Regulation of Cardiovascular Activities Gregory Shen (沈啸), MD Department of Physiology Room 516, Research Building C School of Medicine, Zijingang Campus Email: shenx@zju.edu.cn

Lecture Outline Arterial blood pressure regulation Short-term Long-term Cardiac output regulation

Blood pressure (BP) The major cardiovascular variable being regulated is the systemic arterial BP. BP is gauged by the height it can drive a column of mercury (mmHg) . Systolic pressure, diastolic pressure and pulse pressure. It is the mean arterial pressure (MAP) that is monitored and regulated by the body. When you go to the doctor to get your pressure checked however, those measurements record the arterial systolic and diastolic pressures, which are used as markers to assess MAP. (MAP=1/3 SP + 2/3 DP)

Measure of BP 1. Directly by puncturing the artery

2. Indirectly by a manual sphygmomanometer

How the Test is Performed Rest for 10 minutes before BP is taken. DO NOT take your blood pressure when you are under stress, have had caffeine or used tobacco in the past 30 minutes, or have exercised recently. Sit in a chair with your back supported. Your legs should be uncrossed, and your feet on the floor. Your arm should be supported so that your upper arm is at heart level. Roll up your sleeve so that your arm is bare. wrap the blood pressure cuff snugly around your upper arm. The lower edge of the cuff should be 1 inch (2.5 cm) above the bend of your elbow. The cuff will be inflated quickly. You will feel tightness around your arm. Next, the valve of the cuff is opened slightly, allowing the pressure to slowly fall. As the pressure falls, the reading when the sound of blood pulsing is first heard is recorded. This is the SP. As the air continues to be let out, the sounds will disappear. The point at which the sound stops is recorded. This is the DP.

Gravity produces a hydrostatic pressure “0” height is the level of the heart. When standing, + height from the heart to the foot to the BP of foot (a 180cm tall person is 95 mmHg) − height from the heart to the head to the BP of head (a 180cm tall person is 37 mmHg)

Mean arterial pressure is the principal variable that the cardiovascular system controls Each organ receives almost the same MAP. Each organ controls local blood flow by regulating local arteriole resistance. As long as the MAP is maintained, a change in blood flow in one vascular bed does not affect blood flow in other beds.

Determinants of systemic MAP Blood Volume – the more volume of blood present means heart have to work hard to pump that blood through the Circulatory system (higher BP). Peripheral Resistance – the resistance of the arteries is related to the Overall Compliance Characteristic. When peripheral resistance increases, the overall compliance decreases. Cardiac Output – CO is related to two other factors: heart rate and stroke volume. When the heart rate is fast, CO is increases and when stroke volume is high, CO also increases. Therefore when CO increases, then the arterial pressure will also increase. Mean arterial pressure = Cardiac output x Total peripheral resistance *Mean pulmonary arterial pressure = Cardiac output x Total pulmonary vascular resistance

Neural reflexes mediate the short-term regulation of MAP

Negative feedback loops A detector: a sensor or receptor quantitates the controlled variable and transduces it into an electrical signal. Afferent neural pathways: convey the massage away from the detector to the central nervous system (CNS). A coordinate center: in the CNS compares the signal detected to a setpoint, and generates a message encodes the appropriate response. Efferent neural pathways: convey the message from the coordinating center to the periphery. Effectors: execute the appropriate response and alter the controlled variable.

Negative Feedback Control System Reference (Set-Point) + _ Integrator Feedback (Sensor) Controlled Variable Disturbance Positive or Negative Effector

Baroreceptor reflexes: are stretch receptors or mechanoreceptors. The Detectors Baroreceptor reflexes: are stretch receptors or mechanoreceptors. Chemoreceptors: detect changes in blood PO2, PCO2 and PH.

Baroreceptor Reflexes Arterial baroreceptors Carotid sinus receptor Aortic arch receptor Afferent nerves Cardiovascular center: medulla Efferent nerves: cardiac sympathetic nerve, sympathetic constrictor nerve, vagus nerve Effector: heart & blood vessels

Baroreceptor control of MAP Negative feedback loop: MAP vasodilation and bradycardia MAP vasoconstriction and tachycardia

Baroreceptor neurons function as sensors in the homeostatic maintenance of MAP by constantly monitoring pressure in the aortic arch and carotid sinuses.

Characteristics of baroreceptors: Sensitive to stretching of the vessel walls Proportional firing rate to increased stretching Responding to pressures ranging from 60-180 mmHg Receptors within the aortic arch are less sensitive than the carotid sinus receptors

The action potential frequency in baroreceptor neurons is represented here as being directly proportional to MAP.

The medulla coordinates afferent baroreceptor signals

Reflex pathway

i.e., reduce cardiac output i.e., MAP is above homeostatic set point i.e., reduce cardiac output Baroreceptor neurons deliver MAP information to the medulla oblongata’s cardiovascular control center (CVCC); the CVCC determines autonomic output to the heart.

Typical carotid sinus reflex

Physiological Significance Maintaining relatively constant arterial pressure, reducing the variation in arterial pressure

The principal effectors are the heart, the arteries, the veins and the adrenal medulla Sympathetic input to the Heart (Cardiac nerves) increase both HR and muscle cell contractility Paraympathetic input to the Heart (Vagus nerve) decrease both HR and conduction through AV node, to some extent reduces muscle cell contractility Sympathetic input to blood vessels (Vasoconstrictor response) increase blood vessel tone

The principal effectors are the heart, the arteries, the veins and the adrenal medulla Parasympathetic input to blood vessels (Vasodilator response) release ACh and NO; supply the salivary and gastrointestinal glands, vasodilation of erectile tissue in the genitalia. Adrenal medulla preganglionic sympathetic splanchnic nerves innervate the adrenal medulla by releasing ACh; the chromaffin cells of the adrenal medulla release the hormone epinephrine which have effects on both heart and blood vessels.

