REGULATION OF CARDIOVASCULAR FUNCTION

Valvalsa response is divided into four phases:

(1) Phase I: start of strain and sudden rise in arterial pressure (heightened intrathoracic pressure is transmitted directly through the aorta to the arterial tree), HR typically shows a small decrease (2) Phase II: diminished venous return to right heart, cardiac filling becomes inadequate and MAP begins to follow Reflex tachycardia and peripheral vasoconstriction occur limiting the pressure drop MAP may actually rise above control at the end of phase II (3) Phase III: immediately after release, blood pressure drops quickly b/c of the sudden fall in intrathoracic pressure and the HR increases further (4) Phase IV: BP rebounds as a result of rapid surge of venous return and the ejection of the increases SV into the constricted arterial system About 5-6sec after release, BP overshoots inducing marked bradycardia

Renin- Angiotensin pathway

(1) The liver secretes angiotensinogen into the blood (2) Renin released into the blood by the kidney converts angiotensinogen to the decapeptide ANG I (3) Angiotensin-converting enzyme (ACE), primarily present on endothelial cells (particularly lung) cleaves ANG I to the octapeptide ANG II. (4) Aminopeptidases further cleave it to the heptapeptide ANG III, which is somewhat less vasoactive than ANG II.

Blood Pressure Feedback Loop:

(1) baroreceptors in the carotid sinus (CNIX) and aortic arch (CN X) respond to stretch, which occurs in the instance of increased BP (2) The NT released by the baroreceptor afferents onto the nucleus tractus solitarii (NTS) neurons is glutamate (3) Inhibitory interneurons secreting GABA project from the NTS onto the vasomotor area (A1 & C1 areas) in the ventrolateral medulla (4) the C1 area is tonically active to cause vasoconstriction, so inhibitory interneurons projecting from the NTS inhibit the C1 area resulting in vasodilation (5) Excitatory projections also extend from the NTS to the vagal motor neurons in the nucleus ambiguus and dorsal motor nucleus

Contraction of Vascular Smooth Muscle

- An increase in Ca2+ in sk. muscle elicits contraction by interacting with troponin C BUT an increase in Ca2+ in VSMCs elicits contraction by activating calmodulin (CaM) - ↑[Ca 2+ ] i → ↑Ca 2+ -CaM → ↑MLCK activity → ↑phosphorylation of MLC → VSMC contraction. - ↓[cAMP] i → ↓PKA → ↓phosphorylation of MLCK → ↑MLCK activity → ↑phosphorylation of MLC → VSMC contraction. - ↓[cGMP] i → ↓PKG → ↓phosphorylation of MLCK → ↑MLCK activity → ↑phosphorylation of MLC → VSMC contraction. * myosin light-chain kinase (MLCK) * regulatory myosin light chain (MLC)

Feedback control of blood pressure

- An increase in neural output from the brainstem to sympathetic nerves leads to a decrease in blood vessel diameter (arteriolar vasoconstriction) and increases in stroke volume and heart rate, which contribute to a rise in blood pressure. - This in turn causes an increase in baroreceptor activity, which signals the brainstem to reduce the neural output to sympathetic nerves.

Redistribution of blood during orthostasis

- As one stands, the output from the heart for a number of beats exceeds venous return into the thoracic pool - This excess blood ends up filling the vessels in the dependent regions of the body. - The result is a net transfer of blood (by way of the heart) from the intrathoracic vascular compartments to the dependent vessels.

Autoregulation of blood flow

- Autoregulatory behavior takes time to develop and is due to an active process; If perfusion pressure increases abruptly, immediately after the Pressure increases, the pressure flow diagram would look like one for a rigid tube - The vascular arteriolar tone then slowly adjusts itself to produce the characteristic autoregulatory pressure-flow diagram - The concentration of VSMCs that underlies autoregulation is autonomous (entirely local and independent of neural and endocrine mechanisms) - Myogenic and metabolic mechanisms play an important role in the adjustments of sm. Muscle tone during autoregulation EX: the stretch of VSMCs that accompanies the increased perfusion pressure triggers a myogenic contraction that reduces blood flow the increase in Po2 (or decrease in Pco2 , or increase in pH) that accompanies increased perfusion pressure triggers a metabolic vasoconstriction that reduces blood flow

The muscle metaboreflex(exercise pressor reflex)

- During exercise, afferent nerves originating from metabolically active skeletal muscle reflexly activate sympathetic outflow from the medulla, and this contributes to a rise in MAP. - products of metabolism from muscle activate type III/IV afferents in muscle; these go all the way to the medulla.

