrates. Nicotinic cholinoceptor agonists,
such as nicotine, have the same effect (19, 191). The
excitatory effect of vagal stimulation or nicotinic agonists
can be blocked by nicotinic cholinoceptor antagonists
such as tubocurarine and hexamethonium (19, 191, 405).
According to Ariens Kappers (16, 17), the CNS of the
cyclostomes represents the prototype of the vertebrate
brain. The hindbrain is identical in superficial appearance
to that of the rest of the vertebrates, with vagal rootlets
leaving on either side to innervate the viscera. No study
has been made of the topographical representation of
vagally innervated structures within the vagal motor column of cyclostomes. In Lampetra, two separate divisions
of the vagal motor column have been identified using
normal staining techniques: a rostral and a caudal motor
nucleus of X (467). The caudal motor nucleus of X, which
cannot be delineated from the spinal visceromotor cells,
is thought to represent a splanchnic center, and the rostral nucleus is considered to be branchiomotor in nature
(i.e., to innervate the branchial pouches) (5). The location
of the caudal motor nucleus in cyclostomes, which centers around the obex, is similar to the region of the DVN
in the cat (59) and to the nucleus motorius nervi vagi
medialis (Xmm) in the dogfish (53) in which the cell
bodies contributing axons to the cardiac vagi are found.
C. Elasmobranch Fish
Innervation and control of the cardiorespiratory system in the cartilaginous elasmobranch fishes differs in
important respects from that in the teleosts and in the
air-breathing fishes. Accordingly, they are each described
separately in the following account. The elasmobranchs
are phylogenetically the earliest group of vertebrates in
which a well-developed autonomic nervous system with
clearly differentiated parasympathetic and sympathetic
components has been described (465). They are also the
earliest group known to have an inhibitory vagal innervation of the heart.
In the elasmobranch fish Scyliorhinus canicula, the
vagus nerve divides to form, at its proximal end, branchial
branches 1, 2, 3, and 4 that contain skeletomotor fibers
innervating the intrinsic respiratory muscles of gill arches
2, 3, 4, and 5, respectively (Fig. 1). The first gill arch is
innervated by the glossopharyngeal (IXth cranial) nerve.
The vagus also sends, on each side of the fish, two
branches to the heart. One arises close to the origin of the
visceral branch of the vagus, the other from the posttrematic projection of the fourth branchial branch of the
vagus (614). The two cardiac vagi pass down the ductus
Cuveri and then break up into an interwoven plexus on
the sinus venosus, terminating at the junction with the
atrium (665). The sinoatrial node is thought to be the site
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877
FIG. 6. Rostrocaudal distribution of vagal
preganglionic motoneurons with respect to obex in
medulla of dogfish, Scyliorhinus canicula. Majority
of labeled motoneurons are located medially in dorsal vagal motor nucleus. A small number (8%) are
located ventrolaterally and supply axons solely to
branchial cardiac branch of vagus innervating
heart. Medial cells supplying this nerve are indicated by unshaded portion of top histogram. Motoneurons supplying axons to branchial branches 1,
2, and 3 (Br I to Br III) of vagus, innervating gill
arches 2, 3, and 4, occupy rostral part of vagal
motor column, whereas more caudal motoneurons
supply axons sequentially to heart, esophagus, and
stomach. [Modified from Taylor (607).]
of the pacemaker in elasmobranch fishes (542, 551). The
remainder of the vagus is termed the visceral branch, and
this innervates the anterior part of the gut down to the
pylorus and the anterior part of the spiral intestine (665).
Stimulation of the vagus nerve, as well as application
of acetylcholine, has an inhibitory effect on heart rate.
The effects are antagonized by atropine, implying that the
effect is mediated by muscarinic cholinoceptors as in the
higher vertebrates (99, 113, 308, 406 – 408, 614). Variations
in the degree of cholinergic vagal tonus on the heart, in
the absence of an adrenergic innervation (see sect. VC),
serves as an important mode of nervous cardioregulation
in elasmobranchs (50, 99, 614).
There are several historical studies, using classic
neuranatomical techniques, of the gross location of the
vagal motor nucleus in the hindbrain of elasmobranch fish
(607, 658). The vagal motor nucleus was shown to consist
of a continuous column of large, bipolar, tripolar, and
(less frequently) quadripolar cells in conjunction with the
motor nuclei of the IXth and VIIth cranial nerves (581,
582). In the shark Cetorhinus and in the Holocephali,
Addens (5) divided the vagal motor nucleus into separate
rostral and caudal parts and suggested that the rostral
portion is specialized to subserve either a visceromotor or
branchiomotor function, whereas the caudal portion represents a general visceromotor or splanchnic center.
Smeets et al. (582) observed that in Hydrolagus the vagal
nucleus can readily be divided into a caudodorsal nucleus
and a rostroventral nucleus, the latter being continuous
with the nuclei of IX and VII. In Raja, the same authors
noted that the dorsal nucleus appeared to contain somewhat smaller neurons than the ventral nucleus.
In Squalus, an area lateral to the caudal part of the
visceromotor column contains a distinct aggregation of
large bipolar and triangular cells (581). These authors
considered this aggregation of cells represented a part of
the motor nucleus of X and named it accordingly the
nucleus motorius nervi vagi lateralis (Xml). The Xml ex-
tended from 2.0 mm rostral to ;4.0 mm caudal to the
obex. The vagal part of the medial visceromotor column
was designated the Xmm. The Xmm and Xml may, by
virtue of their locations, be the homologs of the mammalian DVN and nA, respectively (49, 581), and will be referred to as such in the following descriptions of their
topography and functional roles.
Retrograde intra-axonal transport of HRP along
branches of the vagus nerve showed that the vagal motor
column of the dogfish, Scyliorhinus canicula, extends
over 5 mm in the hindbrain from 2 mm caudal to 3 mm
rostral of obex (657). This agrees with the extent described by Smeets and Niewenhuys (581) for fish of similar size. Caudal to obex there appeared to be two distinct
groups of vagal motoneurons, the majority found dorsomedially, and a smaller ventromedial group, both close to
the lateral edge of the fourth ventricle. However, the
ventromedial group was continuous with cells in the
spino-occipital motor nucleus and may constitute a forward extension of this nucleus, contributing axons to the
hypobranchial nerve which innervates the ventral muscles of the orobranchial cavity (392). The majority of
vagal motoneurons caudal to obex contributed axons to
the visceral branch of the vagus including the visceral
cardiac branch. Visceral cardiac motoneurons were found
solely in the dorsomedial division of the vagal motor
column (i.e., the DVN).
Rostral to obex the medial motoneurons were no
longer distinguishable into dorsal and ventral divisions;
instead, a single column of medial cells was found clustered close to the ventrolateral edge of the fourth ventricle (constituting the DVN). Most of the vagal motoneurons were found in the DVN, with the caudal one-third
contributing axons to the branchial cardiac branch and to
the visceral branch while the rostral two-thirds contributed axons to the four branchial branches of the vagus
(Fig. 6). There is a clear sequential topography in the
rostrocaudal distribution of the cell bodies supplying ax-
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TAYLOR, JORDAN, AND COOTE
ons to each of the gill arches, with a small degree of
overlap between the pools of neurons supplying adjacent
branches of the vagus (657). This sequential topography
extends rostrally so that visceromotoneurons supplying
axons to the glossopharyngeal, IXth, facial, VIIth and
mandibular, Vth cranial nerves, innervating respiratory
muscles, are distributed in discrete nuclei in a rostrocaudal array (Fig. 2).
A clearly distinguishable group of cells was identified
that had a scattered ventrolateral distribution, outside the
DVN, over a rostrocaudal extent of ;1 mm, rostrally from
obex. They contributed axons solely to the branchial
cardiac branch of the vagus, innervating the heart (53, 49).
Although the cells in this lateral division comprised only
8% of the total population of VPN, they supplied 60% of
the efferent axons running in the branchial cardiac nerve,
with the other 40% supplied by cells in the rostromedial
division. When the medial cells contributing efferent axons to the heart, via the visceral cardiac branches, were
taken into account, then the lateral cells were found to
supply 45% of vagal efferent output to the heart. Thus
CVPN providing axons to the branchial cardiac nerve are
found rostromedially in the elasmobranch equivalent of
the DVN and solely comprise the lateral division or nA of
the vagal motor column (Fig. 6). It is thought that this dual
location of CVPN has important functional implications
(see sect. VIB).
D. Teleost Fish
In teleost fish, the vagus innervates the gills, the
heart, and the viscera (pharynx, esophagus, stomach, and
swimbladder). The cardiac branches of the vagi follow the
ductus Cuveri to the sinus venosus and atrium, but vagal
fibers do not reach the ventricle. A ganglion in the vagal
pathway lies close to the sinoatrial border and appears to
consist solely of nonadrenergic cell bodies (212, 272, 273,
382, 545, 546, 664).
The vagus in teleosts is cardioinhibitory as in all
vertebrates, with the exception of the cyclostomes. This
inhibitory effect is due to the release of acetylcholine
affecting muscarinic cholinoceptors associated with the
pacemaker and atrial musculature (110, 212, 272, 273, 509,
516, 666). Although the negative inotropic influence of the
vagi does not reach the ventricle, cardiac output is greatly
affected by the inotropic control of the atrium, which
directly regulates the filling of the ventricle (307, 313),
although this has recently been questioned (J. B. Graham,
personal communication).
In contrast to elasmobranchs, where the branchial
branches of the vagus are solely skeletomotor (432), the
branchial branches in teleosts have both a vasomotor and
skeletomotor function (493). The vagus supplies vasomotor fibers to the branchial circulation that have been
Volume 79
shown to innervate sphincters at the base of the efferent
filament arteries (470).
Early topological studies of the brain of teleosts identified a single vagal motor nucleus (see Ref. 607). However, application of HRP and immunocytochemistry revealed a lateral subnucleus of the vagal complex that
provided axons to respiratory muscles in goldfish (452).
Application of HRP to the whole vagus nerve and to
selected branches of the vagus in cod (Gadus morhua)
and rainbow trout revealed that vagal motoneurons were
located over a distance of 2.8 mm in the ipsilateral hindbrain from 1.2 mm caudal to 1.6 mm rostral to obex and
that ;11% of these neurons were located ventrolaterally,
whereas the others were found in a dorsomedial location
clustered close to the edge of the fourth ventricle, identified as the DVN (658). The lateral group of vagal motoneurons was divided into two groups: a caudal group
extending for ;1 mm (from 0.75 mm caudal to 0.25 mm
rostral of obex) and a more rostral group that extended
for ;0.75 mm (0.75–1.5 mm rostral of obex). When HRP
was applied to the cardiac branch of the vagus, labeled
neurons were found in the caudal lateral division as well
as in the DVN. The application of HRP to one of the
branchial branches of the vagus also labeled both lateral
and dorsomedial cells, this time with the lateral cells
located in the more rostral group of cells.
The identification of lateral CVPN in teleosts is similar to our findings in elasmobranchs. In contrast, however, some branchial motoneurons are located in the
lateral division in teleosts, whereas they are confined to a
medial location in elasmobranchs. This may reflect the
observation that the branchial branches of the vagus
serve both a vasomotor and skeletomotor function in
teleosts but only a skeletomotor function in elasmobranchs (see above) so that the medial neurons may give
rise to skeletomotor fibers, whereas the lateral neurons
may give rise to vasomotor fibers. This remains to be
demonstrated experimentally.
In teleosts, there is also a sequential topographic
representation of the vagus within the vagal motor column. The most rostral neurons give rise to fibers supplying the most proximal organs (the gill arches), and the
caudal neurons give rise to fibers innervating the viscera.
The cardiac neurons are located in the middle of the vagal
motor column (607). In both classes of fish in which the
topography of the vagal motor column has been studied,
there is a sequential representation of the vagal branches.
E. Air-Breathing Fish
After application of HRP to the second and third
branchial branches of the vagus nerve in the bowfin,
Amia calva (Fig. 7), retrogradely labeled cell bodies were
found in the DVN over a rostrocaudal distance of 4 mm
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FIG. 7. A diagrammatic representation of rostrocaudal
distribution either side of obex of cell bodies of preganglionic vagal motoneurons and ventral motoneurons supplying efferent axons to 2nd and 3rd branchial branches of
vagus, and to nerve supplying glottis and air-breathing
organ (ABO; swimbladder) in bowfin (Amia calva). Sensory projections to 3rd branchial branch of vagus are also
shown (sensory). Horseradish peroxidase-labeled cell
bodies were counted (at 60-mm intervals) from best backfills of each branch in single preparations. Labeled
branchial vagal motoneurons were found in 2 locations
(medial and lateral) in dorsal vagal motor nucleus (DVN).
Labeled motoneurons supplying glottis and ABO consisted
of 2 groups: a small one located rostral of obex in DVN and
a much larger group of cells that was predominantly caudal of obex, in ventral hypobranchial motor nucleus. [Modified from Taylor et al. (613).]
either side of obex (613). There was a sequential topography in the distribution of the cell bodies innervating
branchial nerves 2 and 3, as described in dogfish and cod
(607). In addition, motor cell bodies were located in lateral locations outside the DVN as described in teleosts
(e.g., cod) and all tetrapod vertebrates (608). In the bowfin, some of these lateral cells were of an unusual appearance with large cell bodies and thick, branching dendrites. In one fish, anterograde labeling of the sensory
projections of branchial branch 3 of the vagus was observed. This consisted of a diffuse array of fine dendrites
and small cell bodies in the sensory vagal nucleus on the
laterodorsal edge of the fourth ventricle above the DVN,
which extended for ;2 mm in the brain stem immediately
rostral of obex.
Application of HRP to the nerve supplying the glottis
and ABO revealed cell bodies in a ventrolateral location in
the brain stem and the ventral horn of the anterior spinal
cord over a rostrocaudal distance of 5.3 mm, predominantly caudal of obex (Fig. 7). From their location it is
possible to identify them as cell bodies that typically
supply axons to the hypobranchial nerve (i.e., occipital
and anterior spinal nerves). Consequently, it is apparent
that the glottis and ABO are innervated by nerves of the
hypobranchial complex, which provides nerves to elements of musculature normally associated with feeding
movements in water-breathing fish. Given that feedingtype movements are implicated in air-breathing in bowfin
(397; and see above), the observed hypobranchial inner-
vation of the glottis and ABO may imply nervous coordination of air-gulping and glottal opening, which would
ensure effective ventilation of the swimbladder. Indeed,
even in mammals, there are functional similarities and a
close connection between the central nervous mechanisms controlling breathing and those controlling swallowing (302).
Careful observation of the sections of bowfin brain
after application of HRP to the nerve supplying the glottis
and ABO revealed an additional group of stained cell
bodies that could be identified topographically as preganglionic vagal motoneurons in the DVN (613). This implies
that there is a vagal element to the efferent innervation of
the ABO, as described by Allis (8). These cell bodies
probably provide efferent axons to smooth muscle in the
swimbladder wall comparable to the vagal efferents controlling reflex bronchoconstriction in the mammalian lung
(559). An afferent vagal supply to the ABO would seem
axiomatic but was not revealed by the study of Taylor et
al. (613).