Mechanisms of β1 adrenergic receptor agonists In pacemaker cells: If , phase 4 spontaneous depolarization, autorhythmicity  Ica , phase 0 amplitude & velocity , conductivity  In myocardial cells: Ca2+ influx , Ca2+ release , [Ca2+ ]i , contractility 

Mechanisms of M ACh receptor agonists In pacemaker cells: K+ outward , phase 4 spontaneous depolarization , autorhythmicity  Inhibition of Ca2+ channel, phase 0 amplitude & velocity , conductivity 

Effects of adrenergic receptor in blood vessels Which agonist is released Which adrenal receptors that agonist binds to Whether receptor occupancy tends to cause vasoconstriction or vasodilation Which receptor subtypes are present on a particular VSMC

Effects of sympathetic and parasympathetic pathways on the cardiovascular system Effetor response Pathway Neurotransmitter Receptor Tachycarida Sympathetic NE β1 Bradycardia Parasympathetic ACh M cardiac contractility Vasoconstriction α Vasodilation Adrenal medulla Epi β2 Vasodilation (in erectile blood vessels) Ach, NO Vasodilation (in salivary gland)

Asymmetrical innervation of sympathetic nerve

Other mechanisms of neural regulation Somatic and visceral afferents connect with sympathetic preganglionic neurons in the level of spinal cord. Cerebral cortex and hypothalamus and can integrate cardiovascular responses and acts on the medullary cardiovascular center.

Regulation mediated through chemoreceptor Carotid bodies Aortic bodies Combined with respiratory reflex, physiological response to hypoxia is tachycardia.

Long-term control of the circulation Vasoactive substances Nonvasodilator substances

Vasoactive substances Biogenic amines: Epinephrine: an endocrine hormone, produced by adrenal medulla α receptor: vasoconstrction β2 receptor: vasodilation β1 receptor: increase of heart rate and contractility 2. Serotonin (5-hydroxytryptamine [5-HT]): synthesized by serononergic nerves, enterochromaffin cells and adtenal chromaffin cells; binds to 5-HT receptors on VSMCs causing vasoconstriction; involved in local control of circulation and Important to hemostasis with vessel damage

Vasoactive substances Biogenic amines: 3. Histamine: produced by nerve terminals and also released by mast cells in response to tissue injury and inflammation; binds to H2 receptors on VSMCs causing vasodilation. • Peptides: 1. Angiotensin II (ANG II): binds to AT1 receptor on VSMCs causing vasoconstriction.

Renin-angiotensin system

Physiological effects of angiotensin II Constricts resistance vessels Acts upon the adrenal cortex to release aldosterone Stimulates the release of vasopressin Facilitates norepinephrine release from sympathetic nerve endings Stimulates thirst centers within the brain

2. Vasopressin (antidiuretic hormone, ADH): binds to V1a receptor onVSMCs causing vasoconstriction.

3. Endothelin: produced by endothelial cells; binds to ETa receptor onVSMCs causing vasoconstriction; are the most powerful vasoconstrictors. 4. Bradykinin: breakdown product of kininogen ; eliminated by ACE; binds to B2 receptor on endothelial cells, causing releasing of NO and prostaglandin, thereby vasodilation.

5. Atrial natriuretic peptide (ANP): released from atrial myocytes in response to stretch; binds to ANP receptor A on VSMCs causing vasodilation. Produces natriuresis and diuresis Decreases renin release Reduces total peripheral resistance via vasodilatation Decreases heart rate, cardiac output

Prostaglandins • Nitric oxide derivatives of arachidonic acid; produced by many tissues; PGI2 binds to prostanoid IP receptor on VSMCs causing vasodilation • Nitric oxide Nitric oxide synthase (eNOS) produces NO from arginine in endothelial cells; acts on soluble guanylyl cyclase in VSMCs, causing vasodilation.

Renal control of extracellular fluid volume is the primary long-term regulator of MAP Extracellular fluid volume determines plasma volume and affects blood pressure. The sensors of effective circulating volume send signals to the dominant effector organ—the kidney—to change the rate of Na excretion in the urine. (1) Renin-angiotensin-aldosterone (RAS) axis (2) Autonomic nervous system (3) Posterior pituitary release of AVP (4) Atrial myocyte release of ANP

Blood volume The long-term BP regulation occurs through the blood volume.

Cardiac output = Heart rate × Stroke volume Cardiac output affects BP Cardiac output = Heart rate × Stroke volume 1. Modulation by mechanisms intrinsic to the heart (1). Heart rate: [K+] and [Ca2+] affects the SA node pacemaker. (2). Stroke volume (EDV-ESV): EDV: Filling pressure Filling time (HR) Ventricular compliance ESV: EDV (preload) Afterload (Starling’s law) Heart rate (Treppe effect) Contractility

Cardiac output = Heart rate × Stroke volume Cardiac output affects BP Cardiac output = Heart rate × Stroke volume 2. Modulation by mechanisms extrinsic to the heart (1). Baroreceptor: monitor BP per se, and affect both HR and SV (2). Chemoreceptor regulation: monitor metabolites per se, and affect both HR and SV

Other factors affecting BP Pain Acting and sleeping Mood Cushing phenomenon a physiological nervous system response to increased intracranial pressure that results in blood pressure increase, irregular breathing, and bradycardia. It is usually seen in the terminal stages of acute head injury and may indicate imminent brain herniation. It can also be seen after the intravenous administration of epinephrine and similar drugs.

The End.