Chapter 24:  Vasoactive Peptides

• Overview: Biosynthesis

  1. Renin catalyzed conversion of angiotensinogen to angiotensin I

  2. Conversion of angiotensin I to angiotensin II by converting enzyme

  3. Degradation of angiotensin II by peptidases

• Renin/Regulation of renin secretion:

  • Renin:

    • aspartyl protease (catalyzes the conversion of angiotensinogen  to angiotensin I (decapeptide)

    • preprohormone is conveted to  prohormone which is converted to Renin {glycoprotein}

    • Most circulatory renin is synthesized in the kidneys

      • Nephron synthetic and storage site: juxtaglomerular apparatus

        1. afferent and efferent arterioles } contain granular cells (juxtaglomerular cells -- synthetic, storage, and renin release site)

        2. macula densa-- specialized tubular segment: associated with juxtaglomerular vascular elements

        3. Afferent and efferent arterioles and macula densa are innervated by the adrenergic system

    • Primary determinants of renin-angiotensin system activity:

      • Renin secretion rate.

        • controlled by:

          1. macula densa

             • influenced by changes in rate of sodium or chloride delivery to the distal tubule: decreased delivery, increased renin secretion; increased delivery, decreased renin secretion

               • Mechanism of Action: Na/K/2Cl co-transporter -- sensitive to luminal chloride concentration changes.

          2. renal vascular receptor-- afferent arteriole

             • stretch receptor: less stretch, increased renin release; more stretch, decreased renin release

          3. angiotensin II:

             •  Inhibits renin secretion:

               • Mechanism of Action: direct peptide effect on juxtaglomerular cells {negative feedback}

               • Interference with this negative feedback system results in increased renin secretion

          4.  sympathetic nervous system

             • Increased renal nerve activity: increased renin secretion

             • Norepinephrine (direct action on juxtaglomerular cells) increases renin release.

               • usually b ₁ adrenergic receptor mediated

             • Norepinephrine may increase renin release indirectly through a receptor activation -- { norepinephrine-mediated afferent arteriolar vasoconstriction activates the renal vascular receptor and decreases sodium chloride delivery to the macula densa.}

             • Rate of renin secretion: affected by circulating catecholamines

          5. Drug Effects:

             • Stimulation:

               1.  vasodilators (hydralazine (Apresoline),minoxidil (Loniten), nitroprusside sodium (Nipride))

               2.  beta adrenergic receptor agonists (isoproterenol (Isuprel))

               3.  alpha adrenergic antagonists

               4.  diuretics

               5.  anesthetics

             • Inhibition:

               1.  Sympatholytics (blockade of renin secretion)

               2.  Renin Inhibitors (competitive blockade)

               3.  Converting Enzyme Inhibitors

               4.  Angiotensin Antagonists (e.g., losartin -- AT₁ receptor blocker)

  • Angiotensinogen

    • Renin acts on angiotensinogen protein substrate to form angiotensin I

      • Angiotensinogen:

        1.  synthesized in liver

        2.  important factor in angiotensin formation rate

    • Angiotensinogen production enhanced by:

      • corticosteroids

      • estrogens

      • thyroid hormones

      • angiotensin II

    • Pregnancy, estrogen-containing oral contraceptives, glucocorticoid use, and Cushing's syndrome produce both an increase in angiotensinogen concentration and hypertensive states. There may be a cause-effect relationship.

  •  Angiotensin I

    • Very limited biological activity:

    • May be converted to angiotensin II by converting enzyme OR

    • May be converted to [des-ASP]-angiotensin I by plasma or tissue aminopeptidases;

      • [des-ASP]-angiotensin I may be converted to angiotensin III by converting enzyme

  • Converting Enzyme (peptidyl dipeptidase [PDP], Kininase II)

    • Catalyzes dipeptide cleavage from carboxyl terminal of some peptides.