F. Amphibians
In adult air-breathing amphibians, the vagus innervates the hyoid apparatus and larynx, both structures
derived from the larval branchial arches. It then passes on
to innervate the viscera, including the heart and lungs.
The ventricle in the amphibian heart is completely undi-
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Volume 79
FIG. 8. Rostrocaudal distribution of preganglionic vagal motoneurons either side of obex in hindbrain of the ray,
Raia baetis (a); axolotl, Ambystoma mexicanum (b); clawed toad, Xenopus laevis (c); and cat, Felis cattus (d).
Continuous lines indicate cell bodies in DVN; divided lines indicate cell bodies in ventrolateral nuclei associated with
nucleus ambiguus (nA). There is a sequential topographic representation of vagally innervated structures in dogfish and
in oxolotl, with all vagal presynptic neurons (VPN) to branchial arches sequentially distributed rostral of obex. However,
in axolotl, pulmonary VPN are widely distributed through DVN. This sequential topography remains discernible in
Xenopus because structures derived from branchial arches (hyoid and larynx) have their VPN rostral of obex, but is
virtually lost in cat where all structures are represented over a wide rostrocaudal extent in vagal motor column, both in
DVN and nA. [From Taylor (608).]
vided and receives oxygen-depleted systemic blood from
the right atrium plus oxygen-rich pulmonary blood from
the left atrium. The proportion of the blood ejected from
the heart at systole that enters either the pulmonary or the
systemic circuit is determined by the relative resistance to
flow of each circuit, which is largely determined by the
contraction of a smooth muscle sphincter on the pulmocutaneous artery, innervated by the vagus nerve. Vagal
stimulation both slows the heart and causes constriction
of the pulmocutaneous sphincter. Both responses are primarily cholinergic, although other transmitters such as
somatostatin and galanin are coreleased from vagal nerve
terminals at both sites (640).
The central topography of the vagal motor column in
amphibians is of current interest. In the African clawed
toad Xenopus laevis, there are two cell groups in the
medulla oblongata constituting the motor nuclei of the
vagus and the glossopharyngeal nerves, one group in the
most superficial zone of the central gray and a second
group more laterally in the white matter overlying this
central gray (468). A more recent study has confirmed
that VPN are located ipsilaterally in the hindbrain over a
distance of 2.5 mm with ;32% of all cell bodies identified
in a ventrolateral location (640). Each target organ, including the heart and lungs, is innervated by VPN in both
the DVN and the nA (Fig. 8), in roughly similar proportions (i.e., ;2:1). The increase in the proportion of lateral
VPN, over the condition described in fish, may be partially
attributable to a change from gill to lung breathing (609).
As the amphibians metamorphose from an aquatic
larval stage to air-breathing adults, they provide an ideal
model for testing the hypothesis that progressive ventrolateral location of VPN relates in part to the evolution/
development of lung breathing (608). Of particular interest is the axolotl, Ambystoma mexicanum, which is
neotenous. It retains larval features into the adult (i.e.,
sexually mature) stage including external gills and gill
clefts in the pharynx. The axolotl can be induced to
metamorphose into a salamander-like animal by treatment with analogs of the hormone thyroxine, when they
lose their gills and leave water to become committed lung
breathers. Before metamorphosis, all VPN are in a medial
nucleus within the central gray representing the DVN, and
there is a clear sequential rostrocaudal distribution of
VPN supplying the first, second, and third branchial
branches of the vagus rostral of obex, reminiscent of the
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arrangement described for the dogfish and ray brain
stems, with the cardiac and gastric branches of the vagus
located more caudally (Fig. 8). The pulmonary branch,
supplying the reduced lungs, is widely distributed on
either side of the obex. After metamorphosis, there is an
increase in the number of VPN, and a proportion of them
(;15%) is found in a more lateral location in the white
matter of the medulla (287, 640). Presumably, this relocation of VPN has a functional relevance that may in part
relate to the switch from gill to lung breathing (609).
G. Reptiles
The vagus nerve in reptiles runs to the heart, trachea,
lungs, pulmonary and coronary vasculature, thymus, thyroid, and gut, supplying preganglionic fibers. The vagus
has an inhibitory effect on heart rate (Testudines, Ref.
438; Crocodilia, Refs. 217, 281; Sauria, Refs. 352, 379;
Serpentes, Ref. 216), an effect blocked by atropine (e.g.,
Ref. 216) and therefore cholinergic, as in all other gnathostomes. In addition, a tachycardial response has been
reported following vagal stimulation in some species (64,
216, 352, 438). This may be attributable to the existence of
a connection between the vagus and sympathetic fibers
(64, 216, 352, 438). However, in reptiles, there is little, if
any, sympathetic contribution to the cervical vagus nerve,
and the sympathetic fibers join the vagus nerve near the
heart in both the Crocodilia (217, 218) and the Lacertilia
(64, 352, 438). In contrast, a mixed vagosympathetic trunk
has been reported in widely different species, including
amphibians (112, 217) and mammals (134).
Control of pulmonary blood flow in reptiles is
achieved by vagal cholinergic constriction of the pulmonary artery (86, 87, 567, 651, 652). Peripheral electrical
stimulation of the vagus or intravenous injection of acetylcholine results both in bradycardia and an increase in
pulmonary vascular resistance, which reduces pulmonary
blood flow (269). These cardiovascular changes are abolished by administration of atropine. Blood flow is also
under adrenergic control. Intravenous injection of epinephrine causes a tachycardia and a reduction in pulmonary vascular resistance, resulting in an increase in pulmonary blood flow (269). Electrical stimulation of vagal
afferents in the turtle results in similar cardiovascular
changes that are blocked by administration of bretylium
(124), suggesting that the cardiovascular changes often
associated with brief periods of ventilation may be adrenergically mediated (642). There is also evidence for involvement of nonadrenergic noncholinergic (NANC) factors in the regulation of systemic and pulmonary vascular
resistances in reptiles, which may influence patterns of
cardiac shunting (642).
Few experimental studies have investigated the central projection of the vagus nerve in the brain stem of
881
reptiles. It is still unresolved which fibers, pathways, and
nuclei in the brain stem are specifically related to the
efferent and afferent fibers and whether the information
obtained from mammals is comparable to that in reptiles.
Nevertheless, some information has been obtained regarding the central representation of the cranial nerves
(IXth, Xth, XIth, XIIth) including sensory nuclei (18, 43,
131, 167), motor nuclei (70, 350, 629), and both sensory
and motor nuclei (37, 38, 390).
Applying HRP techniques to some species of reptiles
has revealed the central projections of a number of cranial nerves such as the trigeminal nerve (38), facial nerve
(37), laryngeal nerve (38, 350), vagus nerve (38, 390),
accessory nerve (38), and hypoglossal nerve (38, 350).
Barbas-Henry and Lohman (38) described the motor nuclei and the primary projections of different cranial
nerves in the monitor lizard and found that the motor
nuclei of nerve IX are located ventrally in the brain stem,
both medially in the glossopharyngeal part of the nA and
laterally in the nucleus salivatorius inferior, whereas the
motor nuclei of the Xth nerve are represented in the
motor nucleus of the vagus and in a lateral group of cell
bodies. The motor nuclear complex of nerve XII consists
of a large dorsal nucleus and small ventral nucleus that
extends from the medulla oblongata into the first segment
of the cervical spinal cord.
In reptiles, early studies described two divisions (medial and ventrolateral) of the vagal motor column in a
variety of species, which were provisionally designated as
the DVN and nA (5, 15, 18). The pattern of labeling is on
the whole similar to that observed after applying HRP to
the vagus nerve in mammals, birds, amphibians, and
fishes, except for minor differences, such as degree of
representation of VPN in the lateral nA or the existence or
absence of VPN in other nuclei, such as the nuclei of the
spinal accessory nerve. The lateral division, although
present in turtles, was more prominent in a lizard and an
alligator but absent from a snake (70). A nA was identified
adjacent to the DVN in the tortoise (131), and between 36
and 50% of VPN are located in the nA of the terrapin (390).
Vocal control neurons are located in the nA of the gekko
(350), and comparable motoneurons are present in the nA
of mammals.
An initial HRP study of the vagal motor column in the
agamid lizard Uromastyx microlepis (M. Al-Ghamdi and
E. W. Taylor, unpublished data) revealed that the majority
of VPN are in the DVN with a small proportion (6%)
ventrolaterally located in the nA. However, there was a
clear separation of VPN in the DVN into two distinct
groups with a lateral group making up ;13% of the whole.
Together with the cells in the nA and reticular formation,
laterally displaced cells make up ;20% of the total VPN.
All of these cells were cytoarchitecturally distinct from
the cells in the medial DVN. An exploratory injection of
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TAYLOR, JORDAN, AND COOTE
wheat germ agglutinin-HRP into the heart marked a few
CVPN in the DVN rostral of obex, but none in the nA.
Electrical stimulation of the brain stem caused a
pronounced bradycardia, as well as vasomotor responses,
in spontaneously breathing, anesthetized pond turtles,
Cyclemys flavomarginata. The cardioinhibitory response
depended on the integrity of the vagus nerves and was
particularly marked upon stimulation of areas in the caudal medulla corresponding to the nA, NTS, and DVN
(281).
Thus the situation in reptiles seems to vary between
species, and the somatotopic representation of the vagus
is not yet known. The basis of this variation is likely to be
that they are not a homogeneous group, because the
present-day reptiles are separated by wide evolutionary
divisions (536). The chelonians (turtles and tortoises) are
anapsids, a group regarded as primitive, having arisen
from close to the ancestral reptilian stock (evolved from
primitive amphibians). The snakes and lizards are diapsids, from the same reptilian stock that produced the
archosaurs. These in turn evolved into the ruling reptiles
(“dinosaurs”) represented today by the crocodiles and
alligators and, on another evolutionary line, the birds.
Mammals are recognized as having evolved from a separate, primitive reptilian stock, the synapsids. These were
remote in evolutionary terms from the lines leading to the
present day reptiles and the birds but may have been
closer to their amphibian ancestors and to the primitive
chelonians. Thus the disposition of VPN may have phylogenetic as well as functional correlates.
H. Birds
Cranial nerves IX and X are closely related, both
topographically and functionally, in birds. Their motor
nuclei lie in a continuous zone in the medulla oblongata,
and they separately supply preganglionic fibers to the
heart, lungs, blood vessels, and alimentary canal. An adjacent area in the hindbrain contains motoneurons supplying special visceral efferent fibers to the pharynx, larynx, and palate. Their fibers leave the hindbrain by a
series of rootlets that coalesce at the proximal ganglion.
This ganglion contains the cell bodies of visceral and
somatic sensory neurons which, together with cell bodies
of vagal sensory neurons in the more distal nodose ganglion, send afferent projections into the NTS (348).
Vagal preganglionic neurons in the pigeon were localized in the DVN, in an area identified in the ventrolateral medulla as the avian homolog of the nA in mammals
(18, 71) and the region of the reticular formation extending between the DVN and the nA (119, 347, 349). The DVN
in pigeon is composed of 11 cytoarchitecturally distinct
subnuclei in which individual target organs have discrete
and topographic representation (347, 349). Some neurons
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supplying the viscera are located rostral to obex, whereas
others are located in a typically sequential position caudal
to obex. A lateral subgroup projects to the heart. Similar
dorsoventral and rostrocaudal gradients of target representation are seen within vagal afferent projections to the
NTS (14, 348). Such distinct topographic separation of
groups of neurons innervating specific target organs has
clear implications for the central coordination of their
functioning.
Until recently, there were no figures available for the
proportions of vagal neurons located in the medial (DVN)
or lateral (nA) divisions of the vagal motor column in
birds. However, current work on the tufted duck, Aythya
fuligula, has revealed that VPN are located over a rostrocaudal extent of ;5 mm around obex in the medulla, with
3% of cell bodies in the nA and a diffuse area identified as
the reticular formation. The majority (97%) of cells are in
the DVN where they are separable into subnuclei, according to their cytoarchitecture and topography (72). As yet,
the viscerotopic distribution of these cells is uncertain or
in dispute.
Although of particular interest to this review, currently there is not a consensus on the topographic location of CVPN in birds. After electrophysiological and retrograde degeneration studies in the pigeon, CVPN were
reportedly found exclusively in the DVN, located rostral
to obex (119, 555, 556). Here they may be located with,
and possibly influenced by, activity in respiratory motoneurons, although their central interactions remain unknown. The reported concentration of the majority of
VPN in the DVN as well as the location of the CVPN
rostrally in the DVN is similar to the agamid lizard (see
sect. IVG) but in sharp contrast to mammals, where over
30% of VPN and the majority of CVPN are located in the
nA. This may reflect the diverse evolutionary background
of these two homeothermic groups, referred to above.
However, this conclusion was questioned by Cabot et al.
(107) who demonstrated, using fragment C to tetanus
toxin as a neural tract tracer, that the majority of CVPN
were in a caudal subdivision of the nA in the pigeon,
which may be homologous to the ventrolateral nucleus of
the nA in mammals. A smaller fraction (10 –30%) was
located within the ventrolateral subnucleus of the DVN.
Studies on the tufted duck recorded an apparent compromise between the two previous studies on pigeon, since
;77% of CVPN were located in the ventral subnucleus of
the DVN, with 21% in the nA and 2% in the reticular
formation (72). This distribution represents a relative concentration of CVPN into areas outside the DVN as the
mean number of CVPN in the DVN represents only ;3% of
the total population of VPN, whereas in the nA, CVPN
represent ;30% of total VPN. It is important to our further
understanding of the central control of the heart and of
cardiorespiratory interactions in birds that the exact topographical location of CVPN, in relation to other neu-
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
883
FIG. 9. Schematic of basic principles of organization of
cardiovascular neurons in medulla oblongata and spinal
cord of mammals. Target specificity appears to be retained
throughout multisynaptic pathway from periphery to at
least as far as brain stem. [Based on data from Janig and
McLachlan (301), Lovick (403), McAllen (417), and Pyner
and Coote (508).]
rons such as the respiratory CPG, is resolved for a number of species.
V. SYMPATHETIC INNERVATION OF THE
CARDIORESPIRATORY SYSTEM
A. Mammals
There is very little information on the central location
of sympathetic neurons in lower vertebrates. However,
this location has been described in a number of tetrapods
and most extensively in various species of mammals. For
a comprehensive account the reader is referred to the
review by Coote (127). The advent of retrograde labeling
of cell bodies with HRP and its conjugates, or fluorescent
dyes applied to preganglionic areas, has provided a more
detailed picture of the location of preganglionic neurons
and their anatomical organization. These techniques have
been utilized on the rat (13, 228, 278, 505, 506), guinea pig
(426), rabbit (499, 633), and cat (507).
