Vasoactive peptides

Vasoactive peptides

1. Vasoactive peptides Dr Shinde Viraj Ashok Department of Pharmacology Junior Resident

2. Overview

3. definition Vasoactive peptide means peptide tending to cause vasodilation or vasoconstriction or influencing tone or caliber of blood vessels

4. Renin - ANGIOTENSIN system

5. Renin ( aspartyl protease enzyme) Synthesized & stored - juxtaglomerular apparatus of nephron Control of Renin Release Renin released - activity of renin-angiotensin system Macula Densa ↑ NaCl delivery or concentration to macula densa - ↓ renin release B. Renal Baroreceptor ↑ renal artery pressure - ↓ renin release & vice versa

6. C . Sympathetic Nervous System Norepinephrine - stimulates renin release D. Angiotensin Angiotensin II - inhibits renin release E. Pharmacologic Alteration of Renin Release Renin release stimulated by Vasodilators (hydralazine, minoxidil , nitroprusside ) ß- adrenoceptor agonists, a- adrenoceptor antagonists Phosphodiesterase inhibitors ( eg , theophylline, milrinone , rolipram ) Diuretics & anaesthetics

7. ACTIONS OF ANGIOTENSIN II renin-angiotensin system - regulates of fluid & electrolyte balance & arterial blood pressure Blood Pressure Angiotensin II -potent pressor agent Adrenal Cortex - stimulate aldosterone synthesis & release Kidney - renal vasoconstriction, ↑ proximal tubular sodium reabsorption & inhibit release of renin

8. Cell Growth Mitogenic for vascular & cardiac muscle cells (cardiovascular hypertrophy ) Overactivity of renin angiotensin system - development of hypertensive vascular disease ACE inhibitors & ANG II receptor antagonists slow or prevent morphologic changes ( remodeling ) following myocardial infarction

9. ANGIOTENSIN RECEPTORS ANG II receptors AT 1 receptors & AT 2 receptors G protein-coupled Located on plasma membrane of target cells AT 1 Receptors AT 2 Receptors Location – vascular smooth muscles Foetus – widely distributed Adults – adrenal medulla , vascular endothelium & brain Function – vasoconstriction , cell growth in heart & arteries , secretion of aldosterone , reabsorption from PCT & DCT Vasodilatation Antiproliferative Apoptosis

10. INHIBITION OF RENIN-ANGIOTENSIN SYSTEM

11. Angiotensin-Converting Enzyme Inhibitors All ACEI prodrugs - except captopril & lisinopril Enalaprilat - IV route - meant for use in hypertensive emergencies ↓ systemic vascular resistance without ↑ heart rate & promote natriuresis - effective in treatment of hypertension

12. Continued ACEI ↓ morbidity & mortality in heart failure & left ventricular dysfunction after myocardial infarction Delay progression of diabetic nephropathy Adverse effects – dry cough , rashes , dysguesia Contraindicated - in pregnancy ( fetal kidney damage) , serum creatinine > 3.5 mg/ dl

13. Angiotensin Receptor Blockers Antagonists of AT 1 receptors Orally active, potent Efficacy - hypertension - similar to ACE inhibitors Slow progression of diabetic nephropathy

14. Continued ARB Valsartan - ↓ incidence of diabetes in patients with impaired glucose tolerance Effective in treatment of heart failure (useful alternative - ACE inhibitors not well tolerated) Lower incidence of cough & angioedema

15. Marfan syndrome (Connective tissue disorder) Associated with Aortic disease ↑ transforming growth factor (TGF)-ß signalling ANG II - ↑ TGF-ß levels - blockade of renin-angiotensin system might be beneficial in Marfan syndrome Losartan - Promising initial results & clinical trials are underway

16. Renin Inhibitors E.g. – enalkiren & remikiren limited by low potency, poor bioavailability & short duration of action Aliskiren Approved for treatment of hypertension In healthy subjects - produces dose-dependent reductions in plasma renin activity , ANG I , II & aldosterone concentrations Safety & tolerability comparable to angiotensin antagonists & placebo Contraindicated in pregnancy Eliminates renin rise produced by ACE inhibitors, ARBs & diuretics - results in greater antihypertensive effect

17. kinins

18. Formation & metabolism of kinins The kallikrein-kinin system. Kininase II is identical to converting enzyme peptidyl dipeptidase (ACE) (Plasma) ( Urine )