Temperature Effects on orthostatic pressure

- In a cool environment (arterioles in the lower extremities are constricted) the initial dip in arterial pressure can be small, despite the decrease in stroke volume. The high arteriolar resistance delays the transfer of blood from the thoracic pool to the legs. Resulting in a sympathetic response to the small drop in MAP that may already be in effect before further pooling occurs - In a warm environment (arterioles in the skin are more dilated) orthostasis leads to faster transfer of blood from the thoracic pool to the legs before the sympathetic response can develop; the initial decreases in stroke volume, MAP, and pulse pressure can be large.

Postural Hypotension

- In very sensitive individuals lying on a tilt table, a sudden orthostatic tilt can cause such a large fall in arterial pressure that the individual becomes dizzy or even faints. - Fainting is caused by a transient fall in arterial pressure that causes cerebral perfusion to become inadequate.

causes of vasoconstriction

- Injured arteries and arterioles constrict strongly. - The constriction appears to be due in part to the local liberation of serotonin from platelets that stick to the vessel wall in the injured area. - Injured veins also constrict. - A drop in tissue temperature causes vasoconstriction, and this local response to cold plays a part in temperature regulation

main mechanism for adjusting perfusion of a particular tissue

- Modulation of contractility of vascular sm. Muscle cells (VSMCs) in precapillary vessels

Vasodilators

- NO - Endothelium-Derived Hyperpolarizing Factor - Prostacyclin (Prostaglandin I2) - Endothelins (ETB1) - Thromboxane A 2

Basic pathways involved in the control of heart rate by the vagus nerves

- Neurons in the nucleus of the tractus solitarius (NTS) project to and excite cardiac preganglionic parasympathetic neurons in the nucleus ambiguus. - Some are also located in the dorsal motor nucleus of the vagus; however, this nucleus primarily contains vagal motor neurons that project to the gastrointestinal tract.

Orthostatic hypotension

- Orthostatic hypotension is a sustained reduction of systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of 10 mm Hg within 3 min of standing or head-up tilt to at least 60° on a tilt table. - An individual with orthostatic hypotension may be symptomatic or asymptomatic

PERIPHERALCHEMORECEPTOR REFLEX

- Peripheral arterial chemoreceptors in the carotid and aortic bodies have very high rates of blood flow. - These receptors are primarily activated by a reduction in partial pressure of oxygen (PaO2), but they also respond to an increase in the partial pressure of carbon dioxide (PaCO2) and pH. - Chemoreceptors exert their main effects on respiration; however, their activation also leads to vasoconstriction. - Heart rate changes are variable and depend on various factors, including changes in respiration. - A direct effect of chemoreceptor activation is to increase vagal nerve activity. - Hemorrhage that produces hypotension leads to chemoreceptor stimulation due to decreased blood flow to the chemoreceptors and consequent stagnant anoxia of these organs. - Chemoreceptor discharge may also contribute to the production of Mayer waves. - Under these conditions, hypoxia stimulates the chemoreceptors which raises the blood pressure, which improves the blood flow in the receptor organs and eliminates the stimulus to the chemoreceptors, so that the pressure falls and a new cycle is initiated.

Autoregulation is useful for:

- With an increase in perfusion pressure, autoregulation avoids a waste of perfusion in organs in which flow is already sufficient - With a decrease in perfusion pressure autoregulation maintains capillary flow and capillary pressure - Autoregulation is very important under these conditions for organs very sensitive to ischemia or hypoxia (heart, brain, kidneys) and for organs who filter blood (kidney)

orthostatic response

- The ANS mediates an orthostatic response, that raises the HR and peripheral vascular resistance and thus tends to restore MAP upon standing - Four factors that help reduce blood pooling and maintain right atrial pressure: (1)Nonuniform initial distribution of blood >In humans most of the blood in large veins is located in the central blood volume (vessels near the heart)- not in the head > Majority of the 500 mL of blood that pools in the legs during orthostasis comes from the intrathoracic vascular compartments. (2) nonuniform distensibility of vessels > Assuming a lower distensibility for the leg veins is reasonable because small vessels are far stiffer than larger ones, such as the aorta and vena cava. With the lower relative distensibilit (3) muscle pumps > When a person stands, the muscles of the legs and abdomen tighten. > The presence of valves in the veins, as well as intermittent muscular movement, contributes to the flow of blood upward along the veins > Vessels of the abdominal region remain nearly unaffected by orthostasis because the abdominal viscera are contained in a water-filled jacket that is maintained by the tone of the abdominal muscles (4) autonomic reflexes > Due to decreased venous return, cardiac output tends to fall by ~20% soon after one assumes an erect position. > The fall in cardiac output would be greater in the w/o autonomic reflexes. > Decreased venous return leads to a fall in RAP, which in turn leads to a decrease in stroke volume and thus arterial pressure. > High-pressure baroreceptors sense the decrease in arterial pressure, leading to an increased sympathetic output that raises vascular tone throughout the body and increases heart rate and contractility. constriction of arterioles (raises total peripheral resistance) and increased HR restore the systemic MAP, despite a small decrease in stroke volume > In the dependent regions of the body, the sympathetic response also increases the tone of the veins, decreasing their diameter and their capacity - The extent of the orthostatic response (how much the HR or peripheral vascular resistance increases under the control of the ANS) depends on a variety of factors