The sympathetic preganglionic neurons (SPN) lie in
clusters in four topographically defined nuclei in the intermediate gray on either side of the spinal cord. These
four nuclei, named in turn from the edge of the gray
matter to the central canal, are the intermediolateralis
thoraco lumbalis pars funiculus (ILF), intermediolateralis
thoraco lumbalis pars principalis (ILP) or lateral horn,
intercalatus spinalis (IC), and intercalatus spinalis pars
para ependymatis (ICPe) or central autonomic area.
Quantitatively, the majority of SPN are found in the ILP.
The arrangement is likely to be the same in all mammals
(127).
The rostrocaudal location of SPN in mammals is
limited rostrally by the cervical segments, the last cervical
segment being the most rostral in which these cells have
been identified, for example, cat and rabbit T1 (507, 633),
rat C8 (279, 505, 506), and guinea pig C8 (540). The rostral
location of SPN seems to be fixed at the last cervical or
first thoracic segment, regardless of species or class.
The sympathetic neurons come to lie at these locations by a process of migration. Studies in the rat using
acetylcholine transferase as a marker (494) indicate that
the SPN arise from the ventral ventricular zone of the
developing neural tube, migrate radially into the ventral
horn, then are displaced dorsally, and finally, a smaller
number migrate medially to occupy sites between the ILP
and central canal (413, 414). On reaching the ILP, these
neurons become increasingly multipolar and may undergo a change in alignment from a dorsoventral and
mediolateral orientation to a rostrocaudal one (414, 506).
Dendritic orientation also changes from first being dorsolongitudinally organized to more mediolaterally organized as the rat matures (413, 414). There is also the
development of new rostrocaudal dendrites (413, 506).
1. Topographical distribution of sympathetic
preganglionic neurons
It has been suggested that a clustering of SPN into
small groups is related to similarity of function of the
neurons (13, 492). This remains to be substantiated. However, there is now good evidence that SPN projecting to
different ganglia or to the adrenal medulla are organized
into discrete rostrocaudally orientated columns (Fig. 9)
(13, 301, 505). The idea of a viscerotopic organization of
the cell groups has been extended to the four subnuclei
(46 – 48, 426, 492). Thus SPN projecting to the inferior
mesenteric ganglion of the guinea pig are found mainly in
the IC and ICPe (133), whereas hindlimb vasomotor neurons appear to mainly occupy the ILP and ILF (426). Also,
those neurons supplying the hypogastric nerve in the cat
are located in the lower lumbar spinal cord, just medial to
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TAYLOR, JORDAN, AND COOTE
the main portion of the ILP (46) or very medially just
dorsal to the central canal in the rat (259). However, it
cannot be quite as simple as this, since more recent
studies in the rat show that neurons supplying the adrenal
medulla, the stellate ganglion, superior cervical ganglion,
celiac ganglion, aortic-renal ganglion, or superior or inferior mesenteric ganglion are represented in each of the
four subnuclei (279, 506, 591).
A further extension of the idea of functionally organized specific groups of cells concerns their morphology.
Two types of neurons, one with round-bodied and one
with fusiform somata are most commonly described. A
third, rather rare, larger cell type has also been observed
(23, 506). These three types have been shown in the
projections to the stellate ganglion, superior cervical ganglion, and the adrenal medulla (506). Of interest were the
observations in the rat that round-bodied somata are the
sole type in the IC, and jusiform somata are the sole type
in the ICPe, whereas both types are present in the ILP and
ILF (506). Although at present there is no strong reason to
connect this morphology with electrophysiology, it is of
interest that cat upper thoracic SPN can be classified into
three types on the basis of their electrical properties
(169). However, the biophysical codes are too few to
account for the range of sympathetic functions.
Target specificity has also been related to chemical
coding of these neurons. An elegant study in the guinea
pig revealed that substance P-immunoreactive SPN projected selectively to postganglionic vasodilator neurons
containing vasoactive intestinal polypeptide. In contrast,
SPN that were immunoreactive to antibodies to calcitonin
gene-related peptide were found to project to postganglionic vasoconstrictor neurons containing neuropeptide Y
(NPY) as well as norepinephrine (224, 225). Rat secretomotor preganglionic terminals in the superior cervical
ganglion are selectively immunoreactive to calretinin antibody (243). Using a conceptually similar approach in the
cat, Krukoff et al. (367, 368) measured four peptides
(neurotensin, substance P, enkephalin, and somatostatin)
in SPN throughout the thoracolumbar spinal cord. This
study failed to show any obvious peptide-specific preganglionic neurons associated with specific viscera. It also
appears that nitric oxide synthase is specifically associated with a subpopulation of SPN that projects to adrenal
medulla and viscera (244). As with the biophysical properties, at present too few chemical codes have been identified to account for the range of sympathetic functions.
Nonetheless, this promising direction of research might
be combined with another elegant and powerful technique of transneuronal labeling with neurotropic virus
(592). So far, studies on the projections to the kidney and
the adrenal medulla in rat, rabbit, and hamster have generally confirmed the viscerotopic organization of the SPN
(165, 333, 554).
One of the more interesting features of recent studies
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of SPN has been the descriptions of their dendritic arbors,
which appear to be more extensive than previously assumed. The dendritic arbor and its orientation have functional importance that is relevant to understanding the
organization of the columns of spinal neurons that are
target specified (506). In mammals (rat, rabbit, and guinea
pig), primary dendrites number from six to eight and
branch extensively after passing medially, laterally, and
rostrocaudally (23, 279, 506, 634). It is now clear that a
similar arrangement occurs in the cat (507). The lateral
dendrites pass through the bundles of descending axons
in the lateral funiculus; the medial dendrites converge
from different clusters of neurons to cross the intermediate gray matter in bundles, which on reaching the central
canal turn and pass up and down, while some extend
further to the lateral horn of the opposite side. The longitudinally oriented dendrites are extensive, running for
considerable distances between groups of SPN. These
orientations may allow for reception of similar inputs by
functionally similar SPN.
2. Sympathetic innervation of the heart
Almost all vertebrates have an excitatory sympathetic nerve supply to the heart. Sympathetic nerve fibers
from the stellate ganglia innervate the atria and ventricles
as well as the sinoatrial node in reptiles, birds, and mammals. Sympathetic fibers travel by two pathways: a direct
one which mainly supplies the nonconducting tissue of
the heart and an indirect one where a branch of the
stellate ganglion joins the vagus nerve and from where
fibers travel to the pacemaker regions and conducting
tissue of the heart (342). In amphibians and teleost fish,
the cardiac sympathetic innervation is often in the same
trunk as the vagus (383). Cyclostomes, Elasmobranchs,
Dipnoans, and some teleosts (particularly pleuronectids)
lack adrenergic innervation of the heart (383). In those
vertebrates without a sympathetic innervation of the
heart, the effect of circulating or locally released catecholamines is also excitatory (472). Cardiac cells containing epinephrine or norepinephrine are found in all
vertebrates, including lampreys (73). This phylogenetic
variability is described in some detail below.
In amphibians, reptiles, birds, and mammals, the
sympathetic excitatory influence on the heart is twofold
in that it increases both rate and force. These actions in
mammals, where the most detailed studies have been
conducted, are to some extent dependent on whether
right or left sympathetic supply to the heart is activated.
In the dog, monkey, and probably human, the cardiac
sympathetic projection has highly localized terminal arbors and is capable of causing sharply discrete alterations
in the performance of segments of the myocardium (518).
Broadly, stimulation of the right sympathetic nerves to
the heart in the dog, for example, causes increased heart
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
rate via accelerations of cardiac pacemaker activity. It
also augments atrial inotropism. Stimulation of the left
sympathetic cardiac nerves has a major facilitatory effect
on ventricular contractions and also increases conductance and rate via the atrioventricular node (518, 519).
In mammals, postganglionic sympathetic axons innervating the respiratory and cardiac structures in the
thoracic cavity are located in independent sympathetic
nerves or travel to the effector with the thoracic vagus
nerves, via the sympathetic branch from the stellate ganglion (197, 341, 342, 495, 600 – 602). It is estimated that the
thoracic vagus in cats contains ;1,500 sympathetic fibers
(197, 450). In comparison, the left inferior cardiac nerve,
an independent sympathetic branch of the stellate ganglion, contains on average 2,600 sympathetic axons (374).
It has been pointed out by Balkowiec and Szulczyk (28)
that this large proportion of sympathetic fibers travelling
with the vagus nerve to the heart may contribute to the
axo-axonal synapses observed to occur between these
nerves (183), providing a morphological basis for the
observed cardiac vagal-cardiac sympathetic interaction
(252, 366, 502, 524, 644). An electrophysiological study of
single sympathetic fibers in the thoracic vagus by
Balkowiec and Szulczyk (28) showed they were a homogeneous population, displaying cardiac pulse and respiratory-related rhythmicity in their discharge pattern and
decreasing their activity in response to peripheral arterial
chemoreceptor stimulation. Consequently, it was argued
that they supply a single cardiac effector. It was assumed
that the most likely effector was the conducting tissue,
because stimulation of the sympathetic fibers in the thoracic vagus is most effective at producing increases in
heart rate in dogs (520), cats (56, 341), and sheep (635).
3. Sympathetic nerve supply to airways
There is a large amount of literature detailing the
physiology and pharmacology of the smooth muscle and
secretory responses evoked by stimulation of airway autonomic nerves in mammals. However, these have been
comprehensively reviewed (44, 45, 300, 388), and this
review only provides a summary of this work.
The presence and extent of innervation of the smooth
muscles by sympathetic nerves varies from species to
species. It has been demonstrated in the trachea of guinea
pigs (35) and rabbits (172) as well as in bronchi of dogs
(360), cats (573), and humans (152, 378, 488). It has been
found only rarely or not at all in the bronchi of rats (27, 35,
172), guinea pigs (484), rabbits (412), and humans (172).
Even where an innervation has been demonstrated, it is
rarely very extensive.
Although sympathetic nerves modulate transmission
in enteric ganglia (659), the presence or absence of a
sympathetic innervation of airway ganglia has been
widely debated. An adrenergic innervation of airway gan-
885
glia has been suggested in kittens (360), humans (527),
and calves (299) but has been discounted in dogs (299),
cats (132), guinea pigs, rats, and mice (35). Even in calves,
presumed adrenergic endings were found adjacent to only
10% of principal ganglion cells (299). However, in all
species studied, adrenergic innervation of the airway vasculature has been demonstrated, and in many species, SIF
cells are present in the ganglia. It is possible that when an
adrenergic innervation of the ganglion cells has been
demonstrated, the fibers arise from these SIF cells rather
than an extrinsic sympathetic innervation.
B. Cyclostomes
The heart of cyclostomes, which is without a sympathetic nerve supply, contains large quantities of epinephrine and norepinephrine stored in chromaffin cells
(2, 552). Depletion of this catecholamine store with
reserpine causes a marked slowing of the heart rate in
these animals (73). Epinephrine, norepinephrine, isoprenaline, and tyramine all stimulate the lampetroid
heart, although the effects are less pronounced than the
acceleration produced by acetylcholine. The effect of
the adrenergic agonists is blocked by propranalol, suggesting an effect via b-adrenoceptors in lampetroids as
in the higher vertebrates (19, 191, 464). The isolated
heart of myxinoids is insensitive to exogenously applied acetylcholine and the catecholamines. However,
injected catecholamines have marked cardiostimulatory effects in the intact animal, whereas the b-adrenoreceptor antagonist sotalol causes a markedly negative
chronotropic effect. These responses have been attributed to simulation of the effects of catecholamines
released from chromaffin stores within the heart of the
normal animal (474).
Little is known about the origin and nature of vasomotor nerves in cyclostomes, and there is no evidence for
vasomotor innervation of their branchial vasculature.
However, spinal autonomic nerve fibers, containing adrenergic elements, innervate some blood vessels in lampreys (230), and both catecholamines and acetylcholine
increase vascular resistance in Myxine (21).
C. Elasmobranch Fish
The sympathetic system of elasmobranchs consists
of an irregular series of ganglia, approximately segmental,
lying dorsal to the posterior cardinal sinus and extending
back above the kidneys (667). These paravertebral ganglia
are arranged approximately segmentally, except in the
most anterior part, and there are one or two ganglia
connected to each spinal nerve by white rami communicantes (469). The existence of recurrent gray rami communicantes has been denied (665). The spinal autonomic
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TAYLOR, JORDAN, AND COOTE
outflow in elasmobranchs appears to occur chiefly in the
ventral roots of the spinal nerves (665), but a dorsal
outflow to blood vessels is not excluded (497). The segmentally arranged ganglia are irregularly connected longitudinally and with the contralateral paravertebral ganglia, but there are no distinct sympathetic chains of the
type found in higher vertebrate groups. There are no
prevertebral (collateral) ganglia in elasmobranchs (469,
473).
The most anterior pair of paravertebral ganglia of
elasmobranchs are the axillary bodies that are situated
within the posterior cardinal sinuses. These are made up
of ganglion cells and also large masses of catecholaminestoring chromaffin cells. The axillary body ganglia receive
white rami communicantes from several of the anterior
spinal nerves and give off the anterior splanchnic nerves.
These are composed mainly, if not entirely, of postganglionic fibers. The left anterior splanchnic nerve crosses to
join the right, forming a plexus along the celiac artery to
the gut and the liver (465, 665). An anastomosis between
the vagus and the anterior splanchnic nerves occurs in
some elasmobranchs (666). The paravertebral ganglia behind the axillary bodies are smaller and lie in the dorsal
wall of the cardinal sinuses. The suprarenal chromaffin
tissue is often associated with the ganglia (as in the
axillary bodies) but may exist separately (469).
A peculiarity of the sympathetic system of elasmobranchs is that it does not extend into the head. This
condition is unique among vertebrates, but it is not clear
whether it is primary or the result of a secondary loss
(667). Contributions to the vagi or direct cardiac nerves
from paravertebral ganglia are, with rare exceptions (e.g.,
Mustelus, Ref. 497), absent (297, 406 – 408, 497, 665).
There are only single observations of fibers from the
axillary bodies to the heart (Mustelus, Ref. 497). As a
result, there is no direct sympathetic innervation of the
heart or the branchial circulation in elasmobranchs (465),
and there is no evidence for branchial vasomotor control,
other than by circulating catecholamines (102, 155).
Circulating catecholamines exert a tonic influence on
the cardiovascular system in elasmobranchs under resting, normoxic conditions (572). In elasmobranchs like the
dogfish, which again have no cardiac sympathetic innervation, circulating catecholamines are important for
maintaining and increasing heart rate (517). It has recently been demonstrated that circulating catecholamines
modulate vagal control of heart rate in dogfish. The degree of inhibition of an in situ preparation of the dogfish
heart during peripheral stimulation of a cardiac branch of
the vagus was found to be modulated by circulating levels
of norepinephrine (C. Agnisola and E. W. Taylor, unpublished data). In addition, an adrenergic influence on the
heart may be exerted by specialized catecholamine-storing endothelial cells in the sinus venosus and atrium.