19. PHYSIOLOGIC & PATHOLOGIC EFFECTS OF KININS Effects on Cardiovascular System Vasodilatation results from Direct inhibitory effect - arteriolar smooth muscle Release of nitric oxide or vasodilator prostaglandins (PGE 2 & PGI 2 ) Venous contraction result from Direct stimulation - venous smooth muscle Release of venoconstrictor prostaglandins (PGF2a)

20. cont’d PHYSIOLOGIC & PATHOLOGIC EFFECTS OF KININS Effects on Endocrine & Exocrine Glands Smooth muscle – May modulate tone of salivary & pancreatic ducts Regulate gastrointestinal motility Local modulators of blood flow Regulate transport of substances in gastrointestinal tract & kidney Influencing transepithelial transport of water, electrolytes , glucose & amino acids Kallikreins : Physiologic activation of prohormones ( proinsulin & prorenin )

21. Cont’d PHYSIOLOGIC & PATHOLOGIC EFFECTS OF KININS Role in Inflammation & Pain Bradykinin produce four classic symptoms of inflammation redness , local heat, swelling & pain Kinins - potent pain producing substances - when applied to blister base or injected intradermally

22. Cont’d PHYSIOLOGIC & PATHOLOGIC EFFECTS OF KININS Role in Hereditary Angioedema Rare autosomal dominant disorder Deficiency or dysfunction of C1 esterase inhibitor (C1-INH) Results in activation of kallikrein & ↑ formation of bradykinin ( ↑vascular permeability - recurrent episodes of angioedema of airways, gastrointestinal tract, extremities & genitalia) Treatment - drugs inhibiting formation or actions of bradykinin

23. Kinin receptors & mechanisms of action G protein-coupled receptors B 1 ( bradykinin ) – no subtype B 2 ( bradykinin ) – subtypes B 2A & B 2B Bradykinin - highest affinity in most B 2 receptor systems, followed by Lys- bradykinin B 1 receptors - in inflammatory response , collagen synthesis & cell multiplication B 2 receptors - calcium mobilization, chloride transport, formation of nitric oxide, activation of phospholipase C, phospholipase A 2 & adenylyl cyclase

24. Drugs affecting kallikrein-kinin system Icatibant Second-generation B 2 receptor antagonist Absorbed rapidly - SC Treatment of hereditary angioedema Third generation of B 2 -receptor antagonists e.g. FR 173657, FR 172357 & NPC2 Orally active Reported to inhibit Bradykinin - induced bronchoconstriction in guinea pigs Carrageenin -induced inflammation in rats Capsaicin-2 - induced nociception in mice

25. Cont’d Drugs affecting kallikrein-kinin system Synthesis of kinins inhibited Kallikrein inhibitor – Aprotinin Human plasma C1-INH preparations - Cinryze & Berinert (used for intravenous prophylaxis or treatment of hereditary angioedema ) Ecallantide – Recombinant plasma kallikrein inhibitor More potent & selective than C1-INH Administered by subcutaneous injection

26. VASOPRESSIN Arginine vasopressin (AVP) , Antidiuretic hormone (ADH)

27. VASOPRESSIN RECEPTORS G protein coupled receptors Characteristic V 1a V 1b V 2 Location Vascular & other smooth muscles, platelets , hepatocytes Anterior pituitary Colleting duct cells of kidney , vascular endothelium Function Vasoconstriction , visceral smooth muscle contraction , platelet aggregation ACTH release Antidiuretic action

28. Vasopressin receptor agonists Vasopressin – V 1 /V 2 receptor actions non selective Desmopressin – t 1/2 2 hrs – action lasts for 10 hrs V 2 receptor selective action Terlipressin - V 1 >> V 2 receptor selective action Felypressin - V 1 receptor selective action

29. Therapeutic uses -Vasopressin receptor agonists Based on V 1 receptor action – Preferred drug terlipressin Treat Bleeding of oesophageal varices Treat post operative paralytic ileus Prevent bleeding in acute haemorrhagic gastritis Based on V 2 receptor action – Preferred drug desmopressin Diabetes insipidus Primary nocturnal enuresis To relieve post lumbar puncture headache

30. Vasopressin receptor antagonists Convaptan – First non peptide ADH receptor antagonist Approved for treatment of euvolaemic hyponatremia (SIADH) & congestive heart failure – ADH excess Disadvantages Requires IV administration Non selective action - V 2 & V 1a Cann’t be administered with CYP3A4 inhibitors Orally active V 2 receptor selective , non peptide antagonists approved recently – Tolvaptan , relcovaptan , satavaptan & mozavaptan