autoregulation

- The capacity of tissues to regulate their own blood flow - Most vascular beds have an intrinsic capacity to compensate for moderate changes in perfusion pressure by changes in vascular resistance, so that blood flow remains relatively constant

the hypothalamus and the RVLM

- There are descending tracts to the vasomotor area from the cerebral cortex (particularly the limbic cortex) that relay in the hypothalamus. - These fibers are responsible for the blood pressure rise and tachycardia produced by emotions such as stress, sexual excitement, and anger. - The connections between the hypothalamus and the RVLM are reciprocal, with afferents from the brainstem closing the loop.

factors that regulate VSMCs:

- VSMCs of small arteries and arterioles are under the control of central mechanisms; the ANS and systemic humoral agents - Local regulatory mechanisms can override neural or systemic humoral influences

metabolic theory of autoregulation

- Vasodilator substances tend to accumulate in active tissues, and these "metabolites" also contribute to autoregulation - When blood flow decreases, they accumulate and the vessels dilate; when blood flow increases, they tend to be washed away.

major source of excitatory input to sympathetic nerves controlling the vasculature:

- a group of neurons located near the pial surface of the medulla in the rostral ventrolateral medulla (RVLM) - The axons of RVLM neurons course dorsally and medially and then descend in the lateral column of the spinal cord to the thoracolumbar intermediolateral cell column (IML). - glutamate is the excitatory transmitter they secrete to activate preganglionic sympathetic neurons. - Neurovascular compression of the RVLM has been linked to some cases of essential hypertension in humans - The neurons in the RVLM receive inhibitory input from the baroreceptors via an inhibitory (GABAergic) neuron in the caudal ventrolateral medulla (CVLM). - The nucleus of the tractus solitarius (NTS) is the site of termination of baroreceptor afferent fibers that release glutamate.

Vasomotion

- ability for VSMCs to show spontaneous rhythmic variations in tension leading to periodic changes in vascular resistance and microcirculatory flow - Results from pacemaker currents or from slow waves of depolarization and associated Ca2+ increases in VSMCs - Humoral agents can control VSMCs contraction through increased Ca2+ w/o measurable fluctuations in membrane potential

affects of sympathetic NS on vasculature

- an increase in sympathetic nerve activity to the heart and vasculature, there is usually an associated decrease in the activity of vagal fibers to the heart leading to increased HR and vasoconstriction and rise in BP - a decrease in sympathetic activity causes vasodilation, a fall in blood pressure, and an increase in the storage of blood in the venous reservoirs; There is usually a concomitant decrease in heart rate, but this is mostly due to stimulation of the vagal innervation of the heart.

metabolic changes that produce vasodilation

- decreases in O2 tension and pH - These changes cause relaxation of the arterioles and precapillary sphincters - A rise in temperature exerts a direct vasodilator effect, and the temperature rise in active tissues (due to the heat of metabolism) may contribute to the vasodilation. - K+ is another substance that accumulates locally, and has demonstrated dilator activity secondary to the hyperpolarization of vascular smooth muscle cells. - Lactate may also contribute to the dilation. - In injured tissues, histamine released from damaged cells increases capillary permeability; it is probably responsible for some of the swelling in areas of inflammation. - Adenosine may play a vasodilator role in cardiac muscle but not in skeletal muscle; It also inhibits the release of norepinephrine.

circulating vasoconstrictors:

