Polypeptide Autocoids PDF

POLYPEPTIDE AUTACOIDS  INCLUDES: Renin angiotensin system Kinins Vasopressin Natriuretic peptides Endothelins Vasoactive intestinal peptide Substance P  Neurotensin Calcitonin gene related peptide Adrenomedullin Neuropeptide Y Urotensin ...

POLYPEPTIDE AUTACOIDS  INCLUDES: Renin angiotensin system Kinins Vasopressin Natriuretic peptides Endothelins Vasoactive intestinal peptide Substance P  Neurotensin Calcitonin gene related peptide Adrenomedullin Neuropeptide Y Urotensin  KININS Kinins are potent vasodilator peptides formed by the action of enzymes, kallikreins or kininogenases on precursors, kininogens. Kallikreins are found in plasma and several tissues-kidneys, pancreas, intestine, sweat glands, salivary glands. They are formed from plasma prekallikreins by action of trypsin,  Kininogens are present in plasma, lymph, interstitial fluid. Two forms exist in plasma- LMW (80-85%) and HMW (15-20%). Thought LMW kininogens cross capillary walls to become substrate for tissue kallikreins, and HMW kininogens is confined to plasma. Three kinins known: bradykinin released by plasma kallikrein, lysilbradykinin (kallidin) by tissue kallikrein, methionyllysylbradykinin by pepsin and pepsin-like enzymes.  All three are found in plasma and urine. Bradykinin is the predominant kinin in plasma, lysylbradykinin the major urinary form.  KININ ACTIONS 1. Marked vasodilation in vascular beds in the heart, kidney, intestine, skeletal muscle and liver. 10 times as potent as histamine. Action direct or through NO, PGE2, PGI2. 2. Vasoconstriction on veins, directly or via PGF2α 3. Contraction of most visceral smooth muscle 4. Can at times directly release catcholamines from adrenal medulla  5. Causes a transient decrease in BP 6. Increased capillary permeability and tissue edema. Lymph flow increases. 7. Endocrine and exocrine glands- role in gland secretions unknown. May act as modulators of local blood flow. May regulate tone of salivary and pancreatic ducts, and help regulate intestinal motility.  Infuences transepithelial transport of water, electrolytes, glucose and Amino acids and may regulate their transport in GIT and Kidneys. 8. Role in Inflammation – production of kinins increased in inflammation. Kinins and kallikreins cause redness, local heat, swelling and pain. 9. Sensory nerve ends- They are potent pain producers, eliciting pain by stimulating n. ends  In skin and viscera. MECHANISM OF ACTION Receptors B1, B2a, B2b Bradykinin has the highest affinity for B2, followed by lysylbradykinin, then meth-lys-bradykinin. Only B2 on venous SM are most sensitive to lysylbradykinin. B2 are widespread, linked to G- proteins,  Multiple signal events are stimulated including calcium mobilization, chloride transport, formation of NO, activation of phospholipase C, phospholipase A2 and adenylyl cyclase B1 very limited in spread and participates in inflammation and is thought responsible for kinin long term effects as collagen synthesis  METABOLISM Rapidly metabolized with half lives of ~ 15 secs. By kininases. Kininase I is synthesized in the liver. Kininase II in plasma and vascular endothelial cells. Is identical to ACE.  DRUGS AFFECTING THE KALLIKREIN-KININ SYTEM 1. Peptide analogues blocking receptors only available for research. 2. Icatibant – B2 receptor antagonist, orally active and selective. Duration of action over 1 hour. Used for studies. 3. Aprotinin inhibits kinin synthesis by inhibiting kallikrein 4. NSAIDS inhibit kinin actions mediated by PGs.  5. ACE inhibitors enhance kinin actions by inhibiting its breakdown  VASOPRESSIN(ADH) Plays vital role in regulating blood pressure, by reabsorbing water in the kidneys Has vasoconstrictor action in low doses. Effects increased in cardiac disease, Idiopathic orthostatic hypotension and at higher doses. V1a mediate vasoconstrictor action, V1b release of ACTH, and V2 antidiuretic action. 1. Vasotocin is a specific V1 vasoconstrictor agonist.  