Block 2 (HSFP) NEURAL CONTROL OF THE HEART & BLOOD VESSELS Dr. M

The above effects are intrinsic and are related to increased free Ca2+ in the myocardial cell. Increased end diastolic volume, when it occurs, also contributes to the increased contractile force.

1. A rapid increase in heart rate causes a progressive increase in contractile force, or a positive "treppe". This is associated with increased free calcium levels in the cells. 2. An abnormal delay between beats (as with a skipped beat) causes an increase in force of contraction of the beat after the missed one (rest potentiation). 3. An extra systole is often followed by a pause, then a stronger-than-normal contraction. The extra systole produces a weak contraction, which is followed by a stronger- than-normal contraction. This is referred to as post- extrasystolic potentiation.

Effects of Hormones & Physiological State on Contractility Certain hormones and drugs also may have an effect on contractile properties of the myocardium. The following cause an increase in contractility:

1. Catecholamines (norepinephrine and epinephrine) released from the adrenal medulla. 2. Angiotensin II produced from plasma peptides by the enzyme renin (via precursors). 3. Thyroxine. 4. Insulin and glucagon from the pancreas. 5. Drugs such as the cardiac glycoside, digitalis. A decrease in contractility may result from 1. Severe hypoxia (moderate hypoxia may enhance contractility via reflexes). 2. Hypercapnea (elevated blood carbon dioxide levels; direct effect is to depress, reflex effect is to stimulate). 3. Increased hydrogen ion concentration (decreased pH).

Cardiovascular stress using a test called the Valsalva Maneuver. This test simulates the type of stress associated with such activities as lifting, coughing, playing a trumpet and straining while passing stool (e.g., constipation).

1. Closing the mouth and nose and forcibly expiring (up to a pressure of 40 mm Hg), 2. Increases pressures in the pharynx and airways and compresses the great veins. -----Venous return and cardiac output are decreased and arterial pressure falls----

Non-neural Control of SV Starling's Law

Adjustments to changing preload Definition: the volume of blood at the end of diastole that sets the length of cardiac muscle fibers prior to the onset of systole). Preload is the end diastolic volume (EDV).

The Intrathoracic Respiratory Pump:

Another aid to venous return is the "abdomino-thoracic pump". The great veins (vena cavae) and atria are exposed to intrathoracic pressure, which is normally negative and becomes more so during inspiration. Furthermore, during inspiration intrabdominal pressure rises due to descent of the diaphragm, which compresses the viscera. As a consequence, inspiration causes a decrease of the pressure outside of the atria and great veins but increases pressure in the abdominal cavity, which causes compression of abdominal veins. These two factors enhance venous return. Expiration has the opposite effect, impeding venous return.

Interventions that lower or raise blood pressure invoke a reflex response that is intended to stabilize blood pressure and heart rate. It is the most important mechanism for controlling blood pressure on a day-to-day, minute-to-minute basis. Using the components described, the system is able to correct perturbations in the system, through negative feedback. For example, if a subject is changed from the supine to the upright posture, cardiac output falls, due to venous pooling (gravity). Arterial blood pressure falls, reducing stretch in the aorta and carotid sinus (CS). As a result, action potential frequency in the CS nerve falls, the vasomotor center receives less input, the pressor portion of the center is activated, and the depressor center is suppressed. Concomitantly, the Vagal center in the medulla is also suppressed.

As a result, heart rate and contractility increase (causing cardiac output to return toward normal), arterioles constrict (causing increased TPR), and veins constrict (causing increased preload). These changes tend to return arterial blood pressure to normal levels. A rise in blood pressure elicits opposite responses that return blood pressure to control levels. The vasomotor center also participates in other complex responses. For instance, immersing the face in cold water elicits bradycardia (the diving reflex). The baroreceptor "set point" is also variable. During sleep, arterial blood pressure pressure falls (10 to 20 mmHg in some cases), yet the vasomotor center makes no attempt to correct for it. Hypertensive individuals who experience a hypotensive episode have a "normal" response, i.e., rate, contractility, and TPR increase to return blood pressure to the elevated level.

Modulation of Contractility by Neurotransmitters Contractile force can be affected by extrinsic cardiac factors as well as by intrinsic ones. If one considers only the influence of preload on cardiac function, it might be concluded that a single ventricular function or Starling curve exists for a given heart, and changes in stroke volume or cardiac output can be accomplished only by changing preload. In the denervated heart isolated from blood-borne hormonal influences, this is indeed the case. In the isolated or intact heart exposed to inotropic agents, however, the heart responds by shifting to a different ventricular function curve, that is, contractility changes.

