Download 05_chapter_2_doc


Review of literature
Chapter (2)
PHYSIOLOGY
The arterial baroreflex (ABR) plays a critical role in the shortterm regulation of arterial blood pressure (BP) via adjustment of
autonomic neural activity directed to the heart and vasculature.
Notably, reduced ABR sensitivity has been associated with increased
cardiovascular risk, cardiac electrical instability and orthostatic
intolerance.(25)
The central nervous system receives continuous information
about changes in blood pressure through the pressure or
baroreceptors. They play an essential role in blood pressure
regulation. Investigating the physiological characteristics of the
arterial baroreceptors in dogs, the physiologist Koch (1932) made
unexpected observations; baroreceptor stimulation not only led to
cardiovascular regulatory responses, but when prolonged, put the
animal to sleep.(26)
The ancient Greek scholars must have been aware of this
effect of baroreceptors in the carotid artery, as ‘carotis’ means ‘deep
sleep’. The other name of this artery, ‘arteria lethargica’ points to the
calming effect, a massaging or rubbing in the region of the carotid
sinus (which stimulates the baroreceptors) may have.(27)
11

Review of literature
Chapter (2)
Normal Physiology
Arterial baroreceptors are located in the aortic arch and carotid
sinuses, and are formed by small nerve endings present in the
adventitia of these vessels. Baroreceptors are mechanosensors that
are activated by pressure-induced stretch of the vessel wall.
Although the mechanism is unclear, activation of baroreceptors
results in an electrical signal (neural discharge) that is transmitted to
the central nervous system (CNS).(28)
Baroreceptors respond both to blood pressure level and to its
change (i.e., firing increases when blood pressure rises, the more so,
the higher the existing pressure). Thus, there is an increase in the
firing rate in the course of the heart cycle during every systole. The
adaptation to a tonic enhancement is slow, allowing increased firing
rates for hours.(4)
Typically, the firing threshold for humans is around 60 mmHg
in the carotid artery. Firing here is continuous, with the firing rate
being modulated by blood pressure. Baroreceptor afferents from the
carotid sinus travel in the carotid sinus nerve (Hering’s nerve) before
joining the glossopharyngeal nerve.(29)Primarily, in humans, the
afferent fibers from aortic baroreceptors pass centrally via the vagus
nerve (in other species, it might travel as a separate aortic nerve).(30)
Baroreceptor afferents in both the glossopharyngeal and vagus
nerves terminate in the nucleus of the tractus solitarius (NTS) in the
medulla of the brain. In turn, nucleus of the tractus solitarius neurons
project to neurons in the dorsal and caudal lateral parts of the
12

Review of literature
Chapter (2)
medullary reticular area, and activation of nucleus of the tractus
solitarius neurons inhibits bulbospinal neurons in the medullary
reticular area that provide tonic excitatory input to sympathetic
preganglionic neurons that control sympathetic output to the
peripheral circulation. Thus, activation of the baroreflex inhibits
sympathetic outflow from the CNS.(31)
Other
investigators
have
identified
novel
molecular
mechanisms involved in the generation of this neural activity.
Chapleau et al showed that action potential discharge and chemical
autocrine
and
paracrine
factors
are
important
mechanisms
contributing to changes in baroreceptor sensitivity during sustained
increases in arterial pressure. Also, prostacyclin might provide an
autocrine feedback that restores and enhances the responsiveness of
arterial baroreceptor neurons after their inhibition from excessive
neuronal activation.(32)
Because of the importance of the kidneys in long-term control
of arterial pressure, renal sympathetic nerve activity may be an
especially important determinant of the severity of hypertension.
Postganglionic fibers to the kidneys innervate the vasculature,
tubules, and renin containing juxtaglomerular cells.(33)
Increases in renal sympathetic nerve activity decrease sodium
excretion by promoting sodium reabsorption, by decreasing renal
blood flow and glomerular filtration rate, and by increasing renin
release. In fact, increased renal sympathetic nerve activity is
commonly present in subjects with primary hypertension.(33)
13

