2c

COURSE OUTLINE

I. INTRODUCTION

  • Vasoactive peptides are defined as short chains of amino acids that play crucial roles in
    • Regulating blood vessel diameter and blood pressure.
  • Key examples include:
    1. Angiotensin
    2. Bradykinin
    3. Endothelin
  • Functionality:
    • Can induce either vasoconstriction or vasodilation, influencing vascular tone and systemic blood pressure.
    • Their intricate interactions contribute to the complex regulation of cardiovascular function.
  • Cellular Communication:
    • Used by most tissues for cell-to-cell communication
    • Important as transmitters in the autonomic and central nervous systems
    • Several peptides exert significant direct effects on vascular and other smooth muscles.
  • Categories of Vasoactive Peptides:
    • Vasoconstrictors include:
    • Angiotensin II
    • Vasopressin
    • Endothelins
    • Neuropeptide Y
    • Urotensin
    • Vasodilators include:
    • Bradykinin
    • Natriuretic peptide
    • Vasoactive intestinal peptide (VIP)
    • Substance P
    • Neurotensin
    • Calcitonin gene-related peptide
    • Adrenomedullin
  • Clinical Relevance:
    • Initially regarded as physiological curiosities, it is now recognized that they play important roles not only in physiological regulation but also in various disease states.
    • Synthetic drugs targeting these peptides (e.g., ACE inhibitors) are now routinely used in clinical settings.

II. ANGIOTENSIN

  • Significance:
    • Central to the renin-angiotensin-aldosterone system (RAAS), crucial in regulating blood pressure and fluid balance.
    • Produced in response to low blood pressure or sodium levels.
  • Conversion Process:
    • Angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II, a potent vasoconstrictor.
    • Angiotensin II stimulates aldosterone release, promoting sodium and water retention, thereby influencing blood pressure.
  • Dysregulation:
    • Can lead to hypertension and cardiovascular diseases.
  • Biosynthesis Steps:
    1. Enzymatic cleavage of angiotensin I from angiotensinogen by renin.
    2. Conversion of angiotensin I (ANG I) to angiotensin II (ANG II) by ACE.
    3. Degradation of angiotensin II by various peptidases.
  • Renin:
    • An aspartyl protease enzyme
    • Catalyzes the hydrolytic release of the decapeptide ANG I from angiotensinogen.
    • Synthesized and stored in the juxtaglomerular apparatus of the nephron.
A. ACTIONS OF ANGIOSTENSIN II
  • Role in Regulation:
    • Key in fluid and electrolyte balance, arterial blood pressure regulation
    • Excessive activity can lead to hypertension and fluid/electrolyte imbalances.
  • Blood Pressure Regulation:
    • ANG II is a potent pressor agent, more so than norepinephrine.
    • Causes direct contraction of arteriolar smooth muscle with little to no reflex bradycardia due to simultaneous CNS effects resetting baroreceptor reflex control to higher pressures.
  • Effects on Adrenal Cortex and Kidney:
    • Directly stimulates aldosterone synthesis and release.
    • Stimulates glucocorticoid synthesis.
    • Causes renal vasoconstriction, increases sodium reabsorption, inhibits renin release.
  • CNS Impact:
    • Stimulates drinking behavior (dipsogenic effect) and increases vasopressin and ACTH secretion.
  • Cell Growth Effects:
    • Mitogenic for vascular and cardiac muscle cells, contributing to cardiac hypertrophy.
B. INHIBITION OF THE RENIN-ANGIOTENSIN SYSTEM
CLASSIFICATION
  • Drugs That Block Renin Release:
    • Propranolol:
    • Blocks renal β receptors involved in sympathetic control of renin release.
  • Renin Inhibitors:
    • Aliskiren:
    • First non-peptide renin inhibitor approved for hypertension treatment.
    • Produces dose-dependent decreases in plasma renin activity, ANG I, ANG II, and aldosterone concentrations.
    • Suppresses plasma renin activity similar to effects of ACE inhibitors and ARBs.
  • ACE Inhibitors:
    • Captopril and Enalapril:
    • Decrease systemic vascular resistance without increasing heart rate; promote natriuresis.
    • Block conversion of ANG I to ANG II and inhibit degradation of bradykinin, substance P, and enkephalins.
  • Angiotensin Receptor Blockers (ARBs):
    • Losartan and Valsartan:
    • Oral, potent competitive antagonists at angiotensin AT1 receptors.

