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Angiotensin and its Biosynthesis

  • Angiotensin II (ANG II)

    • Pathway: Formation begins with angiotensinogen (from liver), converted to angiotensin I (ANG I) by renin, and then ANG I is converted to ANG II by angiotensin converting enzyme (ACE).

    • Renin: Aspartyl protease that catalyzes the hydrolytic release of ANG I from angiotensinogen. It exists in a prepromolecule form, converting to prorenin, then to active renin by N-terminal prosegment cleavage.

    • Renin levels are significantly affected by renal conditions (e.g., nephrectomy).

Clinical Case Study: Vasoactive Peptides

  • Man diagnosed with high blood pressure (hypertension): Initial treatment with hydrochlorothiazide, but replaced with enalapril, an ACE inhibitor, to manage high renin and aldosterone levels.

  • Enalapril lowers blood pressure by inhibiting conversion of ANG I to ANG II; side effects include cough and angioedema due to increased bradykinin.

  • Alternative renal and angiotensin inhibitors being explored to mitigate side effects of ACE inhibitors.

Peptides and Their Roles

  • Peptides are essential for cell communication in various biological processes, affecting vascular and muscle function.

  • Major roles:

    • Vasoconstrictors (e.g., ANG II, vasopressin)

    • Vasodilators (e.g., bradykinin, natriuretic peptides).

    • Many peptides arise from families that exhibit similarities in structure and function (e.g., tachykinins, natriuretic peptides).

Renin Release Control Mechanisms

1. Macula Densa

  • Detects changes in NaCl concentration in the distal tubule and signals changes in renin release inversely.

  • Factors: Prostaglandin E2 and nitric oxide stimulate renin release; adenosine inhibits it.

2. Renal Baroreceptor

  • Inversely related to renal artery pressure; increased stretch leads to decreased renin release. Mediated by paracrine factors (PGE2, nitric oxide, adenosine).

3. Sympathetic Nervous System

  • Norepinephrine from sympathetic nerves stimulates renin release directly (via β1 adrenoceptors) and indirectly through macula densa and baroreceptor feedback mechanisms.

4. Angiotensin II Feedback

  • ANG II itself inhibits renin release through short-loop negative feedback: elevated ANG II levels reduce renin secretion via renal responses.

Renin-Angiotensin System (RAS) Components

Key Peptides and Enzymes

  • Angiotensinogen: Glycoprotein produced in the liver; substrate for renin.

  • Converting Enzyme (ACE): Converts ANG I to ANG II, also involved in inactive peptide breakdown (e.g., bradykinin).

    • ACE2: Functions similarly but leads to ANG 1-7 formation, which may have vasodilatory effects.

Actions of ANG II

  • Significant effects include:

    • Vasoconstriction in arterioles (40x more potent than norepinephrine).

    • Increased Blood Pressure: Rapid onset after IV administration, minimal reflex bradycardia.

    • Sympathetic Nervous System Interaction: Facilitates adrenergic activity leading to further norepinephrine release.

    • Aldosterone Secretion: Acts on adrenal cortex to increase sodium retention and potassium secretion.

Blood Pressure Regulation Effects of Ang II

  • Increases blood volume through aldosterone and vasoconstriction.

  • CNS Impact: Stimulates thirst and vasopressin secretion, affecting fluid balance.

Angiotensin Receptors & Mechanisms

Receptor Types

  • AT1 Receptors: Predominantly mediates vasoconstriction and increased blood pressure.

  • AT2 Receptors: Associated with vasodilation and potentially protective cardiovascular effects during excess ANG II presence.

Pharmacological Agents Targeting RAS

1. ACE Inhibitors (e.g., enalapril)

  • Function: Prevent ANG I to ANG II conversion.

  • Benefits: Lower blood pressure without reflex tachycardia; improve outcomes in heart failure.

  • Side Effects: Cough, angioedema due to bradykinin accumulation.

2. Angiotensin Receptor Blockers (ARBs)

  • Drugs like losartan selectively block AT1 receptors; less cough than ACE inhibitors but may increase ANG II.

3. Renin Inhibitors (e.g., Aliskiren)

  • Inhibit renin directly; decreases plasma renin and ANG II levels, reducing blood pressure.

4. Combination Therapies

  • ARNI: Combination of neprilysin inhibition and angiotensin receptor blockage has entered clinical practice (e.g., LCZ696).

Kinin System Overview

  • Kinins (e.g., bradykinin): Potent vasodilators with rapid metabolism, chiefly affecting renal function and smooth muscle contraction.

  • Kallikreins: Enzymes that produce kinins from kininogens. Exist in both plasma and tissues.

  • Physiological Effects: Kinins contribute to inflammation, vascular responses, and modulate pain sensation.

Substance P and Neuropeptides

  • Substance P: Involved in pain pathways and vasodilation, has implications for treating nausea and depression.

  • Neurotensin: Affects dopamine and may hold therapeutic promise for psychiatric disorders.

Summary of Strategies Against Vasoactive Peptide Systems

  • Drugs targeting VASOACTIVE PEPTIDES section broadly include:

    • AT1 antagonists, ACE inhibitors, neprilysin inhibitors, and various peptidergic receptor blockers aimed at cardiovascular and renal pathologies.