Blood Vessel Regulation Lecture (2024) PDF

Biochemical Regulation of Blood Vessels Ahmad Hamim Sadewa, MD, PhD  Content I. Introduction II. Catecholamine III. Angiotensin IV. Vasopressin V. Endothelin VI. NO VII. Bradykinin  I. Introduction The aim of the circulatory regulation is to regulate the blood flow of org...

Biochemical Regulation of Blood Vessels Ahmad Hamim Sadewa, MD, PhD  Content I. Introduction II. Catecholamine III. Angiotensin IV. Vasopressin V. Endothelin VI. NO VII. Bradykinin  I. Introduction The aim of the circulatory regulation is to regulate the blood flow of organs to fit their metabolic requirement in different condition. The regulation of blood flow are of three major types: Humoral Neural Local (autoregulation)  Humoral regulation Various hormones and chemicals Start at a low pace but have long-lasting influences on cardiovascular function. Hormones are classified into two groups Vasoconstrictors Vasodilators Vasoconstrictors and Vasodilators Vasoconstrictors Catecholamines Angiotensin II Vasopressin Endothelin Vasodilators Endothelial-derived Relaxing Factor (EDRF/ Nitric Oxide) Bradykinin  II. Catecholamines Catecholamines: an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. Adrenaline, Noradrenaline and Dopamine are physiologically active molecules known as catecholamines. Synthesis of Catecholamines Tyrosine hydroxylase (TH) Aromatic acid decarboxylase (AADC) Dopamine β-hydroxylase (DBH) Phenylethanolamine-N-methyl transferase (PNMT) L-dihydroxyphenylalanine (L-DOPA) Adrenal medulla produces adrenaline and noradrenaline. Renal proximal tubule (RPT) cells do not express TH or DBH; Dopamine, synthesized from L-DOPA taken up from the glomerular filtrate and the circulation, is not converted to norepinephrine. Cell in substantia nigra and jejunum also produce dopamine  Adrenaline and Noradrenaline The adrenal medulla secrete both epinephrine (80%) and norepinephrine (20%) carried by blood flow to everywhere in the body. only a little norepinephrine comes form the endings of the adrenergic fibers.  Adrenergic receptors α1 receptor on vessels Vasoconstriction Epinephrine β1 receptor on heart Positive effect β2 receptor on vessels Vasodilation Norepinephrine (skeletal muscle and liver)  Effect On heart in vitro (contractility and automaticity). both increase the force and rate of contraction of the isolated heart. mediated by β1 receptors. Effect 1. On peripheral resistance. Norepinephrine produces vasoconstriction in most if not all organs via α1 receptors epinephrine dilates the blood vessels in skeletal muscle and the liver via β2 receptors. overbalances the vasoconstriction produced by epinephrine elsewhere, and the total peripheral resistance drops.  Effect 2. On heart in vivo (heart rate and cardiac output). When norepinephrine is infused introvenously the systolic and diastolic blood pressure rise. The hypertension stimulates the carotid and aortic baroreceptors, producing reflex bradycardia that override the direct cardioacceleratory effect of norepinephrine. Consequently, the heart rate and cardiac out falls.  Effect On heart in vivo Epinephrine causes a widening of the pulse pressure baroreceptor stimulation is insufficient to obscure the direct effect of the hormone on the heart, cardiac rate and output increase.  Dopamine Dopamine is an endogenous catecholamine serves as neurotransmitter and precursor of adrenalin’s synthesis When given as an exogenous drug, dopamine activates a variety of receptors in dose dependent manner. Regulates cardiac, vascular and endocrine function. There are at least five subtypes of dopamine receptors, D1, D2, D3, D4, and D5. At a global level, D1 receptors have widespread expression throughout the brain. Furthermore, D1-2 receptor subtypes are found at 10–100 times the levels of the D3-5 subtypes Dopamine also binds to adrenergic alpha and beta-1 receptors (but not beta-2)  Dopamine In low level : increase blood flow in renal and splanchnic region; increase sodium (Na) excretion In intermediate level : stimulates adrenergic beta receptor in heart and vessels, increase myocardial contractility and heart rate. In high dose : stimulate adrenergic alpha receptor in the systemic and pulmonary circulation, resulting in progressive vasoconstriction.  