These cells are innervated by cholinergic vagal fibers
Volume 79
(493, 543). The effects of epinephrine and norepinephrine
on the elasmobranch heart are somewhat variable, so the
possibility of a selective cardiac control via the two naturally occurring amines exists, although the mechanisms
of this action remain unknown (469).
D. Teleost Fish
Historically, a sympathetic cardioaccelatory innervation had been generally assumed to be lacking in teleosts
(510). However, the sympathetic chains extend into the
head where they contact cranial nerves, forming a vagosympathetic trunk (225), and adrenergic fibers have been
found to innervate the heart of some teleosts (e.g., trout,
Refs. 212, 664). An adrenergic tonus on the hearts of cod
(Gadus) and goldfish (Carassius) has been demonstrated, but the relative importance of the neuronal and
humoral adrenergic control of the heart remains uncertain (469). The positive chronotropic and ionotropic effects on the teleost heart produced by adrenergic agonists
and adrenergic nerves are mediated via b-adrenoceptor
mechanisms associated with the pacemaker and the myocardial cells (111, 212, 272, 516). b-Adrenoreceptors
generally mediate positive chronotropy in fish and amphibians, whereas a-adrenoreceptors mediate negative
chronotropy in fish (194, 195, 469). As a whole, the teleosts may be considered as the earliest group of vertebrates in which there is both sympathetic and parasympathetic control of the heart.
There is adrenergic innervation of the branchial and
systemic vascular beds in teleost and other actinopterygian fishes. They contain adrenergic fibers that innervate
vessels in both the arterioarterial, respiratory circuit and
the arteriovenous, nutritive circulation in the gill filaments, possibly controlling and directing blood flow
through these alternate pathways (454). Thus the patterns
of blood flow in the gills are regulated by vagal cholinergic
(see sect. IVD) and sympathetic adrenergic fibers that
increase vascular resistance by stimulation of muscarinic
and a-adrenergic receptors, respectively, or decrease it by
b-adrenoreceptor stimulation (196, 469, 471, 511).
E. Amphibians
The most primitive arrangement of the sympathetic
ganglia in amphibians is found in the urodeles (the newts
and salamanders). Ganglionated sympathetic chains extend from the level of the first spinal nerve down into the
tail. Except in Necturus, the sympathetic trunk does not
project into the cranial region, although there are connections with the vagus nerve in all species examined. In
Triturus, the subclavian plexus gives rise to cardiac sympathetic nerves. In anurans, all sympathetic innervation to
the heart travels in the vagal trunk, whereas urodeles
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
possess both a vagosympathetic and direct cardiac sympathetic nerves (94, 469). As in fish, chromaffin tissue
occurs in the walls of the posterior cardinal veins.
In anurans such as the frog (Rana pipiens) and the
bullfrog, sympathetic outflow extends from the 2nd to the
10th spinal nerve along the shortened spinal column. The
vagus nerve is a major pathway for postganglionic sympathetic fibers reaching the stomach, lungs, and heart so
that it constitutes a vagosympathetic trunk (225). Sympathetic preganglionic neurons in spinal segments 2 and 3
innervate the first sympathetic ganglion that sends postganglionic fibers to heart and lungs (663), as well as upper
digestive tract and structures in the head. The preganglionic neurons are located between segments 3 to 8 and
mainly lie in the ILP and IL in about equal numbers (277,
534).
All the postganglionic neurons in the sympathetic
chain of amphibians synthesize epinephrine. Epinephrine
is the most important neurotransmitter of the positive
chronotropic and ionotropic effects of sympathetic innervation on the heart, but in some species, there is corelease
of NPY and ATP (455). In the toad and the bullfrog, the
SPN are segregated into larger B and smaller C neurons
(277, 454). The small C neurons, with slow conduction
velocities, contain the neuropeptides NPY and galanin
and innervate blood vessels (277, 454).
F. Reptiles
The spinal sympathetic pathways of reptiles and
birds have clearly defined paravertebral chains, and some
share features not seen in other vertebrates. The sympathetic trunk extends craniad and probably makes extensive connections with cranial nerves (3). The arrangement
of the sympathetic ganglia is similar in lizards and chelonians (270). Both have a large ganglion at the level of the
branchial plexus, which gives rise to cardiac and pulmonary nerves. A large ganglion in the same position in
crocodilians, which corresponds to the stellate ganglion
of mammals, gives rise to a prominent cardiac nerve.
Catecholamine-synthesizing autonomic neurons project
from the paravertebral sympathetic ganglia to all chambers of the reptilian heart. Their nerve fibers either run
with the vagus in a vagosympathetic trunk or project
directly from the sympathetic chain to the heart. These
spinal autonomic neurons exert positive inotropic and
chronotropic effects on the reptilian heart, mediated by
stimulation of b-adrenoreceptors (455).
In reptiles (e.g., terrapin, Tryonix sinensis), SPN are
located in the intermediolateral gray matter of the spinal
cord, with a majority of neurons in the ILP and IC cell
columns and a smaller population dorsal to the central
canal (389). In the lower spinal cord segments 13–18 of
the turtle, the sympathetic neurons form a small cluster in
887
an area lateral to the central canal, perhaps equivalent to
IC (375).
G. Birds
In birds, the sympathetic chain extends as a series of
segmental ganglia from upper cervical to sacral levels,
with the most rostral ganglion lying in the skull between
the origins of the glossopharyngeal and vagus nerves.
However, the preganglionic neurons have a more restricted rostrocaudal distribution (e.g., chicken and pigeon C14, Refs. 105, 280), and there is no cervical preganglionic contribution to the cervical sympathetic ganglia
(225). This is despite birds having more cervical segments
than mammals (e.g., 14 in pigeon, 15 in chickens). Most
postganglionic neurons in the sympathetic chains contain
catecholamines and innervate structures such as blood
vessels. In contrast to reptiles, there are well-developed
prevertebral ganglia in birds. Splanchnic nerves from the
paravertebral chain supply a ganglionated plexus that
surrounds the aorta and the origins of the celiac and
mesenteric arteries (225).
In some avian species there is no lateral horn in the
spinal cord, and the main location of SPN is in the central
autonomic area. However, a few neurons in birds are
present in more lateral nuclei such as the IC in the pigeon;
in the chick, they also appear in an area close to the
lateral border of the gray matter equivalent to the ILP
(106, 107, 280). Therefore, although SPN are mainly located medially in birds and laterally in mammals, reptiles,
and amphibians, their distribution areas are strikingly
similar.
In pigeons and chickens, the dendritic arbors of sympathetic preganglionic neurons pass medially, laterally,
and rostrocaudally in the spinal cord. The lateral dendrites of the principal nucleus above the central canal
converge into bundles that traverse the entire width of the
intermediate gray matter and often project into the lateral
funiculus. These bundles are like rungs of a ladder in the
longitudinal horizontal plane, similar in appearance to
those in mammals, although projecting outward (laterally) rather than inward (medially). The medial dendrites
pass to the contralateral part of the central nucleus where
they form a network (280).
The spinal sympathetic neurons of the upper thoracic
segments in birds innervate all chambers of the heart via
the stellate ganglia, also contributing to the intracardiac
plexus formed by vagal neurons (62). As in mammals, the
cardiac sympathetic neurons are tonically active and
elicit both chronotropic and inotropic responses, via the
release of norepinephrine acting on b-adrenoreceptors
(62, 309, 455, 628).
Little is known of the sympathetic innervation of the
lungs and airways and pulmonary vasculature in birds.
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TAYLOR, JORDAN, AND COOTE
There is a sparse sympathetic innervation that is without
effect on bronchial muscle (66) but supplies the scattered
bundles of smooth muscle fibers in the air sacs (245) and
the smooth muscle of the oblique septum separating the
air sacs from the abdominal cavity (62, 245). A sympathetic vasoconstrictor supply to pulmonary blood vessels
has been described (60, 61, 62, 353).
VI. CENTRAL CONTROL OF
CARDIORESPIRATORY INTERACTIONS
The importance of a linkage between the mechanisms controlling the respiratory and the cardiovascular
systems has long been recognized, since in many physiological responses there are appropriate changes in both
systems. For example, during exercise there is a close
matching of the respiratory and cardiac outputs, which
generate the increase in oxygen uptake and transport. In
addition, many reflex responses evoked by stimulation of
peripheral afferents evoke change simultaneously in the
two systems. This linkage is engendered in the mechanisms that ensure optimal ventilation-perfusion matching
within the lungs of air-breathing mammals. It is now
becoming clear that there is a similar matching of the
counterperfusions with water and blood of the gills of
aquatic animals, so (for example, in dogfish) gill ventilatory movements and heart rate are often coordinated
(548, 604). Centrally, there are also mechanisms by which
these ventilatory and vascular control systems are coupled. They have been discussed in several reviews (121,
135, 137, 329, 532, 605, 607). Although the modification of
cardiovascular control by the respiratory system seems to
dominate, it is also clear that stimulation of cardiovascular afferents can modify the respiratory system. For example, when arterial baroreceptors are stimulated by
rises in arterial pressure, respiratory output is depressed.
Even at rest, the coupling between the respiratory and
cardiovascular systems may manifest itself. Changes in
heart period in phase with breathing (respiratory sinus
arrhythmia) are due to respiratory modulation of the vagal parasympathetic innervation of the heart. Similar
modulation can also be seen in the activity of many
sympathetic nerves (see below), and this may, in part,
explain the rhythmical changes in arterial pressure that
are sometimes observed, although mechanical changes
within the thoracic cavity affecting venous return to the
heart are also involved. In both vagal and sympathetic
outflows, the respiratory modulation of activity is due in
part to activity in the “central respiratory network” and
partly to sensory input related to lung inflation or gill
ventilation. For a detailed discussion of the autonomic
control of the heart and circulation in various vertebrates,
the reader is referred to several very comprehensive re-
Volume 79
views (135, 194, 307, 313, 383, 457, 469, 470, 472, 570, 607,
609).
A. Mammals
1. Control of heart rate
In mammals, the level of background resting activity
in cardiac vagal nerves, and consequent cardiac vagal
tone, appears to vary from species to species and also
within species. In dogs and humans, heart rate increases
markedly after injection of atropine, whereas in anesthetized cats, there is little change in heart rate when atropine is applied (289). In addition, in any particular organ,
the relative tone in vagal and sympathetic innervations
also varies. Even in those animals in which cardiac vagal
tone is low, there is a predominant vagal tone in airway
smooth muscle innervation, with sympathetic activity
having little, if any, direct action here (322).
Vagal tone appears to derive from ongoing activity in
peripheral sensory receptors and from other groups of
central neurons (Fig. 10). One important ongoing excitatory drive to cardiac vagal outflow arises from the arterial
baroreceptors, the level of vagal drive to the heart being
related to the level of arterial blood pressure. Baroreceptor denervation reduces (421) but does not abolish cardiac vagal discharge (290), implying that other inputs
must also be important. The arterial chemoreceptors may
provide one alternative drive. They have ongoing activity
at rest, and hypocapnia produced by hyperventilation
produces a tachycardia and reduction in cardiac vagal
efferent activity (139, 264). The fact that anesthetics reduce vagal tone (289) may suggest that tonic influences
also arise from other parts of the nervous system. In this
respect, decerebration produces a vagally mediated fall in
heart rate (41), suggesting that there is a tonically active
descending inhibitory pathway. This may originate in the
hypothalamic defense area, since lesions here also produce cardiac slowing (402). Conversely, stimulation here
inhibits cardiac vagal activity (326). This may act via the
inhibitory neurotransmitter GABA, since GABA antagonists attenuate the tachycardia evoked by defense area
stimulation (41). Vagal tone is greatly increased by stimulation of the superior laryngeal nerve because it induces
apnea by inhibiting both inspiratory activity and the consequent lung inflation. This results in an increase in activity in cardiac vagal efferent fibers (329). Evidence suggests that superior laryngeal nerve stimulation may also
excite CVPN directly and via a subpopulation of postinspiratory respiratory neurons that show firing patterns
similar to CVPN, a situation reminiscent of the synchronous firing of respiratory motoneurons and CVPN in the
DVN of the dogfish (see sect. VIB).
In mammals, respiratory-related changes in heart period are due mainly to alterations in vagal drive to the
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
889
FIG. 10. A summary of possible mechanisms that
interact at level of cardiac vagal motoneurons to evoke
cardiac slowing. Excitatory mechanisms are shown as
solid lines, and inhibitory mechanisms are shwon as
dotted lines. Lines indicate pathways of unknown synaptic complexity, not individual neurons. ACh, acetylcholine; GABA, g-aminobutyric acid; HDA, hypothalamic defense area; PIN, subpopulation of postinspiratory neurons; SAR, slowly adapting lung stretch
receptor afferents; SLN, superior laryngeal nerve afferents; ?, postulated pathways. [Modified from Jordan
and Spyer (329).]
heart, so it is not surprising that respiratory-related variations in activity were seen in recordings from cardiac
vagal efferent fibers (154, 291, 292, 303, 346, 373). The
fibers fired preferentially during expiration and were also
powerfully excited by stimulating the arterial chemoreceptors and baroreceptors, which would account for the
cardiac-related component of their activity. The respiratory-related activity survives section of the vagus peripheral to the recording site and is thus of central origin.
However, there is also a component due to activity in
pulmonary afferents, since vagotomy does abolish the
respiratory component if the animals are first hyperventilated to neural apnea. Koepchen et al. (362, 363) proposed that the respiratory modulation of vagal outflow
could be explained either by a direct respiratory modulation of the preganglionic neurons or if the excitatory
reflex inputs were somehow “gated” before arriving at the
preganglionic neuron, or by a combination of the two.
Experiments performed in vivo using intracellular recordings from identified CVPN in cats have demonstrated that
these neurons do indeed receive a respiratory-related input. During each inspiration, their membrane potential is
hyperpolarized due to the arrival of acetylcholine-mediated inhibitory postsynaptic potentials (226) which makes
the neurons less amenable to excitatory inputs during
inspiration.
A clear role for central respiratory drive modulating
ongoing cardiac vagal drive has been elucidated. In addition,
however, activity in afferents arising in the lungs also contributes to respiratory sinus arrhythmia (11, 12). Lung inflation inhibits cardiac vagal efferent activity (290, 303, 501)
and evokes a tachycardia (142, 143, 211, 255). The effects of
lung inflation may be so powerful that they reverse the
bradycardia evoked by arterial chemoreceptor stimulation
into a tachycardia (137, 143). Unlike the actions of central
respiratory drive, the modulatory effects of lung inflation on
cardiac vagal outflow do not appear to be imposed at the
level of the preganglionic neurons (501).