Contractility is defined as a change in contractile force that is independent of the initial fiber length. Thus, increased contractility can be defined as an increase in work output (SV or CO, and rate of force development) with no increase in preload (preload constant). The figure depicts an increase in contractility (the ventricular function curve is shifted up and to the left) in response to an infusion of norepinephrine (NE), a positive inotropic agent. The ventricular function curve is shifted down (depressed) and to the right by agents that depress contractility such as acetylcholine (ACh). Myocardial hypoxia will also shift the ventricular function curve down and to the right.

The standard deviation (measure of range) of the time intervals between the heart beats (interbeat intervals,

ECG RR intervals) is a measure of respiratory sinus arrhythmia, the only named arrhythmia that is normal.

Acetylcholine binds to muscarinic-3 receptors coupled to the Gq protein which on (vascular) endothelial cells activates nitric oxide synthase, increases NO (aka endothelium-derived relaxation factor,

EDRF), which diffuses to local vascular smooth muscle cells, activates guanidylate cyclase, increases cGMP, activates PKG, causing vasodilation, mimicking the effects of PKA.

Control of Heart Rate

Heart rate is normally controlled by the Autonomic Nervous System (ANS), and under normal resting conditions the heart beats at about 72/min. During sleep this falls by 10 to 20 beats and during exercise may increase by 2 to 3 times. Nervous input to the heart is received from both sympathetic and parasympathetic divisions of the ANS. Parasympathetic output to the SA node occurs with high frequency bursts (e.g., associated with respiratory feedback) compared to the sympathetic low frequency bursts (e.g., associated with baroreceptor feedback). This creates variations in the ECG R-R intervals known as respiratory sinus arrhythmia. Parasympathetic modulation of the heart rate predominates at rest, meaning that the resting heart rate is slower than it would be if the heart would be denervated; e.g., in a heart transplant patient.

Respiratory chemoreceptor and blood pressure

Hypoxia and hypercapnia cause blood pressure to increase. These receptors also are sensitive to flow, so that even if blood gas levels are normal, hypotension (which results in low blood flow) may result in increased ventilation. Cerebral chemoreceptors also sense O2 and CO2 levels in brain tissue. They are especially sensitive to CO2 Increased CO2 (mainly) increases blood pressure by increasing heart rate and TPR. This provides a backup emergency system during extreme hypoventilation.

Pulmonary

Increased pulmonary artery pressure results in increased efferent activity to the effectors associated with blood pressure regulation. Afferent input from these receptors is to the medulla.

The Bainbridge reflex is an increase in heart rate due to an increase in the blood volume. Increased blood volume is detected by stretch receptors located in both atria at the venoatrial junctions. A scientist by the name of Francis Arthur Bainbridge reported this reflex in 1915 when he was experimenting on dogs. Bainbridge found that infusing blood or saline into the animal increased heart rate. This phenomenon occurred even if arterial blood pressure did not increase. He further observed that heart rate increased when venous pressure rose high enough to distend the right atrium, but denervation of the vagi to the heart eliminated these effects. The Bainbridge reflex and the baroreceptor reflex act antagonistically to control heart rate. The baroreceptor reflex acts to decrease heart rate when blood pressure rises. When blood volume is increased, the Bainbridge reflex is dominant; when blood volume is decreased, the baroreceptor reflex is dominant. As venous return increases, the pressure in the superior and inferior vena cavae increase. This results in an increase in the pressure of the right atrium, which stimulates the atrial stretch receptors. These receptors in turn signal the medullary control centers to increase sympathetic stimulation of the heart, leading to increased heart rate, a.k.a. tachucardia.

Increasing the heart rate serves to decrease the pressure in the superior and inferior vena cavae by drawing more blood out of the right atrium. This results in a decrease in atrial pressure, which serves to bring in more blood from the vena cavae, resulting in a decrease in the venous pressure of the great veins. This continues until right atrial blood pressure returns to normal levels, upon which the heart rate decreases to its original level. In the right atrium, the stretch receptors occur at the junction of the vena cavae. In the left atrium, the junction is at the pulmonary veins. Increasing stretch of the receptors stimulates both an increase in heart rate and a decrease in vasopressin (a.k.a. anti-diuretic hormone) secretion from posterior pituitary. This decrease in vasopressin secretion results in an increase in the volume of urine excreted, serving to lower blood pressure. In addition, stretching of atrial receptors increases secretion of atrial natriuretic peptide (ANP), which promotes increased water and sodium excretion through the urine.