2. dDAVP and dVDAVP are V2 anti- diuretic analogues 3. Conivaptan – V1a and V2 antagonist, approved for treatment of hyponatremia.  NATRIURETIC PEPTIDES The family made of ; Atrial natriuretic peptide (ANP) Brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) All same in structure but have different actions. ANP – A 28 amino acid peptide with a single disulfide bridge that forms a 17-residue ring.  Derived from a common precursor, pre-pro- ANP. Synthesized primarily in atrial cells, but small amounts in ventricular cells. Also synthesized by neurons in CNS and peripheral nervous system and lungs. The most important factor increasing release is atrial stretch via mechanosensitive ion channels. Also increased by volume expansion, head-out water immersion, changing from standing to supine and exercise.  Also adrenergic stimulation, endothelins, glucocorticoids and vasopressin. Also increases in heart failure, primary aldosteronism, chronic renal failure and in SIADHS. ACTIONS Increases sodium excretion and urine flow Inhibits secretion of renin, aldosterone and vasopressin.  Decreases arterial BP via vasodilation Reduces sympathetic tone to peripheral vasculature Antagonizes vasoconstrictor action of angiotensin II and other vasoconstrictors. BNP has 26 and 32 AAs. Is produced mainly in the heart. Release is volume related. Causes natriuretic, diuretic and hypotensive actions, but circulates at lower levels.  CNP has 22 Aas, is mainly in the CNS but is also present in endothelial cells, kidneys and intestines. Has less natriuretic and diuretic action, but is a potent vasodilator. MEHANISM OF ACTION Via surface receptors ANPa, ANPb, ANPc. ANPa main ligands are ANP and BNP ANPb main ligand is CNP  The natriuretic peptides have short half lives in the circulation. Are metabolized in the lungs, kidneys and liver by a neutral endopeptidase. They are removed by binding to ANPc in vascular endothelium. A synthetic BNP is neseritide. In severe heart failure it increases natriuresis and improves hemodynamics. Given by constant IV infusion, but has caused fatal renal damage.  Neutral endopeptidase inhibitors are omapatrilat, sampatrilat and fasidrotrilat. They lower BP and improve heart failure but are not yet licensed for clinical use because of adverse effects, of angioedema, cough and dizziness.  ENDOTHELINS Are potent vasoconstrictors. Three types known: ET1, ET2 and ET3 Widely distributed in the body. ET1 vascular endothelium prodominantly. Also in neurons and astrocytes of CNS, endometrium, renal mesangial, sertoli, breast epithelial and other cells. ET2 mainly in kidney and intestine  ET3 mainly in brain, but also in GIT, lungs and kidneys. They are blood pressure regulators and act locally. Production increased by TGF-β, IL- 1, vasoactive substances like angiotensin II and vasopressin, and mechanical stress. Production inhibited by NO, prostacyclin and ANP. They are rapidly cleared from circulation by  Enzymes and by binding to ETb receptors. ACTIONS Dose dependent vasoconstrictor action in most vascular beds. BP at first decreases followed by sustained increase. Positive ionotropic and chronotropic effects and are potent coronary vasoconstrictors  Decreased GFR, and decreased sodium and water excretion In the lungs bronchoconstriction In the Endocrine system, increases secretion of renin, aldosterone, vasopressin and ANP Various actions in CNS and PNS, GIT, liver, urinary tract, reproductive systems, eye, skeletal system and skin  ET1 is an important mitogen for vascular smooth muscle cells, cardiac myocytes and glomerular mesangial cells. Receptors are widespread- ETa in smooth muscle cells mediating vasoconstriction. Have high affinity for ET1, low affinity for ET3. ETb found in vascular endothelial cells where they mediate NO and PGI2 release. Has equal affinities for ET1 and ET3.  