Download Special At*tide Some Controversial Cardiovascular Reflexes

Circulation Research
JUNE
VOL. X
1962
NO. 6
An Official Journal of the American Heart Association
Special At*tide
Some Controversial Cardiovascular Reflexes
By Domingo M. Aviado, M.D.
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• In recent years, interest in cardiovascular
reflexes has been steadily growing and has
been marked by the appearance of two review
articles1'- and a monograph.3 Many of the
reported experiments deal with a number of
reflexes which have become controversial in
their nature. The previous issue of Circulation Research contains four articles pertaining
to such reflexes arising from the coronary
vascular bed.
A selected list of controversial cardiovascular reflexes is contained in table 1. These
reflexes have two common features:
A. The organ containing the sensory receptors is also the responding organ; thus the
following names can apply to each of the five
groups of reflexes: cardio-cardiac, inter-coronary, venoarteriolar or systemic vascular,
inter pulmonary, and broncho-bronchomotor.
This particular feature renders the demonstration of the reflex more difficult than if the responding organ did not contain the sensory
receptors. For example, the well-known carotid sinus reflex to the heart is easily demonstrable; an increase in carotid sinus reflex
causes bradycardia. On the other hand, the
Prom tlie Department of Pharmacology, University
of Pennsylvania School of Medicine, Philadelphia,
Pciiiisylviiniii.
Supported by a research grant from the U. S.
Army Medical Research and Development Command,
Department of the Army, under contract no. DA49-193-MD-2093.
Received for publication January 4, 1962.
Circulation Research, Volume X, June 1968
bradycardia or tachycardia elicited by increasing pressure in the chambers of the heart
has been questioned because the distention of
the heart may simply bring about a local
change in cardiac rhythm without necessarily
involving a reflex. The vascular reflexes have
been similarly criticized. The vasoconstrictor
reflexes that have been reported to exist have
been interpreted to mean either a mechanical
effect of embolization or an autoregulating
mechanism for the vascular bed that does not
involve the nerve supply to the vessels.
B. A second feature common to the controversial reflexes listed in table 1 is the common pathway for the afferent and efferent
arms of the reflex. It is technically difficult
to denervate selectively either the sensory or
the motor arm. The vagal reflexes affecting
the heart, coronary vessels, and bronchial
muscles have been criticized because vagotomy has resulted in a change in the control
state of the organ. For the heart, the disappearance of the tachycardia reflex from infusion (Bainbridge reflex) has been explained
not by the loss of a reflex but by the almost
maximal tachycardia following vagotomy.
Two groups of reflexes will be discussed in
some detail because recent work suggests possible approaches to settling the controversies
pertaining to them. The items that are listed
below are some that have been uncovered by
the author and are not intended to be more
than examples.
831
832
AVIADO
TABLE 1
Some Controversial
Organ containing
receptors and
responding reflexly
Heart
Cardiovascular
Afferent and
efferent nerves
Vagus
Sympathetic
Coronary vessels
Systemic vessels
Reflexes
Reflex response
Sensory stimuli
t Eight atrial pressure
(Bainbridge reflex)
t Bight atrial pressure
f Left ventricular pressure
Veratridine
t Eight ventricular pressure
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Vagus (?) or/
and
sympathetic
Ligation
Sympathetic
(?) or somatic
nerves (?)
Distention of descending
aorta
T Mesenteric arterial pressure
Embolization
f Systemic venous pressure
References
Tachycardia
4
Bradycardia
Bradycardia
Bradycardia
Tachycardia
5, 6
7-11
12
13
Vasoeonstriction
None
Coronary vasoeonstriction
Coronary vasodilatation
14
15
16
17
Vasodilatation
18
Vasodilatation
None
Arteriolar constriction
Nono
19
20-22
23
24
Pulmonary vessels
Sympathetic
Embolization
Pulmonary vasoeonstriction
None
25, 26
27-30
Bronchial* muscle
Vagus
Histamine injection into
bronchial artery
Bronchoconstriction
31, 32
* This example does not pertain to the cardiovascular system, but is included because of the possibility that
the events surrounding the bronchomotor reflex may have counterparts in the cardiovascular system.