Modulation of heart

Other factors can also influence heart rate. Changes in plasma ion concentration (especially K+), circulating hormone levels (thyroxine, epinephrine and norepinephrine), body temperature (fever), and drugs. Cerebral cortical influences such as stress, anxiety, and fear. Increased venous volume that causes an increase in right atrial volume and wall stretch Inspiration causes an increase in heart rate, while the heart rate slows during expiration. Stimulation of chemoreceptors associated with respiratory control by hypoxia, hypercapnia, or acidosis also cause an increase in both heart rate and In addition, regular cardiac arrhythmias are frequently associated with respiration.

Parasympathetic Cholinergic Control: Genitalia & Glands

Other fibers release ACh and cause NO-mediated vasodilation from endothelial cells but these are parasympathetic and are distributed to the blood vessels of genitalia and some glands. No parasympathetic fibers are involved in the normal regulation of blood pressure via resistance changes, only sympathetic.

INSPIRATION (Paradoxical Pulse) Increases Lung Outflow Resistance, Pulmonary Veins Pooling of Blood in Lungs Decreases Left Atrial, Ventricular Pressures Decreases Systolic Blood Pressure < 10 Torr

PULSUS PARADOXUS Decreased Systolic Pressure > 10 Torr High Airways Resistance Mitral Valve Disease High LVEDP, High LAP

Autonomic Modulation of Heart Rate By Breathing

Paced Breathing, Carotid & Eyeball Pressure and the Diving Reflex Increase Parasympathetic Tone and Heart Rate Variability, Short Latency & Fast Breakdown of Acetylcholine at Muscarinic Receptors Contributes to Respiratory Sinus Arrhythmia Breath-Holding (Apnea, Hypoxemia) Increases Sympathetic Tone and Decreases Heart Rate Variability, Long Latency & Slow Breakdown of Norepinephrine at Adrenergic Receptors Contributes to Respiratory Sinus Arrhythmia

Orthostatic Hypotension

Prolonged, quiet standing leads to dependent edema and eventually to fainting (orthostatic hypotension) if venous pooling occurs and persists. There are valves in veins of the limbs that direct the flow of blood toward the heart and help prevent peripheral pooling and edema. This is effected by the "skeletal muscle pump" which compresses veins during skeletal muscle contraction. As a consequence of the extravascular compression, and the presence of venous valves, blood is forced toward the heart and, when the muscle relaxes, venous pressure in that segment of vein is very low, which permits filling and lowers capillary pressure. The next skeletal muscle contraction repeats the process, moving blood toward the heart and keeping distal vein pressure low. In the absence of muscle contraction, blood tends to pool, venous pressure rises, and consequently capillary absorption is reduced. This may lead to increased interstitial fluid volumes and swelling.

Neural control of artery pressure

Short-term regulation is a function of the cardiovascular system. Since MAP=CO x TPR, effective regulation of MAP involves the ability to monitor the pressure (sensors). Long-term regulation of blood pressure involves body fluid balance, which is a function of the kidneys.

Strong stimulation of a peripheral sensory nerve fiber can elicit a pressor response. This is probably due to stimulation of pain fibers.

Stimulation of 'deep pain' fibers from viscera and large blood vessels may elicit a very strong depressor response and actually cause fainting (Vasovagal or Neurocardiogenic Syncope). On the other hand, cutaneous pain and chronic pain usually increase BP.

Chronotropic, Inotropic, Dromotropic, Lusitropic

Stimulation of sympathetic fibers increases the rate of depolarization of pacemaker cells (by increasing permeability to sodium, potassium, and calcium) and also increases conduction velocity of action potentials through the AV node. There is no effect on the resting membrane potential. By increasing the speed of relaxation (decreasing the relaxation time), Ca2+ influx for the next beat (stroke) is larger, thereby increasing contractility.