Review of literature
Chapter (2)
However, although net sympathetic outflow is increased in
primary hypertension, this does not necessarily exclude a sustained
inhibitory influence of the baroreflex on sympathetic activity.
Rather, this may indicate that central excitatory inputs predominate
over the inhibitory effects of the baroreflex on sympathetic activity.
If this notion is correct, however, the baroreflex must be chronically
activated in hypertension.(33)
The Valsalva maneuver (VM) is a standardized procedure
commonly used to evaluate the sympathetic adrenergic component
of baroreflexes.(34) The Valsalva maneuver represents a natural
challenge for the baroreceptors as autonomic reflexes are produced
by voluntary abrupt transient elevations in intrathoracic and
intraabdominal pressures provoked by straining.(25)
The maneuver is carried out by performing a forced expiration
against a closed glottis or obstruction, for instance, a plastic pipe
connected to a manometer. The recommended expiratory force,
measured by the pressure increase in the manometer, amounts to 35–
60 mmHg (most frequently 40 mmHg). The duration of straining
varies from 10 to 40 seconds (typically 15 seconds). The maneuver
is generally performed in the supine position.(35)
The maneuver has four phases. Phase one is a transient rise in
blood pressure (BP) caused by mechanical compression of the aorta
due to increased intrathoracic and intra-abdominal pressure. Phase II
occurs in two parts. In early phase II (phase II_E), blood pressure
falls due to reduced venous return and stroke volume. This results in
14

Review of literature
Chapter (2)
reduced
venous
preload,
evoking
baroreflex
mediated
vasoconstriction which arrests the fall in blood pressure. This rise in
BP is late phase two (II_L). The abrupt drop in intrathoracic and
abdominal pressure at the end of the maneuver results in a second
fall in BP (phase III) that typically lasts 1 to 2 seconds. Venous
return and cardiac output then return to normal while the arterial
vascular bed remains constricted. This results in a transient phase IV
BP overshoot.(36)
Arterial baroreflex function is an important short-term neural
control system aiming at guaranteeing the homeostasis of the
organism.
(37)
The characterization of baroreflex is based on the
assessment of the baroreflex sensitivity derived as the variation of
heart period, approximated as the time interval between two
consecutive R peaks on the ECG (RR), per unit change of systolic
arterial pressure (SAP).(38)
Mechanisms regulating the action of baroreceptors:
Several
mechanisms
have
been
proposed
to
explain
baroreceptors’ action regulation. Among these are:
1. Glioelastic relaxation of the vessel: AP increase causes distention
of the vascular wall and distortion of the baroreceptors nerve
endings. As soon as maximum AP is reached, the glioelastic
relaxation may reduce the tension exerted on the nerve endings,
despite the continuous increase of the vessel’s diameter.(39)
15

Review of literature
Chapter (2)
2. Activation of the Na+-K+ pump: Inhibition of the Na+ pump with
ouabain or K+ solutions prevents or significantly reduces the
postexcitatory depression and the resetting of baroreceptors
following AP increase.(40)
3. Activation of the K+ channels: The administration of specific K+
channels inhibitor reduces the adaptation of baroreceptors without
influencing their maximum potential.(41)
4. Hormones and local chemical agents such as:
a) Norepinephrine, that circulates in the blood or is released by the
endings of the sympathetic neurons of the carotid sinus and the
aortic arch, may either reduce the action of baroreceptors, by
reducing the diameter of the vessel due to vasoconstriction, or
increase their sensitivity, acting directly on the nerve endings.(42)
b) Prostacyclin that seems to directly affect the baroreceptors since
prostacyclin injection in the carotid sinus increase the sensitivity
of the baroreceptors, without changing its diameter, while
indomethacin reduces it. The reduction of baroreceptor sensitivity
that is observed in atherosclerosis and hypertension may be due to
the decreased prostacyclin production that characterizes such
diseases.(43)
c) Nitrogen oxide (NO), which when injected in the carotid sinus
increases
the
baroreceptor
sensitivity
vasodilating action.(44)
16
regardless
of
its

Review of literature
Chapter (2)
d) Oxygen free radicals that seem to act only on atheromatic vessels
since the administration of the anti-oxidant enzymes superoxide
dismoutase and catalase increases the action of baroreceptors in
atheromatic vessels but not in normal vessels.(45)
e) Agents secreted by activated platelets in the carotid sinus area,
that activate the baroreceptors leading to reflex abolishment of
the sympathetic system and hypotension.(46)
The influence of baroreceptors’ stimulation on the heart, the
sympathetic and parasympathetic nervous system:
Baroreceptors may influence heart function in three different ways:
a) Direct modification of the influence of the sympathetic and
parasympathetic system on the myocardium, the sinus node, the
conductive system and the peripheral vasomotor tone,
b) Indirect effect on the afterload (that follows the changes in
vascular resistance) and
c) The preload (following reflex changes in the capacity of the
veins).(47)
Downing and Siegel showed that the depolarization of the
sympathetic nerves of the heart follows the rhythm of the heart beat;
it increases during systole and is depressed during diastole.(47)
Following bilateral dissection of the vagal nerves as well as of
Hering’s nerves, the stimuli become random and cease to correlate
with the arterial pulse wave. A reduction of the sympathetic tone
17