Cardiac Reflexes
The controversies pertaining to the cardiac
reflexes are based on three concepts which
have evolved consecutively, rather than concurrently.
REFLEXES ELICITED BY RAPID
VENOUS INFUSION
The original report of Bainbridge4 states
that the rapid intravenous injection of defibrinated blood or saline in anesthetized dogs
causes an acceleration of heart rate without
any consistent change in arterial blood pressure or respiration. Bainbridge believed that
the cardiac acceleration was a reflex initiated
by the rise of pressure in the venae cavae and
right atrium because it was eliminated by
cervical vagotomy. This is the Bainbridge
reflex. Subsequent attempts by others to elicit
a similar tachycardia in response to infusion
have given varied results (for references, see
2). Some investigators have succeeded in dogs,
cats, rats, and humans, but just as many have
failed. Even bradycardia without a rise in
carotid blood pressure has been reported.
This is not surprising in view of the diverse
types of infusion used, such as saline, hypertonic glucose, acacia, dextran, plasma albumin, whole plasma, defibrinated blood, and
fresh whole blood. These were introduced in
varying amounts at different rates, so that
there must have been considerable variation
in the pressure changes elicited in the vena
cava and elsewhere. But even when precautions were taken to infuse, at a certain speed,
fixed amounts of fresh mixed venous blood
from the same species, the results were still
variable.3 In the most reactive preparations,
the initial infusion was always followed by a
reflex bradycardia, but repetitions more frequently elicited a tachycardia. This seems to
the reviewer to indicate that inhibitory and
excitatory reflexes are both elicited by intravenous infusion, but the mechanism of the
latter is more rugged. When the former is
not activated by fatigue and trauma, it overshadows the cardio-accelerator reflex.
Circulation Research, Voluvie X, June 19(12
833
CARDIOVASCULAR REFLEXES
REFLEXES ELICITED BY VERATRIDINE
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An intravenous injection of a minimal effective dose of this alkaloid causes the typical
triad of cardiac slowing or arrest, hypotension, and apnea. The effects are entirely reflex in nature, arising from t^e lungs (for the
apnea) and heart (for the circulatory depression). The exact location of the cardiac
receptors is still uncertain, but they definitely
are accessible by means of the coronary arteries only. This was shown by Dawes,1 who
performed careful cannulations of individual
branches of these vessels. In the cat, both
coronaries were cannulated by inserting a
long tube in one aortic branch and maneuvering it inside the aorta until the tip reached
the coronary orifice, where it was tied in place.
Both the right and left coronary branches of
the cat were found to be effective in eliciting
the coronary chemoreflex of veratridine. In
the dog, a similar transaortic cannulation of
both coronaries was not performed by Dawes,
and the individual branches were therefore
cannulated externally. In such preparations,
the reflex could be elicited only from the
vessels supplying the left ventricle.
REFLEXES ELICITED FROM THE
PERFUSED HEART
The evidence has been derived entirely
from experiments in which the pressure stimulus is limited to the heart, which is possible
only by segregating the blood flowing inside
the heart chambers from that in other parts
of the circulatory system. To satisfy this requirement, cross-circulation experiments were
performed in which the blood flowing in the
right side of the heart was isolated.5 The
characteristic effects of elevating the pressure
in the right side of the heart (by increasing
pump inflow to the right atrium) in such
preparations were bradycardia and hypotension. The receptors appeared to be in the
right atrium and not in the ventricle. These
pressoreceptors were connected centrally by
the vagus nerves, since the bradycardia response was eliminated by vagotomy or atropinization but not by sympathetic denervation.
Pressoreceptors in the left side of the heart
Circulation Research, Volume X, June 1902
were first suggested by Daly and Verney in
1927.7 In an innervated heart-lung preparation, they found that increasing pressure in
the left side of the heart while aortic pressure
was kept constant caused cardiac slowing.