31. NATRIURETIC PEPTIDES Parameters Atrial natriuretic peptide ( ANP) Brain Natriuretic peptide (BNP) C type natriuretic peptide (CNP) Site of synthesis Cardiac atrial cells , ventricular cells ,central & peripheral neurons , lungs Ventricle Vascular endothelium, CNS , kidney , intestine Factors stimulating release Atrial stretch , volume expansion , endothelins , heart failure , primary aldosteronism Volume expansion Unclear

32. NATRIURETIC PEPTIDES Parameters Atrial natriuretic peptide ( ANP) Brain Natriuretic peptide (BNP) C type natriuretic peptide (CNP) Actions Natriuresis , diuresis , ↓ arterial BP (vasodilatation) Natriuresis , diuresis , ↓ arterial BP (vasodilatation) Vasodilator ; lesser natriuretic & diuretic Uses Diagnostic / prognostic marker in heart failure - Synthetic form nesiritide is used for CHF Nil Pharmacokinetics Shorter t1/2 Metabolised neutral endopeptidase ( NEP – 24.11) Removed by binding to ANPc receptors

33. Characteristics ANP A ANP B ANP C Location On surface of target cells On surface of target cells Vascular endothelium Ligand ANP + BNP CNP ANP + BNP + CNP Natriuretic peptide receptors

34. Clinical role of natriuretic peptides Recombinant ANP ( carperitide ) or BNP ( nesiritide ) Clinical studies in treatment of congestive heart failure have produced variable results Vasopeptidase (Neutral endopeptidase + angiotensin converting enzyme) inhibitors - omapatrilat , sampatrilat & fasidotrilat Lowers BP - Animal models of hypertension & Hypertensive patients Improves cardiac function in heart failure Causes angioedema , cough & dizziness Not approved for clinical use

35. ENDOTHELINS Biosynthesis , Structure, & Clearance Three isoforms - ET-1, ET-2 & ET-3 ET-1 - predominant endothelin vascular endothelium , brain & kidney ET-2 produced - kidneys & intestine ET-3 found in highest concentration in brain , gastrointestinal tract, lungs & kidneys

36. Characteristic ET A ET B Location Vascular smooth muscle , brain , lungs , kidney , adrenal gland Vascular endothelium , brain , intestine , kidney , adrenal gland G – protein coupled Function Vasoconstriction , bronchoconstriction & aldosterone secretion , mitogenesis Vasodilatation , mitogenesis Agonist ET 1 > ET 2 > ET 3 ET 1 = ET 2 = ET 3 Antagonist Bosentan , Sitaxsentan & Ambrisentan Bosentan

37. Inhibitors of endothelin synthesis & action Bosentan Active orally – Treatment of pulmonary hypertension Ambrisentan & sitaxsentan - Approved by FDA to Treat pulmonary artery hypertension Macitentan Dual endothelin receptor antagonist approved by FDA ↑ efficacy in pulmonary hypertension compared with other antagonists & well tolerated with fewer side effects Inhibitor endothelin converting enzyme - phosphoramidon

38. Physiologic & Pathologic Roles of Endothelin : Effects of Endothelin Antagonists Systemic administration - ER antagonists or endothelin -converting enzyme inhibitors → vasodilation & ↓ arterial pressure Activity of system is Higher in males than in females ↑ with age - can be counteracted by regular aerobic exercise ↑ production of ET-1 implicated in CVS diseases (hypertension , cardiac hypertrophy, heart failure, atherosclerosis, coronary artery disease & myocardial infarction) Pulmonary diseases (asthma , pulmonary hypertension; renal diseases ; several malignancies -ovarian cancer) Endothelin antagonists - potential for treatment of these diseases

39. VASOACTIVE INTESTINAL PEPTIDE Belongs to glucagon-secretin family Distributed in CNS (neurotransmitter or neuromodulator) Peripheral nervous systems (peptide neurotransmitters) Significant effects on CVS Causes coronary vasodilation & exerts + inotropic & chronotropic effects

40. Cont’d VASOACTIVE INTESTINAL PEPTIDE Effects mediated by VPAC1 & VPAC2 (G protein coupled receptors) Distributed in CNS & in heart, blood vessels & other tissues Potential as therapeutic agents for cardiovascular, pulmonary , gastrointestinal & nervous system diseases (Alzheimer ’s & Parkinson’s disease ) Use is currently limited by several issues including poor oral availability & hypotension

41. SUBSTANCE P Belongs to tachykinin family Present in CNS- neurotransmitter ( behavior , anxiety, depression, nausea & emesis) Gastrointestinal tract - transmitter in enteric nervous system & local hormone Peripheral afferent pain fibers CVS - Potent arteriolar vasodilator (release of nitric oxide from endothelium) – marked hypotension