There are several sites at which the respiratory modulation of reflexes may be imposed before the preganglionic neurons. The NTS where many cardiorespiratory
afferents terminate is also the site of the dorsal respiratory group, so this is one possible site. Detailed descriptions of the neural organization and pharmacological
modulation of transmission within the NTS have appeared (322, 323, 328, 387). Within the NTS, modulation
may occur by presynaptic actions on the sensory terminals themselves, or alternatively, at postsynaptic sites on
NTS neurons (see Fig. 11). Afferents from the lungs and
airways travelling in the superior laryngeal and vagus
nerves are amenable to presynaptic influences, both from
central respiratory drive and from activity in other vagal
afferents (39, 532). Recent studies have demonstrated that
many NTS neurons receiving SLN input also receive convergent input from afferents travelling in the carotid sinus, aortic, and vagus nerves (158, 435). Arterial baroreceptor and chemoreceptor terminals appear to be
unaffected by central respiratory activity (324, 327, 530)
so that respiratory modulation of these reflexes must
occur at a later site in the reflex pathway. This is unlikely
to be within the NTS itself since NTS neurons receiving
baroreceptor (436, 437) or chemoreceptor (433) inputs
failed to show any such modulation of the membrane
potential, in phase with either central respiratory drive or
lung inflation. Although laryngeal afferent inputs converge onto NTS cells, which also receive input from either
lung stretch afferents (P cells, Ref. 63) or central respiratory drive from dorsal inspiratory neurons (173), there is
also a population of NTS neurons that receives laryngeal
input which do not receive any identified respiratoryrelated activity (158, 434, 435). Clearly, at least some
afferent input can pass the NTS without being modulated
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TAYLOR, JORDAN, AND COOTE
Volume 79
FIG. 11. Diagrammatic representation of organization of second-order neurons within NTS (shaded) that receive
monosynaptic inputs from slowly (SAR) and rapidly adapting (RAR) lung stretch receptor afferents and superior
laryngeal nerve afferents (SLN). At least 2 discrete groups of P cell (P) are found. One receives SAR input alone, whereas
the other also receives SLN inputs. Ib neurons (a subgroup of dorsal respiratory neurons) receive monosynpatic SAR
input and, in addition, an input related to central respiratory activity (CIA). Putative inputs to a group of output neurons
(C), thought to be responsible for triggering a cough, are also illustrated. [Modified from Jordan (322, 323).]
by respiratory activity. It should not be forgotten that
respiratory modulation of baroreceptor firing, induced by
the mechanical events of inspiration and expiration altering venous return and hence cardiac filling, cardiac output
and blood pressure, is likely to be an important contributor to respiratory sinus arrhythmia in humans (65, 162,
627).
The effectiveness of certain cardiac reflexes is markedly modified by respiration. Brief stimuli applied to the
arterial baroreceptors or chemoreceptors only evoke falls
in heart rate if they are applied during expiration, with
stimuli given during inspiration being less effective or
totally ineffective (154, 264). Because the preganglionic
neurons themselves are under respiratory control, it
might be predicted that any cardiac reflex that is mediated
by these CVPN would be modulated by respiration. Indeed, stimulation of trigeminal receptors in the facial
skin, receptors in the nasopharynx and larynx, and cardiac C-fiber receptor stimulation all evoke reflex excitation of cardiac vagal outflow that is modified by respiratory drive. The degree of respiratory modulation imposed
by lung inflation and central respiratory drive on the
bradycardia evoked by stimulation of the arterial baroreceptors and chemoreceptors, cardiac receptors, and pulmonary C-fiber afferents has been compared quantitatively (136, 141). The arterial chemoreceptor-evoked
bradycardia was almost abolished by lung inflation and
during inspiration, whereas those evoked by stimulating
the baroreceptors and cardiac C fibers were reduced by
50 – 60%. Surprisingly, that evoked by stimulation of pulmonary C-fiber afferents was unaffected by respiration.
Several possibilities exist. Stimulation of the pulmonary C
fibers may uncouple the linkage between the respiratory
and cardiac control mechanisms; stimulation of the different reflexes may modify the central respiratory control
system differently, or the bradycardia evoked by one
group of afferents may be mediated by a different group
of preganglionic neurons to those activated by the other
afferents. Comparing the respiratory responses evoked by
stimulation of baroreceptors and pulmonary C fibers,
Daly et al. (140) could find no evidence for differential
effects on the respiratory pattern that would explain the
different respiratory modulations of the evoked bradycardias. With respect to the suggestion that there may be two
separate populations of cardiac vagal motoneurons, it has
been demonstrated recently in both cats and rats that
C-fiber cardiac preganglionic neurons in the DVN are
activated by stimulation of pulmonary C fibers but are
unaffected by the arterial baroreceptors or the respiratory
cycle (315–317). The ongoing activity of these neurons is
rather regular, unlike those located in the nA that fire with
respiratory- and cardiac-related rhythms.
Thus, as demonstrated in the dogfish (see sect. VIB),
mammals appear to have two separate groups of CVPN
that have either tonic or phasic firing patterns and may be
topographically separated into groups in the DVN or the
nA. This separation arises during embryological development as neurons that form the nA migrate ventrolaterally
from a more dorsomedial position, possibly the equivalent
of the DVN, in the fetal brain stem (656). Power spectral
analysis of recordings of heart rate and breathing movements in human neonates revealed that respiratory sinus
arrhythmia (RSA) is a major contributor to heart rate
variability (HRV) in healthy term (38 – 40 wk gestation)
newborn infants (621). Although RSA was detected in the
near-term fetus (.35 wk), it was not discernible in the
fetus before this gestational age or in early premature
neonates (,30 wk), appearing later in postnatal development (at ;33 wk). Thus the contribution of RSA to HRV
varies both with pre- and postnatal age, which may reflect
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
a maturational development of the underlying mechanisms (609). This is more likely to reflect myelination of
nerve fibers than ventrolateral migration of CVPN at this
late stage of development. However, the onset of airbreathing at metamorphosis in the axolotl was accompanied by ventrolateral relocation of a subpopulation of
VPN (287, 608).
2. Control of the airways
The respiratory-related modulation of cardiac vagal
outflow is not unique. Tracheal muscle tension fluctuates
in phase with central respiratory drive (448), and reflexes
that increase respiratory drive also increase tracheal tension. Vagal efferent fibers innervating airway smooth muscle have an inspiratory pattern of firing that is augmented
when central respiratory drive increases and that is inhibited by moderate degrees of lung inflation (303, 331, 420,
653, 654). The origin of the respiratory-related inputs to
the motoneuronal pools is, as yet, unknown. However,
there is a close association between the ventral respiratory group and the regions of the nA containing the VPN
(67, 184). Also, because the respiratory rhythm is thought
to be generated in the region of the rostroventral medulla
(529, 585), it is possible that this is the more likely site. In
fact, Mitchell and Richardson (448, 525) have argued that
there are probably more than one “respiratory oscillator”
within the brain stem. In addition to the eupneic CPG,
there is also a slower, and phylogenetically older, CPG for
the branchial musculature and a faster pattern generator
invoked during gasping (see Ref. 525 for discussion).
The organization of the afferent and efferent control
of airway smooth muscle and their central nervous integration have been discussed in recent extensive reviews
(45, 322, 323), and readers are directed to them for a
detailed consideration. It is established that the resting
tone in airway smooth muscle is due mainly to activity in
the vagal bronchoconstrictor innervation (344, 448). The
origin of this tone is as yet undefined but, as with the
heart, it is likely to be the sum of a number of competing
influences from sensory afferents in the airways and certain central mechanisms. Slowly adapting lung stretch
receptor afferents and unmyelinated airway afferents provide tonic inhibitory and excitatory drives, respectively
(533). In addition, both peripheral and central chemoreceptors have ongoing activity at resting levels of arterial
oxygen and CO2, and because these afferents both evoke
bronchoconstriction (460, 655), they may provide part of
the resting bronchomotor tone.
Vagal parasympathetic activity is important in maintaining resting airway tone (485) and in mediating reflex
bronchoconstrictions (122), airway secretion (496), and
bronchial vasodilation (377). Sympathetic stimulation can
evoke bronchial vasoconstriction (134), relaxation of airway smooth muscle (104, 157), and increased mucus se-
891
cretion (210), but the importance of these latter effects is
species dependent. In general, many of the effects of
sympathetic stimulation are evoked by modification of
parasympathetic activity (26, 104, 157). Activity in these
nerves shows respiratory modulation (322).
After pharmacological blockade of airway adrenergic
and cholinergic receptors, responses to vagal stimulation
can still be evoked, mediated by a NANC system. These
responses can be inhibitory and/or excitatory depending
on the species (9, 44, 172, 246, 526, 616, 632). Indeed, in
human airways, the NANC system provides the predominant inhibitory control of smooth muscle.
3. Ongoing activity in cardiac sympathetic and
vasomotor nerves
There is a large body of evidence that sympathetic
nerves supplying the heart and blood vessels in most
vertebrates studied show a continuous activity on the
range of 0.1–7 Hz referred to as cardioaccelatory or vasomotor tone (see Refs. 127, 455 for review). For example,
a 2- to 6-Hz periodicity is entrained to the cardiac cycle via
inhibitory feedback from the arterial baroreceptors (219).
This cardiac-related inhibition is dominant in muscle and
splanchnic sympathetic vasoconstrictor nerves and probably in cardiac sympathetic nerves (475).
Spontaneous activity of most sympathetic cardiovascular neurons exhibits a respiratory modulation. This has
been shown in a number of mammals such as the dog, cat,
rabbit, and rat (6, 74 –76, 227, 254, 482, 669 – 671). The
mechanisms involved in the respiratory modulation of
sympathetic cardiac and vasomotor discharge are complex, probably depending on several components interacting predominantly at the medullary level (253, 531). In
general terms, there are two inputs to consider: one a
central feed-forward excitatory input related to central
respiratory drive and another peripheral feedback mechanism related to lung inflation. This is currently a topic of
much interest and debate, and as yet, there is no consensus because of the lack of hard data. It is possible that
respiratory neurons of the medulla make synaptic contact
with vasomotor neurons situated nearby or both groups
of neurons receive synaptic input from a common rhythm
generator either directly or via bulbospinal pathways (22,
40, 125, 504, 532, 587). These respiratory inputs may have
substantial effects on the excitability of SPN in the spinal
cord (170, 399).
At least two afferent influences are likely to be important in a peripheral feedback mechanism. One is
stretch receptor afferent input excited by lung inflation.
During lung inflations, which were dissociated from central respiratory drive in artificially ventilated cats, the
majority of SPN in the third thoracic segment were hyperpolarized (399). However, a minority were depolarized. This might relate to the finding in other studies that
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TAYLOR, JORDAN, AND COOTE
lung inflation decreases sympathetic activity to the heart
yet increases vasoconstrictor activity to peripheral vascular beds (135). A second important peripheral mechanism
is that dependent on alterations in baroreceptor afferent
activity, caused by changes in arterial pulse pressure
consequent on the fluctuations in left ventricular filling
induced by ventilation (177, 251, 253, 627).
The evidence relating to central and peripheral influences on sympathetic activity to the heart and blood
vessels has been comprehensively reviewed (135, 250,
253, 415); therefore, only a brief summary will be provided here. A respiratory-related discharge has been recorded in whole cervical and abdominal sympathetic
nerves in cat and rabbit (6); in postganglionic cardiac and
renal sympathetic nerves in cat (25, 345); in mixed preand postganglionic splanchnic, adrenal, cervical, and lumbar nerves; and in postganglionic cardiac and renal nerves
in the rat (482, 669, 670). Evidence obtained in cats and
dogs supports the idea that the pattern of respiratory
modulation is linked to the function of the sympathetic
neurons (74 –76, 253). Recordings from cardiac sympathetic nerves and sympathetic vasoconstrictor nerves to
skeletal muscle and to skin in the cat indicate that the
inspiratory-related pattern of activity is strong in neurons
that are involved in cardiovascular regulation (25, 28,
241). Furthermore, it appears that the inspiratory influence is important in determining heart rate and vascular
tone. When the central respiratory drive is abolished experimentally (by stimulating the laryngeal nerves), phasic
activity in sympathetic nerve fibers is abolished, and there
is a small decrease in heart rate and a substantial vasodilatation in hindlimb muscles, even though the tonic
activity of sympathetic fibers often increases (22).
Studies in cat and dog show that sympathetic axons
supplying the heart and pulmonary vessels have similar
activity patterns to those supplying other vascular beds
(180, 239, 240, 560, 653, 655). In the case of cardiac
sympathetic innervation, studies show that even those
nerves that probably have different influences on the
heart, like those travelling from the right stellate ganglion
but joining the right vagus nerve to supply pacemaker and
conducting tissue of the heart, have a similar cardiac
rhythm and respiratory periodicity to those nerves in the
left sympathetic outflow, which mainly supply the myocardium and increase the force of contraction (28). This
ongoing activity appears to be largely dependent on a
group of spinally projecting neurons in the ventral medulla oblongata, although spinal sympathetic neurons are
able to generate a small degree of “spontaneous” activity
and forebrain regions may also contribute (127, 148).
The evidence showing the significance of the ventral
medullary region in mammals has been extensively reviewed (109, 148, 403, 404, 588). In summary, the key
region lies close to the ventral surface of the medulla,
extending from the ventral portion of the inferior olive to
Volume 79
the caudal border of the facial nucleus. It is close to the
ventral group of respiratory neurons, which are anatomically associated with the nA wherein also lie cardiac
vagal motoneurons (188, 532). Electrolytic or chemical
lesion of this area abolishes sympathetic vasomotor tone
(151, 419), as does application of inhibitory amino acids
restricted to this region (160, 247, 403, 418, 537). Increases
in sympathetic vasomotor activity are obtained after application of excitatory amino acids to this region (236,
403, 418, 537).
The weight of evidence favors the idea that the ventral medulla oblongata has separate populations of neurons controlling the adrenal medulla, different vascular
beds, cardiac acceleration, cardiac slowing, and ventilation, which in turn are connected to their specific target
sympathetic neurons in the spinal cord (508). This principle of organization, which may be present throughout
the vertebrates, is depicted schematically in Figure 9.
Each of these populations of neurons receives a variety of
common afferent inputs including arterial baroreceptors,
arterial chemoreceptors, trigeminal receptors, and somatosensory receptors (135, 149, 171, 201, 233, 248, 249,
253, 372, 415, 417, 597, 620). It is probable that most, if not
all, these afferents converge at the NTS from where they
diverge to influence the various functionally distinct populations of cardiorespiratory neurons.
Such an organization is observed in the baroreceptor
reflex control of cardioacceleratory sympathetic neurons
and cardiac vagal motoneurons. Thus bilateral lesions in a
circumscribed region of the ventral medulla oblongata
block the vasomotor component of the baroreceptor reflex, leaving the cardiac vagal component intact, whereas
a kynurenic acid lesion of nA blocks the cardiac vagal
component but leaves the vasomotor component (147,
235, 236).