The exact source of the vagal reflex was not
disclosed because the rise in blood pressure
was brought about by ligating the root of the
aorta and this affected not only the left ventricle and left auricle but also the pulmonary
and coronary vessels. The belief by the above
authors that the responsible receptors are in
the left ventricle was subsequently confirmed
in a vascularly isolated left heart.7"11 The
bradyeardia response was found to be dependent on an intact vagus, and the aortic depressor nerve was not concerned in it.
The above results from the perfused heart
have forced the generalization that all known
reflexes from the heart, initiated by either increased intracardiac pressure or veratridine,
are cardio-inhibitory in nature. The theory
originally proposed by Jarisch that the same
cardiac receptors are stimulated chemically
and mechanically now appears more probable
than ever (see references cited in 12). Eecently completed experiments have revealed
an exception to this generalization. Tn anesthetized dogs, partial occlusion of the pulmonary artery causes increased pulmonary
blood flow which is dependent on an intact
sympathetic innervation of the heart.13
Neither the vagi nor the medullary centers
participate in the increase in pulmonary blood
flow. The most probable explanation is that
the increase in pulmonary blood flow is due
to reflex cardiac stimulation initiated by a
rise in right ventricular systolic pressure and
mediated entirely by the cardiac sympathetic
nerves.
PRESENT STATUS
The original thesis that there is a single
reflex arising from the heart (Bainbridge reflex) must be modified to include at least three
additional cardiac reflexes: right a trial reflex, left ventricular reflex, and right ventricular reflex. The last is mediated by the
sympathetic nerves and produces cardio-
834
AVIADO
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acceleration, whereas the two others are mediated by the vagus and cause bradycardia.
It is possible that the original Bainbridge reflex consisting of tachycardia induced by
infusion arises from the right ventricular reflex but vagotomy causes a disappearance of
this but not the sympathetic (accelerator) reflex. The task of classification would be aided
if two techniques could be applied to the study
of reflexes: A first approach is to develop
means of denervating the sensory arm of the
vagus without interfering with the vagal efferents. This is not possible by manipulation
of the peripheral vagus nerve and its roots,83
but a direct intramedullary approach is conceivable; the sensory root of the vagus inside
the medulla is distinct from the motor so that
the former can be cauterized by stereotaxic
instruments. A second approach is to attempt
to record action potentials in the sensory
sympathetic fibers from the heart. The identity of the Bainbridge reflex with the right
ventricular reflex might be settled by recording action potentials during infusion and
partial occlusion of the pulmonary artery.
Pulmonary Reflexes
Here the reports of the existence of a reflex vascular response are challenged by other
reports of denial. An analysis of the experiments pertaining to the pulmonary vascular
reflexes will reveal some reasons for the inconsistency in the appearance of these reflexes.
SECONDARY HUMORAL MECHANISM
A careful duplication of experimental conditions may still lead to differences in results,
due perhaps to the participation of a secondary humoral mechanism which antagonizes the
primary reflex response. Such a mechanism
has been described for the bronchial muscles
and consists of the following steps: (a) The
injection of small doses of histamine directly
into the bronchial artery of a dog causes local
bronchoconstriction, followed by a. reflex vagal
bronchoconstriction.31 (b) An increase in
vagal tone causes a reduction in the constant
release of histamine in the bronchial constriction.32 (c) The reduction in the humoral release of histamine will serve to reduce the
intensity of the bronchoconstriction initiated
by the primary vagal reflex response.
Thus, the intensity of a reflex bronchomotor
vagal response may be antagonized by a secondary humoral response. If an analogous
mechanism exists in blood vessels, the appearance of a primary neurogenic response might
mean a weak secondary humoral mechanism;
the failure to detect a primary neurogenic
response might mean an overwhelming secondary humoral response. If this is the explanation for the existing controversies, the
detection of reflexes will have to include analysis of humoral agents. Beck34 has recently
reviewed the possible participation of histamine in mediating peripheral vasodilatation.