A loose organization of neurons in the ventrolateral medulla comprise the Vasomotor Center (VMC). It is composed of pressor (P) and depressor (D) areas, which communicate with one another and with sympathetic neurons in the spinal cord. This center receives inputs from sensors previously described and, in addition, input from the cortex and hypothalamus. Stimulation of the pressor area causes an increase in rate, force of contraction and dP/dt of the heart, and constriction of vascular smooth muscle in arterioles (increased TPR) and veins (increased venomotor tone).

Stimulation of the depressor area has the opposite effect. These effects are mediated via sympathetic fibers. Parasympathetic fibers do not project from the vasomotor center, but arise directly from the Vagal centers. Fibers also reach the VMC from the hypothalamus. These fibers are involved in temperature regulation (efferents to skin blood vessels) and those from the cortex to the VMC influence vascular changes in response to anger (rate and pressure changes), embarrassment (blushing), and so forth. It is clear that the response to various interventions involves complex circuitry.

Effects of Vagal Stimulation

Stimulation of the right Vagus has a pronounced effect on heart rate, causing it to slow. Strong Vagal stimulation may stop the heart (Vagal arrest). Stimulation of the left Vagus slows or blocks conduction in the AV node. The effect of parasympathetic stimulation is described as a negative chronotropic effect.

Sympathetic efferent fibers originate in segments C5 to T7 of the cord, and short preganglionic fibers enter paravertebral ganglia, where they synapse and send long postganglionic fibers to the heart.

Stimulation of these cardiac sympathetic efferent fibers on the right side has a predominant effect on rate (a positive chronotropic effect), while stimulation of fibers on the left influences contractility, or contractile force (a positive inotropic effect). As with parasympathetic fibers, there is considerable overlap.

Stretch of the blood vessel wall from high circulating blood volume decreases vasopressin (antidiuretic hormone, ADH) release (which results in increased urine output).

Stretch also increases releases of atrial and brain natriuretic peptide (ANP, BNP) which promotes Na+ secretion in the kidney, and decreases renin and aldosterone release. Water accompanies salt loss, so sodium and water loss decreases blood volume and blood pressure. Activation of ventricular, pericardial, and coronary sinus stretch receptors causes a centrally-mediated reflex fall in blood pressure.

Sympathetic Control of Arterioles in Skeletal Muscles

Sympathetic vasodilator fibers release norepinephrine which acts on beta-adrenergic receptors in skeletal muscle vascular beds (arterioles). They are activated in anticipation of exercise and in response to threatening situations (arousal reaction). Activation opens vascular shunts, which permits an increase in muscle blood flow prior to the onset of exercise.

Effects of Sympathetic Stimulation on Contractility In addition to having a pronounced effect on heart rate (chronotropism), as discussed previously, postganglionic fibers of the Autonomic Nervous System also affect the force developed during contraction (contractility or inotropism). Sympathetic innervation has been described previously with respect to changes in heart rate. In addition to supplying nodal tissue, postganglionic fibers also terminate on muscle fibers of the atria and ventricles. Stimulation of these sympathetic postganglionic fibers elicits a positive inotropic effect that has the following results: 1. Shifts the ventricular function curve to the left (increased contractility in the figure). 2. Increases peak systolic pressure. 3. Increases the rate of pressure development (dP/dt). 4. Increases the rate of relaxation (-dP/dt). 5. Shortens the duration of systole.

The increased rate of contraction and relaxation is an index of the rate of cross-bridge cycling on the actin-myosin, or the Vmax of cardiac muscle. The mechanism of action is linked to stimulation of a G-protein (Gs), cAMP and adenyl cyclase, which causes an increase in Ca2+ influx during the plateau phase of the action potential. The effect on the atria is to increase the force of contraction, resulting in an enhanced "atrial kick." Sympathetic stimulation also shortens the duration of diastole (the heart rate increases), which in turn shortens ventricular filling time. Therefore, the shortening of the period of systole tends to partially compensate for the reduced period of diastole and maintains adequate filling even during periods of increased sympathetic activity. Increased heart rate and contractility work through Beta-1 adrenergic receptors, via the Gs mechanism, increasing cAMP. Effects of Vagal Stimulation on Contractility Stimulation of the Vagus nerve causes a negative inotropic effect that includes 1. A shift of the ventricular function curve to the right. 2. Reduced peak systolic pressure. 3. Reduced rate of contraction and relaxation (dP/dt and -dP/dt). These effects appear to be mediated through cGMP, which speeds the breakdown of cAMP. Acetylcholine, the parasympathetic neurotransmitter, also inhibits the release of norepinephrine from sympathetic fibers.