The question of how tonic activity is generated by the
medullary cardiovascular neurons is a topic of current
interest. In vitro studies in which intracellular recordings
are made from ventrally situated neurons in a cranial slice
of the medulla oblongata of rats show that some of these
neurons have pacemaker-like activity (343, 394). However, an in vivo intracellular study of identified ventral
medulla vasomotor neurons was unable to find evidence
of pacemaker-like potentials in these cells (400), thus
indicating that tonic activity was dependent on synaptic
input. Some of these may be respiratory related (253) and
depend on a common cardiorespiratory neural network
(532), or alternatively on an independent network oscillator that can become entrained to respiration (42, 219,
220, 411, 475, 476, 672).
The respiratory modulation of ventral medullary vasomotor neurons, observed in cat, rat, and rabbit, is preserved to a variable degree throughout the multisynaptic
pathway to the peripheral effectors (253). Some sympathetic outflows, like those to the heart, pulmonary vessels,
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
skeletal muscle, vascular bed, and kidney, show stronger
respiratory-related oscillations in activity than those to
other regions (253). A reason for this could be that the
respiratory influence at the brain stem level is reinforced
at the spinal level by direct respiratory-related input to
selected sympathetic neural networks (170, 227, 399, 532,
673).
4. Integrative control
Stimulation of a variety of cardiorespiratory afferents
evokes changes in both respiratory and cardiovascular
outflows and, at least at the peripheral level, these have
been carefully reviewed (256, 415, 440, 529). For example,
in addition to altering heart rate and vascular resistance,
arterial chemoreceptor stimulation augments respiratory
drive. Because the cardiovascular response is modified by
respiration, the overall response evoked by chemoreceptor stimulation is complex. The precise effect on the
cardiovascular system depends on the level of respiratory
drive at the time and on the magnitude of the evoked
increase in pulmonary ventilation. In some animals,
tachycardia is evoked, whereas in others, a biphasic response or a bradycardia is produced. In fact, the primary
response to stimulating the chemoreceptors is a slowing
of the heart, and this is always seen if respiration is
controlled. However, if respiration is allowed to increase,
then this may mask the bradycardia and lead to tachycardia. This has been extremely well documented in recent
reviews (137, 138, 146, 415). Similar interactions can be
seen in the airway effectors. Stimulation of pulmonary C
fibers in apneic animals evokes a constrictor response,
but in animals with central respiratory activity, the same
stimuli evoke an apnea and its concomitant relaxation of
the airways, which fully masks the primary constrictor
response (262). These interactions are not simply experimental curiosities; they do occur under normal physiological circumstances. During breath-hold diving, for instance, apnea is evoked by stimulation of facial receptors
innervated by trigeminal afferents. The breath-hold leads
to a progressive stimulation of the arterial chemoreceptors that would be expected to stimulate breathing. However, the simultaneous stimulation of the facial receptors
blocks this respiratory component of the chemoreceptor
reflex while at the same time augmenting the cardiac
component, to induce a bradycardia (96, 98, 121, 185).
We have described how in mammals there is a tonic
cardioacceleratory and vasomotor activity, which is coupled to the respiratory cycle by central and peripheral
mechanisms. There are so far no studies in vertebrates
other than mammals in which the patterns of sympathetic
cardiac and vasomotor activity have been correlated with
ventilatory control, of either gills or lungs. Although studies on other vertebrates are sparse, it seems likely that
tonic activity in cardiac sympathetic and vasomotor
893
nerves is a common feature. Adrenergic blockade leads to
vasodilatation of most vascular beds in fish (470, 472) and
in amphibians (453). Interestingly, the branchial vessels
of fish constrict after adrenergic blockade because the
sympathetic supply dilates the gill vessels via a b-adrenoreceptor (470). Removal of the influence of sympathetic
nerves either with reserpine or by pithing in frogs leads to
a vasodilatation (455), and a-adrenoreceptor blockade
causes a decrease in heart rate in several amphibians
(455). Furthermore, electrophysiological recordings from
sympathetic nerves supplying blood vessels in frogs reveal ongoing activity that may or may not be grouped
synchronously with the heart beat (630). The main effect
of sympathetic activation on the pulmonary vessels of
reptiles is a vasodilatation, brought about by noradrenergic stimulation of b-adrenoreceptors (455). There are no
studies in other vertebrates linking sympathetic cardiac
and vasomotor activity with neurons controlling ventilation (gill movements or lung inflation). Neither are there
any studies showing the location of presympathetic neurons, apart from one report on the toad (species not
indicated) showing that synchronous bursts of activity
and somatic or visceral afferent evoked responses are
abolished only after removing the caudal part of the medulla (474). A review of the organization of pathways
between the brain and spinal cord in amphibians and
reptiles (619) did not identify respiratory or vasomotor
neurons.
B. Fish
1. Cardiac vagal tone
As described previously, the heart in all fish except
cyclostomes and in all tetrapods is supplied with inhibitory parasympathetic innervation via the vagus nerve. The
inhibitory effect is mediated via muscarinic cholinoreceptors associated with the pacemaker and atrial myocardium (272). The heart in vertebrates typically operates
under a degree of inhibitory vagal tone that varies with
physiological state and environmental conditions. Heart
rate in the dogfish varied directly with PO2; hypoxia induced a reflex bradycardia, a normoxic vagal tone was
released by exposure to moderate hyperoxia, and extreme hyperoxia induced a secondary reflex bradycardia,
possibly resulting from stimulation of venous receptors.
All of these effects were abolished by injection of the
muscarinic cholinergic blocker atropine (607). In addition, cholinergic vagal tone, assessed as the proportional
change in heart rate following atropinization or cardiac
vagotomy, increased with increasing temperature of acclimation (100, 607, 614). These data indicate that variations in the degree of cholinergic vagal tonus on the heart
serve as the predominant mode of nervous cardioregulation in elasmobranchs and that the level of vagal tone on
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TAYLOR, JORDAN, AND COOTE
the heart varies with temperature and oxygen partial pressure. A similar reliance of cardiac vagal tone on inputs
from peripheral receptors has been identified in mammals
(see sect. VIA).
In the teleost fish, the heart receives both a cholinergic vagal supply and an adrenergic sympathetic supply.
Available data on the extent of vagal tone on the teleost
heart give a wide range of values revealing species differences and the effects of different environmental or experimental conditions. Variation in vagal tone affects heart
rate, and a vagal, inhibitory, resting tonus has been demonstrated in some species (e.g., Carassius, Ref. 110). In
the trout, vagal tone on the heart, although higher than in
the dogfish at all temperatures, decreased at higher temperatures. However, the cardioacceleration induced by
epinephrine injection into atropinized fish increased with
temperature (660). In contrast, an inhibitory vagal tonus
was significantly greater in warm-acclimated than in coldacclimated eels, and blocking vagal function with benzetimide reduced a nearly complete temperature compensation (558). These data indicate that adaptation of heart
rate to temperature in the eel was largely mediated by the
parasympathetic nervous system. Further evidence for
temperature-related changes in heart rate being determined centrally was provided by work on Antarctic fishes,
which indicated that the very low resting heart rates in
normoxia at around 0°C are attributable to very high
levels of vagal tone (20, 607). An exception to this general
rule is the sturgeon, which exhibited no change in normoxic heart rate after atropinization (425).
2. Cardiorespiratory synchrony
As mentioned at the outset of this review, the matching of the flow rates of water and blood over the countercurrent at the gills of fish, according to their relative
capacities for oxygen, is essential for effective respiratory
gas exchange (498). The pumping action of the heart
generates a pulsatile flow of blood, which in fish is delivered directly down the ventral aorta to the afferent
branchial vessels. To optimize respiratory gas exchange,
this pulsatile blood flow should probably be synchronized
with the respiratory cycle, which typically consists of a
double pumping action, with a buccal pressure pump
alternating with an opercular or septal suction pump to
maintain a constant but highly pulsatile water flow
throughout the respiratory cycle. The flow is maximal
early in the respiratory cycle and declines during the last
two-thirds of a cycle (283, 286). Thus the supposed functional significance of cardiorespiratory synchrony relates
to the importance of continuously matching relative flow
rates of water and blood over the countercurrent at the
gill lamellae to optimize respiratory gas exchange.
A link between heart beat and ventilation in fish was
first noted in 1895 by Schoenlein (cited in Ref. 548), who
Volume 79
described 1:1 synchrony in Torpedo marmorata. This
observation has been repeated (604). The original observation triggered numerous investigations of the occurrence and mechanisms underlying cardiorespiratory synchrony in fish. Recordings of differential blood pressure
and gill opacity in the dogfish revealed a brief period of
rapid blood flow through the lamellae early in each cardiac cycle (548), and because the electrocardiogram
tended to occur at or near the mouth-opening phase of the
ventilatory cycle, this could result in coincidence of the
periods of maximum flow rate of blood and water during
each cardiac cycle (565, 569). A clear coupling appears to
exist since the heart tends to beat at a particular phase of
the breathing cycle, for example, immediately after the
opening of the mouth. The improvement in gill perfusion
and consequent oxygen transfer resulting from pulsatile
changes in transmural pressure and intralamellar blood
flow (196) may be further improved by synchronization of
the pressure pulses associated with ventilation and perfusion. Cardiorespiratory synchrony may, by a combination of these effects, increase the relative efficiency of
respiratory gas exchange (i.e., maximum exchange for
minimum work).
However, ventilation rate is usually two to three
times faster than heart rate in experimental dogfish so
that if one ventilatory cycle coincides appropriately with
heart beat, then the second or third in a sequence will
occur at a totally inappropriate phase of the cardiac cycle
(565). Hughes (284) explored evidence for phase coupling
between ventilation and heart beat in dogfish released
into a fish box that included a movement restrictor. Sophisticated analysis using event correlograms revealed
that in some cases the heart tended to beat in a particular
phase of the ventilatory cycle for short periods. Use of
polar coordinates revealed some significant coupling at
varied phase angles between the two rhythms, with individual fish varying in both the degree of coupling and the
phase angle, during a period of observation. In the restrained dogfish, ventilation rate was approximately twice
heart rate, and these showed a drifting relationship (604,
610). Experimentally restrained dogfish show no hypoxic
ventilatory response (99) and no evidence of maintained
cardiorespiratory synchrony (284, 610). However, unrestrained fish show reduced normoxic ventilation rates,
synchronous with heart beat, as described previously, and
also exhibit a ventilatory response to hypoxia (431).
The absence of synchrony, or even consistent close
coupling, as opposed to a drifting phase relationship, was
most often attributable to changes in heart rate, which
was more variable than ventilation rate in prepared dogfish (284, 604, 610). Because they lack sympathetic innervation to the heart, this may be reliably interpreted as
variations in cardiac vagal tone. A decrease in vagal tone
on the heart, such as that recorded during exposure to
moderately hyperoxic water, caused heart rate to rise
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
toward ventilation rate (50, 604), suggesting that when
vagal tone was relatively low, a 1:1 synchrony could occur. When cannulated dogfish were allowed to settle in
large tanks of running, aerated seawater at 23°C, they
showed 1:1 synchrony between heartbeat and ventilation
for long periods (604). This relationship was abolished by
atropine, confirming the role of the vagus in the maintenance of synchrony. Whenever the fish was spontaneously active or disturbed, the relationship broke down
due to a reflex bradycardia and acceleration of ventilation
so that the 2:1 relationship between ventilation and heart
rate characteristic of the experimentally restrained animal was reestablished. Thus it is possible that the elusiveness of data supporting the proposed existence of cardiorespiratory synchrony in dogfish was due to experimental
procedures that increase vagal tone on the heart.
The heart in the dogfish operates under a variable
degree of vagal tone (see sect. VIB1). This implies that the
cardiac vagi will show continuous efferent activity. Recordings from the central cut end of a branchial cardiac
branch of the vagus in decerebrate, paralyzed dogfish
revealed high levels of spontaneous efferent activity,
which could be attributed to two types of unit (52, 53,
611). Some units fired sporadically and increased their
firing rate during hypoxia. Injection of capsaicin into the
ventilatory stream of the dogfish, which was accompanied
by a marked bradycardia, powerfully stimulated activity
in these nonbursting units recorded from the central cut
end of the cardiac vagus (318). Consequently, we suggested they may initiate reflex changes in heart rate, as
well as playing a role in the determination of the overall
level of vagal tone on the heart, which as stated previously seems to vary according to oxygen supply. Other,
typically larger units, fired in rhythmical bursts that were
synchronous with ventilatory movements (607). We also
hypothesized that these units, showing respiration-related
activity that was unaffected by hypoxia, may serve to
synchronize heart beat with ventilation (611).
The separation of efferent cardiac vagal activity into
respiration-related and nonrespiration-related units was
discovered to have a basis in the distribution of their
neuron cell bodies in the brain stem. Extracellular recordings from CVPN identified in the hindbrain of decerebrate,
paralyzed dogfish by antidromic stimulation of a
branchial cardiac branch revealed that neurons located in
the DVN were spontaneously active, firing in rhythmical
bursts that contributed to the respiration-related bursts
recorded from the intact nerve (51, 54). Neurons located
ventrolaterally outside the DVN were either spontaneously active, firing regularly or sporadically but never
rhythmically, or were silent. Thus the two types of efferent activity recorded from the cardiac nerve arise from
the separate groups of CVPN, as identified by neuroanatomical studies (607).
Activity recorded from the central cut end of the
895
cardiac vagus, or centrally from CVPN, in the decerebrate,
paralyzed dogfish is likely to be centrally generated. In the
intact fish, stimulation of peripheral receptors will affect
patterns of activity. All of the spontaneously active CVPN
from both divisions and some of the silent CVPN fired in
response to mechanical stimulation of a gill arch, which
implies that they could be entrained to ventilatory movements in the spontaneously breathing fish (607). Support
for this idea was provided by phasic electrical stimulation
of the central cut end of a branchial branch of the vagus
in the decerebrate dogfish (M. J. Young, E. W. Taylor, and
P. J. Butler, unpublished data). This entrained the efferent
bursting units recorded from the central cut end of the
ipsilateral branchial cardiac branch, presumably due to
stimulation of mechanoreceptor afferents (607). The firing rates of the nonbursting units recorded from the
branchial cardiac were also increased, suggesting that
chemoreceptor afferents were being stimulated as well.
Satchell (548) described a cyclical pattern of cardiac inhibition in the dogfish that related to dilatation of the
pharynx at each inspiration. This led to phasic increases
in vagal tone, superimposed on a tonic background of
vagal activity, which he suggested may relate to blood
pressure, although there is no evidence of baroreceptor
inputs in elasmobranch fish (see above).
Consequently, normal breathing movements in the
intact fish may indirectly influence cardiac vagal outflow,
and subsequently heart rate, by stimulating branchial
mechanoreceptors. Thus the typical reflex bradycardia in
response to hypoxia may arise both directly, following
stimulation of peripheral chemoreceptors, and indirectly,
via increased stimulation of ventilatory effort, which by
stimulating branchial mechanoreceptors may increase vagal outflow to the heart. This is reminiscent of, but opposite in kind to, the hypoxic response in the mammal,
where stimulation of lung stretch receptors causes an
increase in heart rate (144).