References
DIFFERENCES IN EXPERIMENTAL
CONDITIONS
Most of the discrepancies in results can
be explained by differences in animal species
and in the manner of eliciting the reflex and
detecting the response. Two extremes can be
cited : Einbolization with glass beads of one
lobe in an anesthetized dog caused vasoconstriction of an adjoining lobe perfused by a
constant flow.25 On the other hand, in the
rabbit an intravenous injection of fibrin clots
failed to show a reduction in the caliber of
Hie vessels on the surface of the lungs under
direct microscopic vision.30 There has been a
widespread tendency to match the negative
evidence from the latter with the positive
evidence of the former.
1. DAWES, Or. S., AND COMROE, J. II., J R . : Chcnio-
reflexes from the heart and lungs. Pliysiol.
Rev. 34: 167, 1954.
2. AVIADO, E>. M., AND SCHMIDT, C. F.:
Reflexes
from stretch receptors in blood vessels, heart,
and lungs. Pliysiol. Rev. 35: 247, 1955.
3. HEYIIANS, C, AND NEIL, E.: Beflcxogeiiic Areas
of the Cardiovascular System. Boston, Little,
Brown & Co., 1958.
4. BAINBRIDGE, F. A.: Influence of venous filling
upon rate of heart. J. Pliysiol. 50: 65, 1915.
5. AVIADO, D. M., et al.: Respiratory and circulatory reflexes from the perfused heart and the
pulmonary circulation. Am. J. Pliysiol. 165:
261, 1951.
6. BARER, G. B., AND KOTTEGODA, S. R.:
Changes
in heart rate and blood pressure of the cat in
response to increased pressure in the right
side of the heart. J. Pliysiol. 143: 1, 195S.
Circulation Research, Volume X, June 196S
835
CARDIOVASCULAR REFLEXES
of mesenteric arterial receptors in the reflex
regulation of systemic blood pressure. Circulation Research 8: 845, 1960.
7. DALY, T. DE B., AND VERNKY, E. B.: Localiza-
tion of receptors involved in the reflex regulation of the heart rate. J. Physiol. 62: 330,
1927.
22.
cular mid respiratory reflexes from the left
Hiflo of tlio heart. Am. J. Physiol. 196: 720,
1950.
!). DOUTHEIL,
IT., AND KRAMER,
K.:
Uebor
10.
a, venous-arteriolar reflex to transmural pressure and resistance in small and large systemic
vessels. Circulation Research 4: 25, 1956.
24. GASKELL, P., AND BURTON, A. C.: Local postural
vasomotor reflexes arising from the limb veins.
Circulation Research 1: 27, 1953.
SALISBURY, P. E., CROSS, C. E., AND RIEBEN, P.
A.: Be flex effects of left ventricular distontion. Circulation Research 8: 530, 19G0.
25.
Downloaded from http://circres.ahajournals.org/ by guest on May 7, 2017
20.
ulation of heart induced by partial occlusion
of pulmonary artery. Am. J. Physiol. 200:
G47, 19C1.
27.
M'OEACTTERN, C. G., MANNING, G. W., AND HALT.,
28.
G. E.: Sudden occlusion of coronary arteries
following removal of cardiosensory pathways.
A.M.A. Arch. Int. Med. 65: 661, 1940.
15. OPDYKE, I). E., AND SELKURT, E. E.: Study of
alleged intercoronary reflexes following coronary occlusion. Am. Heart J. 36: 73, 1948.
Hi. GUZMAN, S. V., SWENSON, E., AND JONES, M.:
Tutercoronary reflex: Demonstration by coronary angiograpliy. Circulation Research 10:
739, 1962.
19.
SARNOFP, S. J., AND YAMADA, S. I.: Evidence for
reflex control of arterial pressure from abdominal receptors "with special reference to the
pancreas. Circulation Research 7: 325, 1959.
20.
21. BOYER, G-. O., AND SCHER, A. M.:
Cirmlatiov
Urnettrrh. Volume X, Jimr. J1K12
Significance
AGREST, A., LANARI, A., AND RONCORONI, A. J.:
Bmbolia pulmonar unilateral experimental con
torax cerrado. Medicina, Buenos Aires 1: 51,
1953.