- endothelins: Endothelial cells produce ETs that bind to ETA receptors on VSMCs causing vasoconstriction On a molar basis, ETs are the most powerful vasoconstrictors - angiotensin II: Part of the renin-angiotensin-aldosterone cascade ANG II is a powerful vasoconstrictor; ANG II is normally NOT present in plasma concentrations high enough to produce systemic vasoconstriction. ANG II plays a major role in cardiovascular control during blood loss, exercise, and similar circumstances that reduce renal blood flow. - aldosterone: - vasopressin: -bradykinin: Bradykinin binds to B2 receptors on endothelial cells, causing release of NO and prostaglandins and thereby vasodilation - norepinephrine: binds to α 1 receptors on VSMCs with high affinity causing vasoconstriction - Arginine vasopressin (AVP): The posterior pituitary releases AVP (aka antidiuretic hormone), binds to VI1A receptors on VSMCs, causing vasoconstriction, but only at concentrations higher than those that are strongly antidiuretic Hemorrhagic shock causes enhanced AVP release and vasoconstriction that contributes to a transient restoration of arterial pressure - Vasoconstriction by these molecules is generally mediated by an increase in intracellular calcium concentration in target smooth muscle cells

VALSALVA MANEUVER

- forced expiration against a closed glottis - occur regularly during coughing, defecation, and heavy lifting. - The blood pressure rises at the onset of straining because the increase in intrathoracic pressure is added to the pressure of the blood in the aorta. - It then falls because the high intrathoracic pressure compresses the veins, decreasing venous return and cardiac output. - The decreases in arterial pressure and pulse pressure inhibit the baroreceptors, causing tachycardia and a rise in peripheral resistance. - When the glottis is opened and the intrathoracic pressure returns to normal, cardiac output is restored but the peripheral vessels are still constricted. - The blood pressure therefore rises above normal, and this stimulates the baroreceptors, causing bradycardia and a drop in pressure to normal levels. - In patients whose sympathetic nervous system is not functional, heart rate changes still occur because the baroreceptors and the vagi are intact. - in patients with autonomic insufficiency, a syndrome in which autonomic function is widely disrupted, the heart rate changes are absent. - For reasons that are still obscure, patients with primary hyperaldosteronism also fail to show the heart rate changes and the blood pressure rise when the intrathoracic pressure returns to normal

principal second messengers responsible for modulating vascular tone:

- intracellular Ca2+ - cAMP - cGMP

myogenic theory of autoregulation

- intrinsic contractile response of smooth muscle to stretch - As the pressure rises, the blood vessels are distended and the vascular smooth muscle fibers that surround the vessels contract. - If it is postulated that the muscle responds to the tension in the vessel wall, this theory could explain the greater degree of contraction at higher pressures; the wall tension is proportional to the distending pressure times the radius of the vessel (law of Laplace), and the maintenance of a given wall tension as the pressure rises would require a decrease in radius.

vasodilators

- local factors: Low tissue PO2, high tissue PCO2, decrease in tissue pH, increase in tissue temperature, accumulation of K, ADP, adenosine - endothelial molecules: Prostacyclin, bradykinin, nitric oxide - Circulating hormones: Epinephrine (liver and skeletal muscle only); substance P; histamine; atrial natriuretic peptide (ANP); VIP - Neural factors: Decreased discharge in sympathetic nerves supplying blood vessels

low pressure baroreceptors

- located in the RA, LA, and entrance to SVC and IVC - decrease in BP causes increase in CO to increase BP

CENTRAL CHEMORECEPTORS: CNS ischemic pressor response

- mean cerebral pressure: ~95 mm Hg - When intracranial pressure is increased, the blood supply to the vasomotor center in the medulla neurons is compromised due to compression, and the local hypoxia and hypercapnia increase their discharge= Increase in sympathetic outflow to heart & resistance vessels - The resultant rise in systemic arterial pressure (Cushing reflex) tends to restore the blood flow to the medulla - The rise in blood pressure causes a reflex decrease in heart rate via the arterial baroreceptors. - This is why bradycardia rather than tachycardia is characteristically seen in patients with increased intracranial pressure.

Mechanisms of local control of VSMCs:

- myogenic activity: intrinsic mode of control of activity in which stretch of the VSMC membrane activates stretch sensitive nonselective cation channels leading to a depolarization that affects pacemaker activity = > contraction of VSMC - local chemical and humoral factors: The most prominent chemical factors are interstitial Po2, PCo2 and pH and local concentrations of K+, lactic acid, ATP, ADP and adenosine. Local regulation of VSMCs is distinct from regulation of systemic BP by peripheral chemoreceptors (which respond to changes in arterial Po2, Pco2 and pH and initiate a complex neural reflex that modulates VSMC activity). In local control, chemical changes in interstitial fluid act DIRECTLY on the VSMCs through intracellular second messenger systems (Ca2+, cAMP, or cGMP) - Changes that accompany increased metabolism (low Po2, high Pco2 and pH) have opposite effects on pulmonary circulation - vasomotion can arise from a local feedback system EX: increased local O2 consumption will cause interstitial Po2 to fall; vasodilation increases O2 delivery to metabolizing cells causing interstitial Po2 to increase again