42. Cont’d SUBSTANCE P Actions mediated - Gq protein-coupled tachykinin receptors (NK 1 , NK 2 , and NK 3 ) Recent clinical trials - antagonists useful in Treating depression Preventing chemotherapy – Induced emesis Aprepitant - approved Fosaprepitant – prodrug of aprepitant Recent studies implicated substance P-NK1 system in cancer Present in variety of tumor cells NK 1 receptor antagonists exert an antitumor action Aprepitant - potential as anti-cancer agents

43. NEUROTENSIN Tridecapeptide Dual function CNS - Neurotransmitter or neuromodulator Hypothermia Antinociception Modulation of dopamine & glutamate neurotransmission ( schizophrenia , Parkinson’s disease & drug abuse) Central administration of NT produces effects in rodents similar to those produced by antipsychotic drugs

44. Peripheral circulation - Local hormone Vasodilation, hypotension, ↑ vascular permeability ↑ secretion of several anterior pituitary hormones Hyperglycemia Inhibition of gastric acid , pepsin secretion, gastric motility NT receptors - NTR 1 , NTR 2 & NTR 3 (NTS 1 , NTS 2 & NTS 3 ) Gq protein-coupled superfamily Neurotensin receptor agonist – PD149163 crosses BBB- undergoing clinical trial as antischizophrenic & antiparkinsonism drug

45. CALCITONIN GENE-RELATED PEPTIDE Member of calcitonin family of peptides (calcitonin, adrenomedullin & amylin) Present in C cells of thyroid gland Central & peripheral nervous systems Cardiovascular ,Respiratory systems & Gastrointestinal tract Actions mediated Single heterodimeric receptor G protein coupled Calcitonin receptor-like receptor (CLR) combined with receptor activity-modifying protein RAMP1

46. Cont’d CGRP Effects produced when Injected into Central nervous system - hypertension & suppression of feeding Systemic circulation - hypotension & tachycardia Evidence Release of CGRP from trigeminal nerves plays a central role in pathophysiology of migraine Peptide is released during migraine attacks Successful treatment of migraine - selective serotonin agonist normalizes cranial CGRP levels Clinical trials showed CGRP antagonists Olcegepant – effective in treating migraine low bioavailability - administered by IV route Telcagepant effective , orally active , exhibited liver toxicity

47. ADRENOMEDULLIN (AM) Found in adrenal glands, hypothalamus, anterior pituitary, kidneys, lungs, cardiovascular system, gastrointestinal tract In animals, AM dilates resistance vessels in kidney , brain, lung, hind limbs & mesentery - long-lasting hypotension Functions as a physiologic antagonist of actions of vasoconstrictors ( ET-1 and ANG II )

48. Cont’d AM AM receptor - CLR co-assembles with RAMP subtypes 2 & 3 Activates Gs Triggers cAMP formation in vascular smooth muscle cells ↑ nitric oxide production in endothelial cells Plasma AM levels ↑ during intense exercise ↑ in essential & pulmonary hypertension, acute myocardial infarction, cardiac & renal failure ↑ in proportion to severity of these diseases & this can be a useful prognostic marker May protect against cardiovascular overload & injury

49. NEUROPEPTIDE Y Multiligand / multireceptor system Three polypeptide agonists Pancreatic polypeptide (PP ) Peptide YY (PYY ) Neuropeptide Y (NPY )

50. Neuropeptide Y ( NPY) Abundant - central & peripheral nervous systems (Neurotransmitter) CNS effects ↑ feeding (one of most potent orexigenic molecules in brain ) Hypotension, hypothermia Respiratory depression Activation of hypothalamic pituitary-adrenal axis Other Effects Vasoconstriction of cerebral blood vessels, + chronotropic & inotropic actions on heart Hypertension Potent renal vasoconstrictor Suppresses renin secretion

51. Cont’d Neuropeptide Y ( NPY) Effects of NPY (and PP and PYY ) mediated by NPY receptors : Y 1 ,Y 2, Y 4 & Y 5 Gi protein-coupled receptors Y 1 & Y 2 receptors - major importance in cardiovascular & other peripheral effects Y 4 receptors - high affinity for pancreatic polypeptide Y 5 receptors – Central nervous system May be involved in control of food intake Mediate activation of hypothalamic-pituitary-adrenal axis by NPY

52. Cont’d Neuropeptide Y ( NPY) First nonpeptide Y 1 receptor antagonist, BIBP3226 short half-life in vivo. in animal models, it blocks vasoconstrictor & pressor responses to NPY SR120107A & SR120819A Orally active Y 1 antagonists Long duration of action Y 5 antagonists - MK-0557 & S-2367 - tested in clinical trials for obesity Studies have implicated NPY in eating disorders,obesity , alcoholism, anxiety,depression , epilepsy , pain , cancer Y 1 & Y 5 receptor antagonists - potential as antiobesity agents.