III. Angiotensin II very potent vasoconstrictor formed in the plasma through a chain reaction. The chain is triggered by a substance, renin, released form kidneys. Renin is released from kidneys in response to renal ischemia, which may be due to a fall in blood pressure. Effect of Angiotensin II powerful constrictor release aldosterone from the adrenal cortex acts on the brain to create the sensation of thirst. inhibit the baroreceotor reflex and increase the release of norepinephrine from the sympathetic postganglionic fiber. Effect of Angiotensin II Effect of Angiotensin II  IV. Vasopressin Also called antidiuretic hormone (ADH), formed in the hypothalamus (mainly) secreted through the posterior pituitary gland. even more powerful than angiotensin as a vasoconstrictor. The high concentration of vasopressin during hemorrhage can raise the arterial pressure as much as 40 to 60 mmHg.  Vasopressin The amount of endogenous vasopressin in the circulation of normal individuals does not normally affect blood pressure. it does not increase blood pressure when small doses are injected in vivo Acts on the brain to cause a decrease in cardiac output. Acts on the tubular cells of kidney  V. Endothelin Endothelin (ET-1), discovered on 1988, is a 21 amino acid peptide that is produced by the vascular endothelium from a 39 amino acid precursor, big ET-1, through the actions of an endothelin converting enzyme (ECE) found on the endothelial cell. ET-1 formation and release are stimulated by angiotensin II, antidiuretic hormone (ADH), thrombin, cytokines, reactive oxygen species, and shearing forces acting on the vascular endothelium. ET-1 release is inhibited by prostacyclin and atrial natriuretic peptide as well as by nitric oxide.  Effect of Endothelin Systemic administration of ET-1 causes transient vasodilation (initial endothelial ETB activation) and hypotension, followed by prolong vasoconstriction and hypertension (smooth muscle ETA and ETB activation). Direct effects of ET-1 on the heart are modified by baroreceptor reflexes in response to changes in arterial pressure following systemic administration of ET-1. ET-1 stimulates aldosterone secretion, decreases renal blood flow and glomerular filtration rate, and releases atrial natriuretic peptide (ANP). Endothelin Synthesis VI. Endothelium–Derived Relaxing Factor (Nitric Oxide/NO)  Synthesis of Nitric Oxide Nitric oxide is synthesized from L-arginine This reaction is catalyzed by nitric oxide synthase, a 1,294 aa enzyme COO- COO- COO- + O2 +H3N C H NADPH NAD+ +H3N C H +H3N C H + NO (CH2)3 (CH2)3 (CH2)3 NOS NOS NH NH NH + C NH2+ C N OH C H H2N H2N O NH2 Arginine N-w-Hydroxyarginine Citrulline  Activation of NOS Glutamate neurotransmitter binds to N-methyl N-aspartat (NMDA) receptors Ca++ channels open causing Ca influx into cell Activation of calmodulin, which activates NOS Mechanism for start of synthesis dependent on body system NO synthesis takes place in endothelial cells, lung cells, and neuronal cells  Types of NOS NOS I (neuronal NOS) – Central and peripheral neuronal cells – Ca+2 dependent, used for neuronal communication NOS II (inducible NOS) – Most nucleated cells, particularly macrophages – Independent of intracellular Ca+2 – Inducible in presence of inflammatory cytokines NOS III (endothelial NOS) – Vascular endothelial cells – Ca+2 dependent – Vascular regulation  The role of Nitric Oxide Nitric Oxide in the human body has many uses which are best summarized under five categories. – NO in the nervous system – NO in the circulatory system – NO in the muscular system – NO in the immune system – NO in the digestive system  Effect of NO Relax the vascular smooth muscle directly Mediate vascular dilator effect of some hormones and transmitters (Ach, bradykinin, substance P) Inhibit the tonic excitation of some neurons in the vasomotor center. Inhibit the norepinephrine release from the sympathetic postganglionic fiber. NO diffuses into adjacent smooth muscle cells , activates its effector enzyme, GC which GTP into the second messenger cGMP, which activates PKG, leading to modulation of myosin light chain kinase (MLCK) and smooth muscle relaxation. PKG also modulates the activity of potassium channels (IK), thereby increasing cell membrane hyperpolarization and causing relaxation.  VII. Bradykinin potent endothelium-dependent vasodilator, leading to a drop in blood pressure. causes contraction of non-vascular smooth muscle in the bronchus and gut increases vascular permeability during injury which causes pain Bradykinin also causes natriuresis contributing to the drop in blood pressure. A short peptide (9 amino acids), precursor is High Molecular Weight Kininogen cleaved by kallikrein Degraded by angiotensin converting enzyme (mainly), aminopeptidase P and carboxypeptidase N Relationship between bradykinin, angiotensin and NO 36