III. KININ

  • Description:
    • Kinin is a vasoactive peptide involved in the kinin-Kallikrein system.
    • Bradykinin:
    • Well-known kinin, acts as a potent vasodilator and increases vascular permeability.
    • Released during tissue injury and inflammation.
    • Binds to 𝛃1 and 𝛃2 receptors, influencing smooth muscle contraction and relaxation.
  • Dysregulation:
    • Could contribute to various vascular and inflammatory conditions.
  • Kallikreins:
    • Serine proteases in plasma (plasma kallikrein) and various organs (tissue kallikrein).
    • Secreted as zymogens and activated through proteolytic cleavage.
  • Kininogens:
    • Substrates for kallikreins and precursors of kinins in plasma, lymph, and interstitial fluid.
    • Two kininogen forms:
    • Low-molecular-weight kininogen (LMW)
    • High-molecular-weight kininogen (HMW)
TWO MAJOR KININS
  1. Bradykinin
    • Released from HMW kininogen by plasma kallikrein; predominant kinin in plasma.
  2. Kallidin
    • Released from LMW kininogen by tissue kallikrein; can be converted to bradykinin by an arginine aminopeptidase.
A. DRUGS AFFECTING THE KALLIKREIN-KININ SYSTEM
  • Icatibant:
    • Second-generation B2 receptor antagonist.
    • Decapeptide with similar affinity for B2 receptor as bradykinin; rapid absorption after subcutaneous administration; used for hereditary angioedema.
  • Newer Generations:
    • FR 173657, FR 172357, NPC 18884:
    • Third-generation B2 receptor antagonists, orally active; inhibit bradykinin-induced bronchoconstriction in guinea pigs, inflammation in rats, and nociception in mice.
  • SSR240612:
    • New potent selective antagonist of B1 receptors; reduces obesity in diabetic rats.
  • Ecabllantide:
    • Recombinant plasma kallikrein inhibitor; more potent than C1INH and can be administered subcutaneously.
  • Urodilatin:
    • More resistant to neprilysin, thus has a longer duration of action compared to other natriuretic peptides.

IV. VASOPRESSIN

  • Also known as Antidiuretic Hormone (ADH).
  • Role:
    • Regulates water balance and blood pressure.
    • Produced in the hypothalamus, released by the pituitary gland.
    • Acts on kidneys to reduce water excretion; has vasoconstrictor effects raising blood pressure.
  • Dysregulation:
    • Can lead to water balance disorders impacting cardiovascular function.
  • V1a, V1b, and V2 Receptors:
    • V1a: Mediates vasoconstriction via Gq activation of phospholipase C, forming inositol trisphosphate, increasing intracellular calcium.
    • V1b: Mediates ACTH release by pituitary corticotropes.
    • V2: Mediates antidiuretic action via Gs activation of adenylyl cyclase.
  • Agonists:
    • Vasotocin: First specific V1 agonist synthesized.
    • Desmopressin (dDAVP): Selective V2 antidiuretic analog.
    • Telepressin: Vasopressin analog effective through conversion to lysine vasopressin.
  • Antagonists:
    • Tolvaptan and Relcovaptan: Non-peptide antagonists.