Review of literature
Chapter (2)
was also shown by Ninomiya et al. who determined the relative
benefit from the action of baroreceptors, taking in account the
intensity of the depolarization of the sympathetic nerves of the
myocardium.(48)
The degree of sympathetic activity was reduced to noise levels
with a mean aortic pressure of 167 mmHg. In most of the cases, the
sympathetic depolarization is regulated by stimuli that come from
peripheral changes of the tension. However, during acute systemic
hypoxia, where there is also significant increase of AP, the
inhibitory action of baroreceptors is abolished and the heart
sympathetic depolarization is more intense.(47)
In general, the increased afferent activity of baroreceptors that
is caused by AP increase inhibits the efferent vasomotor action of
the sympathetic system, whilst the reduced afferent activity of
baroreceptors stimulates the efferent vasomotor action of the
sympathetic system. This is achieved through the inhibitory
GABAergic neuronic connection between the posterior and the
anterior segment of the latero- ventricular system of the medulla
oblongata.(49)
The increased activity of baroreceptors also stimulates afferent
fibers, that extend from the nucleus of the solitary bundle to the
dorsal motor nucleus of the vagal nerve and the ambiguous nucleus.
This leads to an intensification of the action of the parasympathetic
system that is conveyed to the heart through the vagal nerve (fig. 3).
18

Review of literature
Chapter (2)
The nerve fibers of the vagal nerve are mainly located in the atria
and the conductive system up to the level of the sinoatrial node.(50)
Furthermore, cholinergic fibers enter the myocardium of the
ventricles
and
it
has
been
proven
that
the
action
of
acetylocholinesterase in the ventricles is significant and that it is
equal to one third of that of the atria.(51)
Thus, stimulation of the vagal nerve inhibits the sinus node
cells and those of the conductive system, causing bradycardia(52) and
reducing the intensity of the atrium systole.(53)
Fig. 3: Central nervous system baroreceptor pathway linking baroreceptor
afferents to sympathetic and parasympathetic outflow. Plus (+)
and minus (-) symbols refer to excitatory synapses and inhibitory
synapses, respectively. (54)
The effect of the stimulation of the parasympathetic in the
function of the ventricles is not clear. Certain researchers failed to
show negative inotropic action in the ventricles
(55)
while others
showed that electrical stimulation of the peripheral endings of the
19

Review of literature
Chapter (2)
vagal nerves reduces the maximum developing pressure of the left
ventricle, proving in this way that the parasympathetic fibers
participate in the regulation of ventricular contractility.(56) This may
be due either to a parasympathetic dependent reduction of the
myocardial response to a given quantity of norepinephrine(57) or to
the fact that the cholinergic activity changes the quantity of
norepinephrine that is secreted for a given level of sympathetic
activity.(58)
The baroreceptor reflex indirectly affects the endocrine
system through the activation of the sympathetic system and more
specifically:
a) Increases the secretory activity of the adrenal glands medulla
although the increase of catecholamines contributes slightly to AP
increament.
b) Activates the renine- angiotensin-aldosterone system leading to
the direct contraction of the smooth muscle fibers of the vessels
as well as Na+ and water retention with an increase of the volume
of the extracellular space, and finally.
c) The increased vasomotor activity causes increase of vasopresin
through a reflex arch from the medulla oblongata to the
hypothalamus. Vasopresin increases the total volume of water in
the body, thus contributing to the restoration of the extracellular
volume, although its contribution is relatively small. (49)
20