29. WILLIAMS, M. H., J R . : Mechanical vs. reflex
effects of diffuse pulmonary embolism in
anesthetized dogs. Circulation Research 4:
325, 1956.
30.
KNISELY, W. H., WALLACE, J. M., MAHALEY, M.
S., JR., AND SATTERAVHITE, W. M., J R . : Evi-
dence, including in vivo observations, suggesting mechanical blockage rather than reflex
vasospasm as the cause of death in pulmonary
einbolization. Am. Heart J. 54: 483, 3957.
31. MARTINEZ, J. L. DE L., CASTRO, R. DE LA M.,
AND AVIADO, D. M.: Local and reflex effects
of bronchial arterial injection of drugs. J.
Pharmacol. & Exper. Therap. 133: 295, 1901.
32. AVIADO, D. M.: Pharmacology of the bronchial
circulation with special reference to a new
hoineostatic mechanism for bronchomotor tone.
Proceedings of the Eirst International Pharmacological Meeting. To be published.
33. SPERTI, L., AND XAJIIN, E.: Effects of selective
intracranial section and stimulation of vagoaccessory roots: I. Afferent fibers from lungs
and aortic area. Expericntin 16: 550, 1960.
ITEYMANS, C, DE SCHAEPDRYVER, A. E., AND DE
VLEESOHHOITWER, G. R.: Abdominal baro- and
cheniosonsitivity in dogs. Circulation Research
8: 347, 1960.
HARA, JL, AND SMITH, J. R.: Experimental ob-
servations on embolism of pulmonary lobar
arteries. J. Thoracic Surg. 18: 536, 1949.
17. WEST, J. W., KOBAYASTII, T., ANDERSON, E. S.,
AND SCTILESINGER, L.: Effects of selective coronary cmbolization on coronary blood flow and
coronary sinus venous blood oxygen saturation
in dogs "with special reference to coronary reflexes. Circulation Research 10: 722, 1962.
IS. GunnziT, C. C, AND MOE, G. K.: Reflex vasodilntation induced by epinephrine. Am. J.
Physiol. 171: 730, 1952.
SINGER, 13., SALTZMAN, P. W., RIVERA-ESTRADA,
C, PICK, R., AND KATZ, L. N.: Heniodynamic
alterations following niiliary pulmonary cmbolization in relation to the pathogenesis of
the consequent diffuse edema. Am. J. Physiol.
191: 437, 1957.
13. TAQUINI, A. C, AND AVIADO, D. M.: Reflex stim-
14.
NIDEN, A. H., AND AVIADO, D. M.: Effects of
pulmonary embolism on the pulmonary circulation with special reference to arteriovenous
shunts in the lung. Circulation Research 4:
67, 1956.
11. Boss, J., Jit., ERATIM, C. J., AND BRAUNWALP,
E.: Influence of intrncardinc baroreceptors on
venous return, systemic vascular volume and
peripheral resistance. J. Clin. Invest. 40: 563,
1901.
12. KRAYER, O.: History of the bonzold-jarisch effect. Arch. exp. Path. n. Pharniakol. 240: 301,
3961.
Splanchnic
23. BADDY, E. J., AND GILBERT, R. P . : Relation of
die
Di fforenzicrung kreislaufrogulieronder Ecflexc
ims dem linken Herzen. Arch. ges. Physiol.
269: 114, 1959.
SELKURT, E. E., AND ROTHE, C. E.:
barorecoptors in the dog. Am. J. Physiol.
199: 335, 1960.
S. AVIADO, D. M., AND SCHMIDT, C. E.: Cardiovas-
34.
BECK,
L., AND BRODY, M. J.:
vasodilatation.
Physiology
of
Angiology 12: 202, 1901.
Special Article: Some Controversial Cardiovascular Reflexes
Domingo M. Aviado
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Circ Res. 1962;10:831-835
doi: 10.1161/01.RES.10.6.831
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Copyright © 1962 American Heart Association, Inc. All rights reserved.
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