These data support a previous conclusion that synchrony in the dogfish was reflexly controlled, with mechanoreceptors on the gill arches constituting the afferent
limb and the cardiac vagus the efferent limb of a reflex arc
(548). However, the spontaneous, respiration-related
bursts recorded from the branchial cardiac nerve continued in decerebrate dogfish, after treatment with curare,
which stopped ventilatory movements, suggesting that
they originated in the brain stem. Direct connections
between bursting CVPN and RVM are possible in the
dogfish hindbrain, as both are located in the DVN with an
overlapping rostrocaudal distribution (see sect. IVC). Because the bursts are synchronous, the innervation of
CVPN is likely to be excitatory rather than inhibitory as
described for the mammal, and it is equally possible that
a direct drive from a central pattern generator operates
both on the RVM and the CVPN (607). The interactions
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TAYLOR, JORDAN, AND COOTE
FIG. 12. Diagram of possible afferent and efferent connections of
preganglionic vagal motoneurons in hindbrain of dogfish that control
and coordinate gill ventilation and heart rate. There are several established connections in nervous control of ventilation: 1) respiratory
central pattern generator neurons (CPG) show endogenous bursting
activity that drives respiratory motoneurons (RVM); 2) RVM innervate
intrinsic muscles in gill arches; 3) activity of CPG is modulated by
feedback from mechanoreceptors and possibly chemoreceptors located
on or near gills and innervated by vagal sensory neurons (RVS). Heart
rate is controlled by inhibitory input from vagus nerve that receives
axons from cardiac vagal motoneurons (CVM), which are topographically and functionally separable into 4) a ventrolateral group, some of
which fire continuously and may be responsible for reflex changes in
heart rate (e.g., hypoxic bradycardia) and for varying level of vagal tone
on heart, and 5) a medial group, which burst rhythmically and may cause
heart to beat in phase with ventilation. Other more speculative connections may determine activity in CVM. 6) Collaterals from neighboring
RVM may have an excitatory effect on bursting medial CVM (or release
a tonic inhibiton). 7) CPG may connect directly to medial CVM. 8)
Stimulation of receptors on gill arches may directly modify activity in
medial and some ventrolateral CVM. 9) Stimulation of receptors in
cardiovascular system close to heart, innervated by vagal sensory neurons (CVS), may affect vagal outflow to heart. This diagram is highly
schematic and ignores existence and possible roles of interneurons and
inputs from and to higher centers in central nervous system. ‚, Efferent
termination; Œ, afferent termination; S, sinus venosus; A, atrium; V,
ventricle. [From Taylor (607).]
that may determine the patterns of activity in dogfish
CVPN are summarized in Figure 12.
These data from elasmobranchs suggest that cardiorespiratory synchrony, when present, is due primarily to
central interactions generating respiration-related activity
in CVPN located in the DVN, which are then effective in
determining synchronous heart beating when overall cardiac vagal tone, attributable primarily to activity in CVPN
located outside the DVN, is relatively low in normoxic or
hyperoxic fish. Synchrony will be reinforced in the spontaneously breathing fish by rhythmical stimulation of
branchial mechanoreceptors (as described above).
Confirmation that the heart may beat at a rate determined by bursts of efferent activity in the cardiac vagi was
obtained by peripheral electrical stimulation of these
Volume 79
nerves in the prepared dogfish. Although continuous vagal
stimulation normally slows the heart, it proved possible to
drive the denervated heart at a rate either lower or somewhat higher than its intrinsic rate with brief bursts of
stimuli, delivered down one branchial cardiac vagal
branch. At a rate several beats higher than its intrinsic
one, the heart responded to alternate bursts of electrical
pulses so that it began beating at half the rate of the bursts
(Young et al., unpublished data). Interestingly, similar
results were obtained from a mammal. In the anesthetized
dog, electrical stimulation of the vagus nerve toward the
heart with brief bursts of stimuli, similar to those recorded from efferent cardiac vagal fibers, caused heart
rate to synchronize with the stimulus, beating once for
each vagal stimulus burst over a wide frequency range
(393).
Work on teleosts has stressed the importance of
inputs from peripheral receptors in the genesis of cardiorespiratory synchrony. Efferent nervous activity recorded
from the cardiac branch of the vagus in the tench was
synchronized with the mouth-opening phase of the
breathing cycle (509). It was suggested that this activity
maintains synchrony between heart beat and breathing
movements and that both a hypoxic bradycardia and synchrony were mediated by reflex pathways. Randall and
Smith (515) described the development of an exact synchrony between breathing and heart beat in the trout
during progressive hypoxia. In normoxia, heart rate was
faster than ventilation; hypoxia caused an increase in
ventilation rate and a reflex bradycardia that converged to
produce a 1:1 synchronization of the two rhythms. Both
the bradycardia and synchrony were abolished by atropine. In addition, they were able to demonstrate 1:1 synchronization of hypoxic heart rate with pulsatile forced
ventilation, which was clearly generated by reflex pathways, presumably arising from mechanoreceptors on the
gills, because the spontaneous breathing efforts of the
intubated fish were out of phase with imposed changes in
water velocity and were without effect on heart beat
(515). It is interesting in this regard that heart rate was
observed to rise immediately upon the onset of ram ventilation in the trout, implying a reduction in vagal tone
(607). Because this can be attributed to the effect of
cessation of activity both in the CPG and in the respiratory apparatus, it implies that respiratory activity to some
extent generates cardiac vagal tone. This is the obverse of
the situation in mammals, where cessation of ventilation,
for example during SLN stimulation (see above), increases vagal tone on the heart (329).
Thus we are left with an apparent conflict of evidence
on the mode of generation of cardiorespiratory synchrony. In elasmobranchs it may be centrally generated in
inactive, normoxic, or hyperoxic fish when cardiac vagal
tone is low, whereas in teleosts it appears during hypoxia
and is generated reflexly by increased vagal tone. The
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
differences between these two groups of fish may be real,
and it is of interest that branchial denervation increases
fictive ventilation rate in elasmobranchs but decreases it
in teleosts. However, it is as likely that further experimentation will establish that both central and peripheral
mechanisms are important in each group. When cod were
cannulated and released into large holding tanks of normoxic seawater, they showed periods of 1:1 synchrony
(311, 607). The importance of these observations is that
they measured dorsal aortic blood flow, which was markedly pulsatile in phase with variation in buccal pressure,
confirming a role for cardiorespiratory synchrony in the
generation of concurrent flow patterns of ventilation and
perfusion over the gills. Thus both unrestrained dogfish
and cod can show synchrony, and as our understanding of
the underlying mechanisms increases, it seems likely that
elasmobranchs and teleosts will share common characteristics with respect to the generation and potential physiological advantages of cardiorespiratory synchrony.
What emerges from our present understanding is that
a potent mechanism for the generation of cardiorespiratory synchrony in fish exists in the form of entrainment of
the heart by the bursting units present in recordings of
efferent activity in the cardiac vagi, whether these are
generated by central interactions, reflexly by stimulation
of branchial mechanoreceptors, or most likely by a combination of central and peripheral mechanisms. Entrainment of the heart with the bursts of efferent, respirationrelated activity in the cardiac vagi could explain the 1:1
synchrony observed in “settled” normoxic dogfish and
cod and in hypoxic trout. As discussed above, cardiorespiratory synchrony may serve to optimize the effectiveness and/or efficiency of respiratory gas exchange and
transport in fish.
C. Air-Breathing Fish
Air-breathing fish use their gills for breathing water
and intermittently ventilate an accessory ABO. Usually
the circulation to the ABO is derived postbranchially.
Thus the entire cardiac output is directed toward the gills,
but only a portion perfuses the accessory ABO. Selective
perfusion may depend on sympathetic a-adrenergic control (195), but because there is a reflex increase in perfusion of the ABO associated with each air breath, often
without changes in cardiac output, some local efferent
neural mechanism is likely to be important (307, 513).
Lungfish intermittently breathe air, during which there
can be up to a fourfold increase in lung perfusion and
increased cardiac output associated with each breath.
Control of pulmonary blood flow involves branchial
shunts that are neurally regulated and cholinergic vasoconstriction of the pulmonary artery (205, 310).
897
D. Amphibians
A recent authoritative review considered the influences of phylogeny, ontogeny, and season on central cardiovascular function in amphibians (89). The author presented a detailed synopsis of our current understanding of
the progressive development of vagal, cholinergic and
sympathetic, adrenergic control of the heart in amphibians, based largely on the bullfrog tadpole. Early-stage,
fully aquatic larvae show no evidence of reflex adjustments of heart rate. Cholinergic sensitivity of the cardiac
pacemaker increases during larval development, and a
vagal tone on the heart is first apparent at the onset of
air-breathing. At metamorphosis, there is a sharp decrease in cholinergic sensitivity, and adult bullfrogs show
no resting vagal or adrenergic tone on the heart. However,
heart rate varies during intermittent lung ventilation in
adult anurans (see below), and an exercise tachycardia
results in part from b-adrenergic stimulation and a diving
bradycardia from increased vagal tone. These changes
during ontogeny are summarized in Figure 13, which is
taken from Burggren’s review (89).
Cardiac vagal tone varies widely with temperature in
some amphibians. Injection of atropine into Xenopus
caused a doubling of mean heart rate from 6 to 12 beats/
min at 5°C. At 15°C, the increase was from 9 to 35 beats/
min and at 25°C from 12 to 70 beats/min (609, 612). Vagal
control has a major modulating effect on the temperature
dependency of heart rate with Q10 values between 5 and
15°C of 1.5 and 15–25°C of 1.4 increasing to 2.8 and 2.0,
respectively, after atropinization. However, the situation
is complicated by the presence of a b-adrenergic tone on
the amphibian heart. When this was abolished by injection of propranolol, heart rate decreased. This adrenergic
tone also increased with acclimation temperature. Injection of propranolol plus atropine revealed the true level of
the predominant vagal tone that increased with temperature, but in a linear rather than exponential fashion (612).
Amphibians have evolved control mechanisms that
relate to whether they are more or less committed to lung
breathing. Those that are less committed to air-breathing
or have no lungs, like the lungless salamanders (Plethodontidae), rely solely on sympathetic adrenergic regulation of cutaneous blood flow to control blood gases (195).
In intermittent lung breathers like the frog and toad,
control of pulmonary blood flow is achieved by a strong
vagal cholinergic vasoconstriction of the pulmocutaneous
artery that is extrinsic to the lung (112, 647). Vasoconstriction in the pulmonary circuit reduces pulmonary
blood flow and increases systemic recirculation of oxygen-poor blood from the right atrium, whereas decreased
vagal tone on the pulmonary artery is associated with the
increased pulmonary blood flow observed during lung
ventilation (647). Adrenergic sympathetic vasoconstriction of the cutaneous circulation contributes secondarily
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TAYLOR, JORDAN, AND COOTE
Volume 79
FIG. 13. Ontogeny of cardiac regulation in bullfrog, Rana catesbeiana. Horizontal bar represents an individual’s life
span. Major developmental landmarks as well as appearance, modification, and/or disappearance of cardiac regulatory
mechanisms are shown. Vertical arrows represent a single observation of indicated event. A vertical arrow combined
with a horizontal arrow indicates onset of a continuing process. [From Burggren (89). Copyright 1995 Springer-Verlag.]
to increases in pulmonary blood flow (647). The extent to
which withdrawal of vagal tone versus increased sympathetic tone contributes to the increased heart rate and
pulmonary blood flows associated with lung ventilation is
not resolved, but it may be primarily due to release of
vagal tone, because vagotomy or injection of atropine
reduces or abolishes cardiorespiratory coupling (640).
Although most anuran larvae show unchanging heart
rates during episodic lung ventilation (89), there is a clear
cardiorespiratory coupling in adult anurans, in that intermittent lung ventilation is matched by intermittent increases in pulmonary blood flow, without compromising
systemic blood flow (383, 566). The mechanisms underlying these relationships are unknown. Recent experiments
demonstrated increases in heart rate and pulmonary
blood flow during bouts of fictive breathing in decerebrate, paralyzed and through ventilated toads, indicating
central control of cardiorespiratory interactions (640).
These may in part arise from the overlapping central
topography of CVPN and pulmonary VPN (see sect. IVF).
Alternatively, stimulation of lung stretch receptors during
bouts of breathing may result in release of vagal tone on
the heart and pulmonary artery. Artificial inflation of the
lungs in anesthetized frogs and toads elicited cardiovascular responses similar to those observed in normally
breathing animals, which were abolished by deep anesthesia or injection of atropine (640). However, in conscious Xenopus, denervation of pulmonary stretch recep-
tors did not abolish the increase in heart rate associated
with lung inflation (190).
Some of the cardiac responses to intermittent lung
ventilation may be generated directly by mechanical or
chemical factors (640). In anesthetized toads, artificial
lung inflation caused increased pressure in the left atrium
and an elevated heart rate that was not abolished by
atropine injection, implying that direct mechanical effects
on venous return to the heart (i.e., the Frank-Starling
mechanism) may contribute to cardiorespiratory coupling. An alternative mechanism has been proposed for
anesthetized and unidirectionally ventilated toads, in
which hypoxia and hypercapnia reduced pulmonary
blood flow. Some of this response may be locally mediated, by a direct effect on vascular tone.
The existence of phase coupling of heart beat with
ventilation in amphibians is contentious, although recent
observations (T. Wang, E. W.Taylor, S. Reid, and W. K.
Milsom, unpublished data) indicated that coupling was
present for periods of time in decerebrate, paralyzed, and
unilaterally ventilated toads, implying generation by central interactions.
E. Reptiles
Reptiles are typically periodic breathers, and during
bouts of breathing, the degree of shunting of blood flow to
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
the lung increases. Vasomotor control is important in
diverting blood between the pulmonary and systemic systems (662). In turtles and lizards, the net direction and
magnitude of shunt flow is affected by resistance in the
pulmonary circuit, relative to the systemic circuit, by
active vagal, cholinergic regulation of pulmonary arterial
resistance (268).
Reptiles show clear examples of cardiorespiratory
coupling. In the free diving turtle, Trachemys scripta,
pulmonary blood flow increased more than threefold at
the onset of breathing, during recovery from breath-holds
lasting longer than 5 min (641). Systemic blood flow also
increased during ventilation. These increases were accomplished entirely through changes in heart rate during
ventilation, with stroke volume unchanged. Systemic
blood flow always exceeded pulmonary flow so that a net
right to left cardiac shunt prevailed, regardless of ventilatory state. Nevertheless, because pulmonary flow increased markedly during ventilation, the ratio of pulmonary to systemic flow increased from 0.3 to 0.8. These
cardiovascular changes associated with intermittent lung
ventilation in discontinuous breathers have been referred
to as cardiorespiratory synchrony (e.g., Ref. 641), which is
a different use of the term compared with one-to-one
synchrony in fish (see sect. VIB). In both the turtle, Pseudemys scripta, and the tortoise, Testudo graeca, the onset
of lung ventilation was closely accompanied by a tachycardia (86). As stimulation of pulmonary stretch receptors, arterial chemoreceptors and baroreceptors, or water
receptors was without effect on heart rate, it was concluded that this ventilation tachycardia resulted from central interactions between respiratory and cardiac neurons
in the medulla. Because the breathing tachycardia was
unaffected by b-adrenergic blockade, it seems that all
changes in heart rate were mediated by alterations in
vagal tone. This was borne out by the observation that
efferent vagal activity decreased progressively as heart
rate increased at the onset of ventilation. Injection of
atropine increased heart rate during apnea to the rate
observed during breathing, when vagal tone is low. Heart
rate fell slightly before and markedly after hatching in the
snapping turtle, Chelydra serpentina, indicating the establishment of a vagal tone on the heart, coincident with
the onset of lung breathing (69).