V. NATRIURETIC PEPTIDES

  • Types:
    1. Atrial Natriuretic Peptide (ANP)
    2. B-type Natriuretic Peptide (BNP)
  • Function:
    • Promotes natriuresis (sodium excretion) and diuresis (increased urination).
    • Released primarily by heart in response to increased blood volume and pressure; counteracts vasoconstrictors such as angiotensin II.
  • Clinical Applications:
    • Elevated levels related to heart failure; BNP particularly used for monitoring heart failure therapy.
A. ATRIAL NATRIURETIC PEPTIDE (ANP)
  • Synthesized primarily in cardiac atrial cells but also in other tissues.
  • Release is triggered by atrial stretch due to volume changes.
  • Mechanisms:
    • Interrupts renin release; induces vasodilation; increases urinary sodium excretion.
  • Has broader effects on body metabolism, influencing lipid oxidation and insulin sensitivity.
B. B-TYPE NATRIURETIC PEPTIDE (BNP)
  • Primarily synthesized in the heart's ventricles.
  • Useful index for BNP release is the inactive N-terminal fragment, NT-proBNP.
  • Similar functions to ANP but circulates at lower concentrations.
C. C-TYPE NATRIURETIC PEPTIDE (CNP)
  • Found in vascular endothelium; involved in vasodilation.
D. URODILATIN
  • Synthesized in kidney’s distal tubules; regulates sodium and water excretion, induces vascular smooth muscle relaxation.
E. NATRIURETIC PEPTIDE RECEPTOR SUBTYPES
  • NPR-A:
    • Main ligands are ANP and BNP.
  • NPR-B:
    • Primary ligand appears to be CNP.
  • NPR-C:
    • Functions as a clearance receptor for all three natriuretic peptides.
F. THERAPEUTIC APPLICATIONS
  • Carperitide:
    • Recombinant ANP for vasodilation and natriuresis; investigated for treating heart failure.
  • Nesiritide:
    • Recombinant BNP approved for decompensated acute heart failure.
  • Ularatide:
    • Synthetic urodilatin with tested benefits on myocardial structure.

VI. ENDOTHELINS

  • Produced by endothelial cells; play significant roles in blood vessel tone regulation.
  • Endothelin-1: Most studied isoform presenting potent vasoconstrictive effects.
  • Related Conditions:
    • Imbalances may lead to conditions such as pulmonary hypertension and atherosclerosis.
  • Isoforms:
    • Three identified: ET-1, ET-2, ET-3; each derived from their precursor by endothelin-converting enzyme.
A. ENDOTHELIN RECEPTORS
  • ETA Receptor:
    • High affinity for ET-1; mediates vasoconstriction.
  • ETB Receptor:
    • Equal affinities for ET-1 and ET-3; mediates vasodilation via PGI2 and nitric oxide release.
B. INHIBITORS AND CLINICAL USE
  • Bosentan:
    • Nonselective antagonist; used in pulmonary hypertension.
  • Macitentan:
    • Newer dual receptor antagonist entered clinical use.

VII. VASOACTIVE INTESTINAL PEPTIDES

  • VIP: A 28-amino-acid peptide belonging to glucagon-secretin family; a potent vasodilator.
    • Influences smooth muscle in the gastrointestinal tract; involved in immune response modulation and acting as a neurotransmitter.
  • Regulatory Impact:
    • VIP can cause coronary vasodilation and has multiple cardiovascular actions mediated through VPAC1 and VPAC2 receptors.

VIII. SUBSTANCE P

  • Functions as neurotransmitter and neuromodulator, primarily linked with pain transmission and inflammation.
  • Mechanisms:
    • Acts through tachykinin receptors (NK1, NK2, NK3); effect on blood pressure through vasodilation.

IX. NEUROTENSIN

  • A tridecapeptide residing mainly in the CNS and gastrointestinal tract, impacting neurotransmission, appetite, and blood pressure.

X. CALCITONIN GENE-RELATED PEPTIDE (CGRP)

  • Neurogenic vasodilator implicated in migraine and cardiovascular functions.

XI. ADRENOMEDULLIN

  • A 52-amino-acid peptide with vasodilatory properties; associated with cardiovascular health and regulatory roles in fluid balance.

XII. NEUROPEPTIDE Y

  • Plays roles in appetite regulation and stress, influencing cardiovascular function with a wide distribution in the nervous system.

XIII. UROTENSIN

  • Vasoconstrictor peptide that is considered one of the most potent known for its effects on blood vessel contraction.

XIV. SUMMARY

  • Vasoactive Peptides Overview:
    1. Functions: Regulation of blood pressure and inflammation.
    2. Clinical Applications: Various interventions targeting these peptides are used biomarker and therapeutic applications in cardiovascular health.
    3. Drugs: Focus on the mechanism of action and therapeutic implications, including developments in antagonists and inhibitors.