53. uROTENSIN UII - potent constrictor of vascular smooth muscle Actions - Gq protein-coupled receptor (UT receptor ) Palosuran - nonpeptide antagonist – benefit diabetic patients with renal disease but lacks potency More potent UII antagonists are in phase 1 clinical trials, EP2439193 - treatment of diabetic nephropathy SB1440115 - treatment of asthma

54. Conclusion Knowledge of vasoactive peptides can help us to identify newer potential targets in treating various CNS diseases like Anxiety Depression Schizophrenia CVS diseases like Resistant hypertension Congestive heart failure Left ventricular dysfunction Obesity ; w hich are difficult to treat in present scenario.

55. references Katzungs Basic & Clinical Pharmacology 13 th edition by Bertram G. Katzung & Anthony J. Trevor Principles of Pharmacology 2 nd edition by HL Sharma & KK Sharma

56. Major physiologic inputs to renin release and proposed integration with signaling pathways in the juxtaglomerular cell. AC, adenylyl cyclase ; ANG II, angiotensin II; ANP, atrial natriuretic peptide; cGK , protein kinase G;DAG, diacylglycerol ; GC-A, particulate guanylyl cyclase ; ER, endoplasmic reticulum; IP, inositol trisphosphate ; NE, norepinephrine; NO, nitric oxide; PDE, phosphodiesterase ; PKA, protein kinase A; PLC, phospholipase C; sGC , soluble 3guanylyl cyclase.X

57. Prorenin Receptors receptor that preferentially binds prorenin has been identified. Since it also binds active renin, the receptor is referred to as (pro)renin receptor Recent research indicates that the (pro)renin receptor is functionally linked to the vacuolar proton-ATPase (ATP6ap2) and is necessary for Wnt signaling pathways involved (independently of renin) in stem cell biology, embryology, and cancer .

58. KININS BIOSYNTHESIS OF KININS Kallikreins serine proteases present in plasma - plasma kallikrein - activated by Factor XIIa several organs - tissue kallikrein ( kidneys, pancreas, intestine, sweat glands & salivary glands)

59. Kininogens Substrates for kallikreins Precursors of kinins —present in plasma, lymph & interstitial fluid Kininogens present in plasma : Low-molecular-weight form (LMW kininogen ) - tissue kallikreins High-molecular-weight form (HMW kininogen )- plasma kallikrein

60. UT receptors distributed in the brain , spinal cord, heart,vascular smooth muscle, skeletal muscle, and pancreas Effects of peptide including vasoconstriction mediated by phospholipase C, inositol trisphosphate , diacylglycerol signal transduction pathway plasma UII levels are ↑ in hypertension, heart failure, atherosclerosis , diabetes mellitus, and renal failure .

61. Generation of endothelin-1 (ET-1) in the vascular endothelium, and its direct and indirect effects on smooth muscle cells mediated by ETA and ET receptors . ANG II, angiotensin II; ANP, atrial natriuretic peptide; Arg , arginine;BigET-1 , proET-1; ECE, endothelial- converting enzyme; NO, nitric oxide; PreproET-1, precursor of BigET-1; PGI B ,prostaglandin I2

62. Angiotensinogen Synthesized in liver Production of angiotensinogen - ↑ by corticosteroids, estrogens , thyroid hormones & ANG II ↑ plasma angiotensinogen concentration - hypertension Angiotensin I little or no biologic activity

63. Converting Enzyme (ACE, Peptidyl Dipeptidase , Kininase II) ANG I → ANG II, & bradykinin , which it inactivates Located on luminal surface of vascular endothelial cells & close contact with circulation Angiotensinase Angiotensin II - plasma half-life of 15–60 seconds, removed rapidly from circulation by peptidases - angiotensinase

64. Cont’d Drugs affecting kallikrein-kinin system SSR240612 New , potent & orally active - Selective antagonist of B 1 receptors Exhibits analgesic & anti-inflammatory activities in mice & rats Currently in preclinical development for treatment of inflammatory & neurogenic pain