F. Birds
Neural control of the avian heart was reviewed by
Cabot and Cohen (108). The heart in birds is innervated
by branches of the vagus nerve that exert a cholinergic,
tonic inhibitory influence on heart rate so that bilateral
vagotomy causes a marked tachycardia (628). Electrical
stimulation of either vagus elicits a profound bradycardia
or cardiac arrest in birds. However, there is evidence that
899
functional vagal input to the heart may be asymmetric,
with the nerve on one side (often the right) exerting most
of the inhibitory influence over heart rate. Cardiac vagal
tone is reportedly high in many birds, with bilateral vagotomy causing a tripling of heart rate in the pigeon and
duck. Direct evidence of cardiac vagal tone was obtained
from the pigeon, in which the majority of CVPN were
reckoned to be active in the unanesthetized bird (108).
This observation may now be open to question due to the
current debate regarding the central location of CVPN in
birds (see sect. IVG).
The nature of cardiorespiratory interactions in birds
has been elucidated to some extent by study of the responses to submersion of diving species (96, 98, 589).
Both central and peripheral respiratory drives are overridden by submersion of diving birds. Simultaneous stimulation of water receptors in the facial skin, innervated by
the trigeminal (Vth) cranial nerve and in the respiratory
tract, innervated by the glossopharyngeal (IXth) and vagus (Xth) cranial nerves, invokes a reflex apnea. There is
some evidence that the cardiovascular responses to submersion (bradycardia and vasoconstriction in most vascular beds) may arise, in part, directly from stimulation of
water receptors. However, the reflex apnea, because it is
associated with cessation of central respiratory drive and
phasic stimulation of lung receptors, is most likely a
necessary prelude to the full development of these responses. The full development of a diving bradycardia in
the mallard duck, Anas platyrhynchos, was dependent on
the cessation of central respiratory activity and of respiratory movements, and artificial lung inflation during submersion markedly diminished the cardiovascular response (101). Ducks, in common with diving mammals
such as seals, usually enter a dive in the expiratory phase.
Consequently, their CVPN are likely (on the basis of the
mammalian model) to be accessible to afferent inputs,
rather than refractory, as they would be if dives were
executed in the inspiratory phase (96). The progressive
systemic hypoxia, developed during prolonged submersion, then stimulates peripheral chemoreceptors, causing
a profound, vagally mediated bradycardia. Penguins and
whales, however, dive on inspiration and show a relatively slowly developing bradycardia (96).
Clear indications of respiration-related oscillations in
heart rate, similar to the respiratory sinus arrhythmia
described in mammals, were recorded in spontaneously
breathing ducks. The peaks of the accelerations in heart
rate were clipped off when water was poured down an
orally facing tracheal cannula, suggesting that they were
generated by the intact respiratory rhythm and lost during
stimulation of receptors normally responding to submersion, which induce apnea (101). This implies that inhibitory activity in CVPN is modulated by respiratory activity,
and as this modulation reduces vagal tone, it is likely to
resemble the situation described in mammals where ac-
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TAYLOR, JORDAN, AND COOTE
tivity in inspiratory neurons inhibits CVPN (see sect. VIA).
There was a slight increase in heart rate on surfacing from
a period of forced submersion in ducks with denervated
lungs, which was interpreted as evidence for central interactions between inspiratory neurons and vagal cardiomotor neurons (101).
VII. CONCLUDING COMMENTS
As animals our lives are marked by rhythms, and the
rhythmical activities of ventilation and heart beat are
tangible evidence of the life force in each of us. What we
cannot judge by merely feeling or listening are the subtle
processes of generation, regulation, and integration of
these internal rhythms. Present evidence suggests that in
all vertebrates, from jawless fishes to mammals and birds,
innately rhythmic neuronal systems in the brain stem
generate the respiratory rhythm. The central oscillator
driving gill ventilation in fish, initiating lung-breathing
episodes in amphibians, and reptiles and promoting ventilation and suckling in neonatal mammals may reside in
the reticular formation, suggesting that this center of
rhythmicity has a long evolutionary history. Fish use respiratory muscles, innervated by cranial nerves, for gill
ventilation, but can recruit hypaxial feeding muscles, into
forced ventilation. These same muscles are used to gulp
air at the water surface by air-breathing fish and for
buccal and lung ventilation in amphibians. They are innervated by the hypobranchial nerve, comprising occipital and anterior spinal nerves, which is the forerunner of
the hypoglossal nerve, innervating the tongue of advanced
tetrapods. The aspiratory, thoracic pump, characteristic
of mammals and birds, which requires that the CPG in the
brain stem supplies descending fibers to innervate spinal
motoneurons, appears in reptiles but may be forshadowed in some amphibians, whereas some reptiles retain
the use of a buccal pump. Evidence favors the existence
of separate central respiratory rhythm generators for gill/
buccal cavity and ABO/lung ventilation, in air-breathing
fish and amphibians, which may be the evolutionary antecedents of the separate areas generating inspiratory
rhythms in mammals. The relative importance of afferent
input from peripheral mechano- and chemoreceptors in
initiating and sustaining ventilation remains unresolved.
This whole area presents exciting and important opportunities for continued research, because the mechanisms
of control of respiratory rhythms in all vertebrate groups
remain incompletely understood. It is, of course, a prime
example of an area in which an evolutionary approach to
comparative studies is likely to increase our understanding of fundamental mechanisms, as is illustrated by the
recent advances of Feldman and his group working on
neonatal mammals and Remmers and his group on the
frog brain stem (203, 429).
Volume 79
In mammals, the responses to stimulation of arterial
chemoreceptors, baroreceptors, and lung stretch receptors are well characterized. Tracing their afferent projections into the NTS has revealed elements of a topographic
separation of fibers innervating different organs and from
different vagal branches. Slowly adapting pulmonary
stretch receptor afferents (PSRA) project rostral of obex;
rapidly adapting PSRA more caudally, and bronchial and
pulmonary C-fiber afferents project to medial regions of
the NTS around obex, together with arterial chemoreceptor afferents. Afferent projections from the upper respiratory tract converge in the trigeminal nucleus. The detailed topography of these projections is likely to be
fundamental to their functional roles in controlling the
cardiorespiratory system. Similar detail of central projections from reflexogenic sites in the cardiorespiratory system is lacking for other vertebrates, and this is a fertile
area for further study.
Peripheral receptors in fish are less well characterized. Only mechanoreceptors and peripheral chemoreceptors sensitive to oxygen partial pressure, both diffusely
distributed on the gill arches, have been positively identified by nerve transection and recording. There is strong
circumstantial evidence for oxygen content receptors in
the arterial and possibly in the venous system of fish, but
they have not as yet been localized or characterized. Both
peripheral chemoreceptors and pulmonary stretch receptors, which were described as slowly adapting and modulated by CO2, have been identified and characterized in
frogs and toads. Both of these receptor types project to an
area of the hindbrain identified as the NTS. The situation
so well described for mammals seems to have a long
ancestry, extending back to or possibly beyond the evolution of air-breathing.
Central chemoreceptor control of ventilation, although seemingly unimportant in fish, predominates in air
breathers from amphibians, through reptiles, to birds and
mammals. A clue to the origins of a functional role for
central chemoreceptors is provided by ontogenetic studies on amphibians. Fictive ventilation, measured from the
bullfrog brain stem, is insensitive to hypercapnic acidosis
in early larval stages but becomes progressively sensitized
as lung ventilatory bursts begin to predominate over gill
bursts, during metamorphosis. This developing sensitivity
is coincident with recognizable topographical changes in
the nucleus isthmi, an area of the brain stem recognized
as being associated with the integration of chemoreceptor
responses and the generation of episodic breathing in
amphibians and the functional equivalent of the pons in
the mammalian brain stem. It also may relate to the
ventrolateral relocation of VPN at metamorphosis, noted
in the axolotl. Because the ventrolateral medulla is the
site of central chemoreception in mammals, it is an entertaining notion that there may be a direct correlation
between the relocation of VPN and the onset of central
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CARDIORESPIRATORY CONTROL IN VERTEBRATES
chemoreceptor drive in amphibians. Once again, this area
presents itself as ripe for further comparative studies of
the ontogeny and phylogeny of central chemoreceptor
control, to further our understanding of its fundamental
nature and functional roles.
Evidence of the existence of baroreceptor responses
in fish remains controversial, and the evolution of a role
for baroreceptor afferents and for vasomotor control,
exercised via the sympathetic nervous system, in control
of the cardiovascular system, may be associated with the
evolution of air-breathing. The gills of fish are neutrally
buoyant, and ventilation of the gills generates hydrostatic
pressures in their dense respiratory medium that match
blood pressures in the branchial circulation so that the
pressure differential is relatively low. Lungs, in contrast,
are held in air that provides no support and allows the
delicate respiratory surfaces to leak tissue fluid at a rate
determined by their permeability, which of course is high,
and the pressure gradient from blood to air, which consequently must be closely controlled between defined
limits. Possibly because they retain gills, lungfish have
similar, relatively low blood pressures in the respiratory
and systemic circuits. Differences in pressure between
the circuits appear in the amphibians and reptiles but are
complicated by the presence of the variable cardiac shunt
that can create similar pressures with unequal flows in
each circuit. In the mammals, their requirement for a fast
circulation time to satisfy their high metabolic rate results
in very high arterial blood pressures in the systemic circuit, compared with lower vertebrates. However, the
pressures developed in the pulmonary circuit are a little
lower than those measured in fish so that there is a 10-fold
difference between the pressures developed in the systemic and pulmonary circuits. This difference is of course
made possible by their completely separated circulatory
system in which flows must be equal on each side while
pressures are very different. Despite this separation, it is
important that blood pressure is maintained below a maximum to protect against leakage from the lung or lung
damage. Consequently, there are clear roles for baroreceptors monitoring blood pressure and vasomotor control
of peripheral resistance in lung breathers, which are not
present in gill breathers. Control of minimum pressures
are of course equally important, particularly for kidney
and brain function, and no doubt these requirements also
vary between fish and mammals.
Regulation of heart frequency is essentially similar in
mammals, birds, reptiles, amphibians, teleosts, and elasmobranchs. With the exception of the jawless fishes, the
cyclostomes, all vertebrates have an inhibitory muscarinic, cholinergic supply to the heart via the vagus nerve.
A cardioexcitatory b-adrenergic innervation is provided
via sympathetic nerve trunks in all vertebrates other than
the cyclostomes and elasmobranchs. Vagal inhibition of
heart rate seems to predominate in most vertebrates, but
901
cardiac sympathetic excitation becomes more prominent
in endotherms. The heart in most vertebrates operates
under fluctuating levels of inhibitory vagal tone. This
varies with temperature, hypoxia, disturbance, and anesthesia and fluctuates with the breathing cycle, the source
of cardiorespiratory synchrony in fish and respiratory
sinus arrhythmia in mammals. Sympathetic outflow to the
heart and peripheral circulation, responsible for vasomotor tone, as well as outflow to the upper respiratory tract,
also shows fluctuating levels of activity, with respirationrelated components. It is interesting to hypothesize that
respiration-related rhythmicity in the nervous supply to
the cardiovascular system may serve to optimize its functional integrity, as well as respiratory gas exchange and
transport. These possibilities would seem to invite further
functional studies.
The central origins of fluctuations in vagal tone on
the heart, and the consequent variability of heart rate,
together with the origins of fluctuations in vasomotor
tone, in the different vertebrate groups have been a central theme of this review. Central interactions appear to
originate partially as a result of the convergence of sensory projections noted above, and the specific, and sometimes overlapping, distribution of preganglionic and visceral motoneurons in the brain stem and spinal cord. For
example, comparative neuroanatomical studies have revealed that the distribution of VPN between the DVN and
the ventrolateral nA varies between groups. In elasmobranch fish, only 8% of VPN are in the nA, but they are all
CVPN. This ventrolateral group of cells seems to determine the reflex responses of the heart to external stimuli,
such as hypoxia, whereas the CVPN in the DVN show
respiration-related activity, which may generate cardiorespiratory synchrony. This topographical and functional
separation of CVPN has since been found to be reflected
in the brain stem of mammals, in which two functionally
separate populations of CVPN have been identified, only
one of which responds to pulmonary stretch receptor
inputs. The most recent evidence suggests that, as in
dogfish, these are topographically separated between the
nA and DVN, indicating that functional separation of VPN
may be fundamental to their control functions. This clear
link between the primitive elasmobranch fishes and the
mammals is bridged by an intriguing phylogenetic progression. In bony fishes, ;12% of VPN are located ventrolaterally outside the DVN; these are predominantly CVPN,
but some cells supply axons to branchial (respiratory)
branches of the vagus. This proportion rises to 15, 20, and
even 30% in the different classes of amphibians with the
ventrolateral relocation of VPN outside the DVN occurring at metamorphosis, concurrent with the onset of episodic lung breathing and central chemoreceptor responses. This proportion stabilizes at 30 – 40% in
mammals, with up to 80% of CVPN located in the nA,
together with respiratory motoneurons, from which they
902
TAYLOR, JORDAN, AND COOTE
receive inhibitory inputs, generating respiratory sinus arrhythmia, an arrangement established during embryological development. However, this neat progression is confused in the markedly polyphyletic reptiles, with the
turtles and some lizards having high proportions of VPN
in the nA, and other lizards and alligators having ,5% of
VPN in this location. This alternate pattern characterizes
those near ancestors of the dinosaurs, the birds, with ,3%
of VPN found in the nA of the duck. Interestingly though,
a large proportion of the VPN in the nA of the duck are
CVPN. Separate functions have yet to be assigned to the
CVPN in the dual locations in the brain stems of amphibians, reptiles, and birds. Further study of this area seems
likely to be of very great interest and of importance to our
understanding of the development and evolution of the
control systems associated with air-breathing. The amphibians should be a primary target for these studies
because they metamorphose from committed gill breathers to facultative lung breathers, and we already know
that this process is accompanied by topographical
changes in appropriate regions of the CNS. A combination
of neuranatomical, neurophysiological, and functional
studies of the kind previously applied to mammalian species should uncover new and fascinating insights into this
exciting area of study as amphibian ontogeny, at least in
part, recapitulates vertebrate phylogeny.
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