innervation of the blood vessels

- receives innervation from the sympathetic but not the parasympathetic division of the autonomic nervous system. - Sympathetic noradrenergic fibers terminate on vascular smooth muscle in all parts of the body to mediate vasoconstriction. - vasodilation of skeletal muscle vasculature in response to activation of the sympathetic nervous system is due to the actions of epinephrine released from the adrenal medulla. Activation of β2-adrenoceptors on skeletal muscle blood vessels promotes vasodilation. - the arterioles and the other resistance vessels are most densely innervated - all blood vessels except capillaries and venules contain smooth muscle and receive motor nerve fibers from the sympathetic division of the autonomic nervous system. - The fibers to the resistance vessels regulate tissue blood flow and arterial pressure. - The fibers to the venous capacitance vessels vary the volume of blood "stored" in the veins. - The innervation of most veins is sparse, but the splanchnic veins are well innervated. - Venoconstriction is produced by stimuli that also activate the vasoconstrictor nerves to the arterioles; The resultant decrease in venous capacity increases venous return, shifting blood to the arterial side of the circulation. - When the sympathetic nerves are sectioned (sympathectomy), the blood vessels dilate

innervation of the heart

- receives opposing influences from the sympathetic and parasympathetic divisions of the autonomic nervous system. - Release of norepinephrine from postganglionic sympathetic nerves activates β1-adrenoceptors in the heart, notably on the sinoatrial (SA) node, atrioventricular (AV) node, His-Purkinje conductive tissue, and atrial and ventricular contractile tissue. In response to stimulation of sympathetic nerves, the heart rate (chronotropy), rate of transmission in the cardiac conductive tissue (dromotropy), and the force of ventricular contraction (inotropy) are increased. - release of acetylcholine from postganglionic parasympathetic (vagus) nerves activates muscarinic receptors in the heart, notably on the SA and AV nodes and atrial muscle. - In response to stimulation of the vagus nerve, the heart rate, the rate of transmission through the AV node, and atrial contractility are reduced. - release of acetylcholine from vagal nerve terminals inhibits the release of norepinephrine from sympathetic nerve terminals, so this can enhance the effects of vagal nerve activation on the heart. - There is a moderate amount of tonic discharge in the cardiac sympathetic nerves at rest, but there is considerable tonic vagal discharge (vagal tone) in humans and other large animals

multiunit smooth muscle

- smooth muscle cells that act independently from one another instead of as a unit (i.e. unitary sm. muscle) - vascular smooth muscle acts as multiunit

baroreceptors

- stretch receptors in the walls of the heart and blood vessels. - The carotid sinus and aortic arch receptors monitor the arterial circulation. - increased baroreceptor discharge inhibits the tonic discharge of sympathetic nerves and excites the vagal innervation of the heart. - These neural changes produce vasodilation, venodilation, hypotension, bradycardia, and a decrease in cardiac output. - Baroreceptors are more sensitive to pulsatile pressure than to constant pressure - In chronic hypertension, the baroreceptor reflex mechanism is "reset" to maintain an elevated rather than a normal blood pressure. - The changes in pulse rate and blood pressure that occur in humans on standing up or lying down are due for the most part to baroreceptor reflexes.

Relaxation of Vascular Smooth Muscle

- ↓[Ca 2+ ] i → ↓Ca 2+ -CaM → ↓MLCK activity → ↓phosphorylation of MLC → VSMC relaxation. - ↑[cAMP] i → ↑PKA → ↑phosphorylation of MLCK → ↓MLCK activity → ↓phosphorylation of MLC → VSMC relaxation. - ↑[cGMP] i → ↑PKG → ↑phosphorylation of MLCK → ↓MLCK activity → ↓phosphorylation of MLC → VSMC relaxation.

neurogenic hypertension

A long-term change in blood pressure resulting from loss of baroreceptor reflex control

Vasoconstrictors

Circulating vasoconstrictors: - Norepinephrine - Epinephrine (except in liver & skeletal muscle) - Angiotensin II - Vasopressin - Endothelin - Thromboxane A2 - Increased discharge in sympathetic noradrenergic nerve fibers innervating blood vessels

Traube-Hering waves

fluctuations in blood pressure synchronized with respiration.

principal determinant of capillary resistance

resistance upstream of capillary (Rpre) Fcap is inversely proportional to Rpre

Mayer waves

slow, regular oscillations in arterial pressure that occur at the rate of about one per 20-40 s during hypotension.