DRUGS USE Bosentan is a nonselective inhibitor of ETa and ETb, given orally and IV. Blocks pressor ET mediated responses. Used in PAH. Phosphoramidon blocks endothelin converting enzyme These drugs lower BP, decrease cardiac hypertrophy, improve heart failure, atherosclerosis, coronary artery disease and has a role in MI.  Bosentan, and other non-selective ETa inhibitors, sitaxentan and ambrisentan are useful in heart failure, pulmonary and systemic hypertension. An analogue of bosentan, tezosentan is under study for acute heart failure treatment. Endothelin antagonists cause hypotension, tachycardia, facial flushing or edema, and headaches, GIT effects and are teratogenic.  Bosentan may cause fatal hepatotoxicity  VASOACTIVE INTESTINAL PEPTIDE(VIP) A 28 AA peptide structurally related to secretin and glucagon. Widely distributed in CNS and PNS, where it is a neurotransmitter and neuromodulator. Also found in GIT, heart, lungs, kidneys and thyroid gland. VIP neurons innervate many blood vessels. Causes marked vasodilation in most vascular beds, and in heart coronary vasodilation and increased ionotropic and chronotropic effects.  Receptors are VPAC1 and VPAC2 G-protein linked, increases CAMP. Actions may be mediated by NO and CGMP also. Receptor agonists and antagonists are in research stage.  SUBSTANCE P Belongs to tachykinin family of peptides. Other members of the family are neurokinin A and neurokinin B. A neurotransmitter in the CNS and in the GIT a neurotransmitter and a local hormone. Receptors NK1, NK2, NK3 A potent arterial vasodilator Causes contraction of Venous, intestinal and bronchial SMs  Stimulates secretion by salivary glands Causes natriuresis and diuresis in kidneys Implicated in mediation of depression, behavior, anxiety, nausea, and vomiting. NK1 antagonist aprepitant used for prevention of nausea and vomiting in cytotoxic chemotherapy. Its highly  NEUROTENSIN Present in CNS, GIT and the circulation. A precursor produces neurotensin and neuromedin N. A neuroransmitter and neuromodulator in CNS and a local hormone peripherally. Centrally causes hypothermia, antinociception and modulation of dopamine neurotransmission.  Peripherally causes vasodilation, hypotension, increased vascular permeability, increased secretion of several anterior pituitary hormones, hyperglycemia, inhibition of gastric acid and pepsin secretion and inhibition of gastric motility. Receptors NT1, NT2, NT3 Antagonists have potential in hypothermia treatment and analgesia.  CALCITONIN GENE RELATED PROTEIN Belongs to calcitonin family of peptides which also includes adrenomedullin and amylin. Present in large quantities in C cells of thyroid gland. Widely distributed in CNS and PNS, CVS, GIT and GUS. Found with Subsatnce P in some areas and with acetylcholine in others Centrally causes hypertension and  Peripherally causes hypotension and tachycardia. Coronary circulation especially sensitive. Released from trigeminal nerves in migraine attacks. Receptors CGRP1, CGRP2 A peptide antagonist currently available for migraine treatment and prophylaxis.  ADRENOMEDULLIN Widely distributed in the body In animals causes vasodilation in kidneys, brain, lung, hind limbs and mesentery. Increases sodium excretion in kidneys Inhibits aldosterone and insulin secretion Increases during intense exercise Receptors AM1, AM2 and CGRP receptors.  NEUROPEPTIDE Y A member of the family that includes peptide YY and pancreatic polypeptide. Abundant in CNS and PNS, ANS A vasoconstrictor and co-transmitter with noradrenalin Centrally causes increased feeding, hypotension, hypothermia, and respiratory depression.  Receptors Y1-Y6 Antagonists may be useful in hypertension and heart failure Neuropeptide y has been implicated in feeding disorders, seizures, anxiety, diabetes. Y1 and Y5 antagonists have potential for anti-besity.  UROTENSIN Urotensin II – A potent vasoconstrictor of SMs, but may cause vasodilation in some areas. An antagonist palosuran, under study for hypertension, heart failure and renal failure.