Heart rate variability (HRV) is a measure of the variations in heart rate. It is usually calculated by analyzing a time series of beat-to-beat intervals from the ECG or of beat-to-beat intervals derived from an arterial pressure tracing. Various measures of heart rate variability have been proposed, which can roughly be subdivided into time domain, frequency domain and non-linear measures. HRV is regarded as an indicator of the activity of autonomic regulation of circulatory function, although controversy exists over whether this is an accurate metric for analyzing cardiovascular autonomic control. Alterations (mostly reductions) in HRV have been reported to be associated with various pathologic conditions such as hypertension, hemorrhagic shock, and septic shock. It also has some utility as a modest predictor of mortality after an acute myocardial infarction. A simple example of a time domain measure is the calculation of the standard deviation of beat-to-beat intervals. In other words the time intervals between heart beats can be statistically analyzed to obtain information about the autonomic nervous system. Other time domain measures include root mean square of the differences between heart beats (rMSSD), NN50 or the number of normal to normal complexes that fall within 50 milliseconds, and pNN50 or the percentage of total number beats that fall with 50 milliseconds. A common frequency domain method is the application of the discrete Fourier transform also known as the Fast Fourier transform, to the beat-to-beat interval time series. This provides an estimation of the amount of variation at specific frequencies. Several frequency bands of interest have been defined in humans. High Frequency band (HF) between 0.15 and 0.4 Hz. HF is driven by respiration and appears to derive mainly from vagal activity or the parasympathetic nervous system. Low Frequency band (LF) between 0.04 and 0.15 Hz. LF derives from both parasympathetic and sympathetic activity and has been hypothesized to reflect the delay in the baroreceptor loop. Very Low Frequency band (VLF) band between 0.0033 and 0.04 Hz. The origin of VLF is not well known, but it had been attributed to thermal regulation of the body's internal systems. Ultra Low Frequency (ULF) band between 0 and 0.0033 Hz.

The major background of ULF is day/night variation and therefore is only expressed in 24-hour recordings. The most commonly used non-linear method of analyzing heart rate variability is the Poincaré Plot. The Poincaré Plot fits heart rate data points to an ellipse that is fitted to two intersecting lines. SD1 and SD2, or the standard deviations of the data points have also been applied in the context of Poincaré analysis.

The normal resting adult heart rate is 60-100. The maximum heart rate is considered to be 200-220 bpm. The minimum heart rate is 40-50 bpm.

The range of normal resting heart rate results from a predominance of vagal influences (parasympathetic tone). The ANS influences each organ differently; e.g., sympathetic tone predominates in the bronchopulmonary, gastrointestinal and urogenital tracts and systemic circulation when a person is at rest.

Main effect of sympathetic stimulation on large systemic arteries and arterioles is to increase arterial pressure by the mechanism of vasoconstriction by norepinephrine working on alpha-1 and alpha-2 adrenergic receptors. The sympathetic effect on veins is to increase venous pressure and venous return. The main difference between an arteriole and a venule is that constricting the arteriole decreases forward blood flow and constricting a venule increases forward blood flow. The sympathetic influences on arterioles are also used to redistribute the blood flow.

The sympathetic influences on the heart increase heart rate and stroke volume by norepinephrine working on beta-1 adrenergic receptors.