Review of literature
Chapter (2)
We conclude that the baroreceptor reflex constitutes a
powerful mechanism of negative retrograde AP regulation that aims
at normalizing its changes. This is achieved directly by a reflex
inhibition of sympathetic activity, activation of the parasympathetic
system and increase of vascular resistance and heart rate and
indirectly by renin and vasopresin secretion that, in turn, influence
AP regulation. These regulating mechanisms are very important for
homeostasis, both in normal as well as in pathological conditions.(59)
Effector Systems of Arterial Baroreceptor Reflexes:
At the core of baroreceptor reflexes are the changes in
sympathetic outflow, directed at the vasculature and the heart, and in
parasympathetic (vagal) outflow, directed at the heart.(60)
Changes in baroreceptor afferent activity evoke reflexive
changes in autonomic activity to the heart and sympathetic activity
to many (but not all) vascular beds. Baroreceptor reflex control of
autonomic activity to the heart provides a rapid means of adjusting
cardiac output to match ABP.(60)
Imposed increases in ABP, detected by arterial baroreceptors,
reflexively decrease heart rate (and cardiac output) by increasing
parasympathetic activity and decreasing sympathetic activity.
Conversely, decreases in ABP elicit the opposite responses. (61)
However, these two directions of responses should not be considered simply symmetrical responses. Rather, the decrease in
cardiac output elicited by increased ABP is more related to increased
21

Review of literature
Chapter (2)
parasympathetic activity, whereas the increase in cardiac output
elicited by decreased ABP is more related to an increase in
sympathetic activity, at least in some species.(61)
Changes in baroreceptor afferent activity markedly alter
sympathetic nerve activity directed toward certain vascular beds,
particularly those impacting total peripheral resistance. Thus,
whereas baroreceptors readily influence sympathetic activity
directed toward renal, mesenteric, splanchnic, and muscle vascular
beds, they have limited impact on the cutaneous or cerebral
circulations. Increased baroreceptor afferent activity can powerfully
inhibit
sympathetic
vasomotor
outflow,
whereas
decreased
baroreceptor afferent activity powerfully excites it.(62)
While these influences of baroreceptor activity on autonomic
outflow directed to the heart and blood vessels might be at the core
of baroreceptor reflex responses, several other baroreceptor evoked
responses also contribute to cardiovascular homeostasis.(63)
One of the most powerful regulators of renin secretion from
the juxtaglomerular cells of the kidney is the sympathetic
innervation of these cells, and this sympathetic innervation is
controlled in large part by baroreceptor input. Thus, decreases in
ABP result in decreased arterial baroreceptor input to brain and in
turn result in increases in sympathetic stimulation of the
juxtaglomerular cells and increased renin secretion.(63)
The resulting generation of angiotensin II produces a variety of
physiological effects, ranging from increased constriction of blood
22

Review of literature
Chapter (2)
vessels to increased sodium reabsorption by the kidneys and
increased fluid intake. Thus, arterial baroreceptors, by influencing
renal renin secretion, have a wide influence on systemic
physiology.(64)
Arterial baroreceptors also influence secretion of posterior
pituitary hormones. Decreased ABP sensed by arterial baroreceptors
increases vasopressin secretion from the posterior pituitary, with
readily understand- able influences on cardiovascular homeostasis:
increased fluid retention by the kidneys and increased arterial
vasoconstriction (fig. 4). Increases in ABP momentarily inhibit the
activity of vasopressin-secreting cells (a response that has been used
as a defining characteristic of magnocellular vasopressin neurons),
but this effect does not appear to be sustained long enough to have
any physiological impact.(65)
Fig. 4: Baroreceptor reflex effector systems. Changes in baroreceptor
afferent activity reflexively influence many outputs of the brain
relevant to cardiovascular regulation. ACTH, adrenocorticotropic
hormone.(54)
23

Review of literature
Chapter (2)
Arterial hypotension also causes secretion of the other major
posterior pituitary hormone, oxytocin. While the physiological
significance of hypotension-evoked oxytocin secretion is not clear,
recent studies indicate that this hormone promotes renin secretion
from the kidney, at least in rats.(66)
In contrast to vasopressin-secreting cells, increases in ABP
appear to have no effect on oxytocin-secreting cells. Changes in
ABP, sensed by arterial baroreceptors, influence drinking behavior.
Decreases in ABP stimulate fluid intake, an effect that appears to be
mediated entirely via arterial baroreceptor-evoked renin secretion
with the resulting increase in blood levels of angiotensin II acting on
the brain to stimulate drinking. In contrast, increases in ABP inhibit
drinking behavior and this effect appears to bemediated by
baroreceptor stimulated neuronal pathways in the brain.(67)
In summary, changes in the afferent activity of arterial
baroreceptors reflexively elicit a variety of autonomic, endocrine,
and behavioral responses included in cardiovascular homeostasis.
While many of these responses occur in opposite fashion to
increases and decreases in ABP, the mechanisms responsible for
these different effects might be quite distinct.(68)
24