The mammalian diving reflex optimizes respiration to stay underwater for a long time. It is exhibited strongly in aquatic mammals (seals, otters, dolphins, etc.), but exists in a weaker version in other mammals, humans included. Diving birds, such as penguins, have a similar diving reflex. Every animal's diving reflex is triggered specifically by cold water contacting the face -- water that is warmer than 21 °C (70 °F) won't cause the reflex, and neither will submersion of body parts other than the face. Also, the reflex is always exhibited more dramatically, and thus can grant longer survival, in young people and animals. Upon initiation of the reflex, three changes happen to the body, in this order: Bradycardia is the first response to submersion. Immediately upon facial contact with cold water, the human heart rate slows down ten to twenty-five percent. In the seal, the changes are even more dramatic, going from about 125 beats per minute to as low as 10 on an extended dive. Slowing the heart rate lessens the need for bloodstream oxygen, leaving more to be used by other organs. Next, peripheral vasoconstriction sets in. When under high pressure induced by deep diving, capillaries in the extremities start closing off, stopping blood circulation to those areas. Note that vasoconstriction usually applies to artrioles, but in this case is completely an effect of the capillaries. Toes and fingers close off first, then hands and feet, and ultimately arms and legs stop allowing blood circulation, leaving more blood for use by the heart and brain. Human musculature accounts for only 12% of the body's total oxygen storage, and our muscles tend to cramp up during this phase. Aquatic mammals have as much as 25 to 30% of their oxygen storage in muscle, and thus they can keep working long after capillary blood supply is stopped. Finally, and most interesting, is the blood shift that occurs only during very deep dives. When this happens, organ and circulatory walls allow plasma water to pass freely throughout the thoracic cavity, so its pressure stays constant and the organs aren't crushed. In this stage, the lung alveoli fill up with blood plasma, which is reabsorbed when the animal leaves the pressurized environment. This stage of the diving reflex does not occur in humans. Thus, both a conscious and an unconscious person can survive longer without oxygen under water than in a comparable situation on dry land. Children tend to survive longer than adults when deprived of oxygen underwater.

When the face is submerged, receptors that are sensitive to water within the nasal cavity and other areas of the face supplied by cranial nerve V (trigeminal) relay the information to the brain and then innervate cranial nerve X, which is part of the autonomic nervous system. This causes bradycardia and peripheral vasoconstriction of blood vessels. Blood is removed from the limbs and all organs but the heart and the brain, creating a heart-brain circuit and allowing the mammal to conserve oxygen. In humans, the mammalian diving reflex is not induced when limbs are introduced to cold water. Mild bradycardia is caused by the subject holding his breath without submerging the face within water. When breathing with face submerged this causes a diving reflex which increases proportionally to decreasing water temperature. However the greatest bradycardia effect is induced when the subject is holding breath with face submerged.

Maneuvers that decrease or inhibit respiration decrease the standard deviation (range) of the ECG RR intervals, thereby decreasing respiratory sinus

arrhythmia (RSA, aka heart rate variability, HRV). Decreased RSA or HRV is an indicator of increased sympathetic influences on the heart rate.

The Cushing reflex consists of an increase in heart rate, vasoconstriction and blood pressure, (often followed by reflex bradycardia mediated by the baroreceptor reflex)

because of ischemia sensed at the medullary vasomotor centers when ICP approaches values near the patient's diastolic arterial blood pressure. This reflex is an indicator of decreased cerebral blood flow and cerebral ischemia.

Sensors

include stretch receptors (or baroreceptors or pressoreceptors). These receptors are located in the wall of the carotid sinus and the aortic arch and structurally resemble Pacinian corpuscles in the skin. The receptors are modified nerve endings, and distortion (stretch) increases the frequency of action potentials in their fibers, while decreased stretch does the opposite. Afferent signals from the carotid sinus are carried in the carotid sinus nerve (nerve of Hering), a branch of cranial nerve IX, or from the aortic arch in the left aortic nerve, which travels in the Vagus. Action potential frequency is fairly linear over a pressure range of from 100 to 180 mmHg. The frequency increases during systole and falls during diastole. The stretch receptors monitor both the absolute pressure and the rate of change of pressure. The receptors are of the slowly adapting type; if increased pressure is sustained, the receptor firing also will be sustained.

Effectors

include vascular smooth muscle in arteries, arterioles, and veins. The latter two vessels are by far the most important in blood pressure regulation. The other effector is the heart, which receives both sympathetic and parasympathetic input. The effect of ANS input has been covered previously (rate, contractility and rate of pressure development).

Cushing (ischemic brain) reflex: Increased intracranial pressure (ICP) Decreased PO2 (hypoxia),

increased PCO2 (hypercapnea) stimulate massive sympathetic discharge.

Maneuvers that increase or stimulate respiration increase the standard deviation (range)

of the ECG RR intervals, thereby increasing respiratory sinus arrhythmia (RSA, aka heart rate variability, HRV) Increased HRV or RSA is an indicator of increased parasympathetic (vagal) influences on the heart rate.

Vagal stimulation has 2 distinct effects on the heart. It causes the slope of the

pacemaker potential to decrease and also causes hyperpolarization of pacemaker cells.

Cardiac:

these receptors are located in the right and left atria. They sense intravascular volume (atrial stretch or preload). Afferent fibers go to the cortex and the hypothalamus.