    •  Important substrate (angiotensin II is not a substrate):

      • angiotensin I is converted to angiotensin II

    • Tissue Localization:  vascular endothelial cell luminal surfaces

  • Angiotensinase:

    • Catabolizes angiotensin II

    • Enzyme localization: -- vascular beds (except pulmonary)

    • Most angiotensin II metabolites: in active -- exception:[des-ASP]-angiotensin II

• Sites of Action:

  • vascular smooth muscle

  • brain

  • kidney

  • adrenal cortex

• Renin-angiotensin System Physiology:

  • arterial blood pressure regulation

  • fluid and electrolyte balance regulation

Angiotensin II

• Blood Pressure/Cardiovascular Effects: Angiotensin II

  • Properties:

    • Very potent vasopressor (40 times more potent than norepinephrine)

    • Following IV administration, rapid pressor effect

    • Vasopressor response: Mechanisms of Action

      • Direct arteriolar smooth muscle contraction

      • CNS-mediated

      • ANS-mediated

    • Minimal reflex bradycardia (angiotensin II CNS action resets baroreceptor reflex system, making it less sensitive)

• Autonomic Effects:

  • stimulates autonomic ganglia

    • promoting release of epinephrine and norepinephrine

    • enhances adrenergic nerve terminal neurotransmission

      • increases norepinephrine release; reduces norepinephrine re-uptake

• Slight inotropic cardiac effect

• Adrenal Cortical Effects:

  • Angiotensin II:

    • acts on zona glomerulosa, increasing aldosterone synthesis

    • (higher doses) -- increases glucocorticoid synthesis

• Renal Effects:

  • Angiotensin II:

    • Renovascular constriction

    • enhanced sodium reabsorption at proximal tubule

    • inhibition of renin secretion

• CNS Effects:

  • Angiotensin II:

    • central blood-pressure effects

    • stimulates drinking (dipsogenic effect)

    • stimulates vasopressin and ACTH secretion

• Cell Growth--Angiotensin II:

  • Vascular and cardiac muscle cell mitogen

    • may cause myocardial hypertrophy

    • Angiotensin converting enzyme inhibitors may reduce or prevent morphological changes following myocardial infarction (remodeling) -- which may lead to cardiac failure (CHF)

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• Angiotensin Receptors:

  • Overview

    • Angiotensin II receptors -- widely distributed

    • plasma membrane localization-- rapid onset of effects

    • At least two major receptor subtypes:

      •   AT₁ -- high losartin affinity

        • equal affinity for saralasin and angiotensin II

        • predominates at vascular smooth muscle

        •   vascular smooth muscle: G- protein coupled system

          • receptor activation at vascular smooth muscle:

            1. phospholipase C -mediated production of inositol triphosphate IP₃ and diacylglycerol (DAG)

               • Activation of IP₃, DAG cascade: DAG may activate smooth muscle Ca²⁺ channels; IP₃ releases Ca²⁺ from endoplasmic and sarcoplasmic reticulum

            2. smooth muscle contraction

        • non-G protein coupled system at other sites

      •   AT₂ -- low losartin affinity

        • equal affinity for saralasin and angiotensin II

• Blockade of Renin Secretion:

  •  clonidine (Catapres)

    • Mechanism of Action:

      1. decrease in CNS-mediated renal stimulation

      2. direct intra-renal effect

  •  methyldopa (Aldomet)

  •  propranolol (Inderal) (and other b-adrenergic receptor blockers)

    • Mechanism of Action:

      • blockade of renal b-adrenergic receptors

• Renin Inhibitors:

  • Orally active (unapproved) renin inhibitors:

    • Remikiren

    • Enalkiren

  • poor bioavailability

    • poor absorption

    • first-pass effect

  • increased plasma renin levels (interrupts angiotensin II negative feedback effect on renin secretion)

• Converting Enzyme Inhibitors (ACE):

  • Examples: Captopril (Capoten),  Enalapril (Vasotec)

  • Conversion blockade: angiotensin I to angiotensin II

  • Degradation blockade:

    1. bradykinin (important in ACE inhibitors hypotensive effects)

       •  reduced bradykinin degradation: responsible for certain adverse effects-- cough, angioedema.

    2. substance P

    3. enkephalins

  • Clinical Use: ACE inhibitors--

    1. management of hypertension

    2. management of congestive heart failure

    3. may reduce renal vascular injury in diabetic patients

• Angiotensin Antagonists:

  • Amino acid substitutions:

    • Saralasin -- antagonist

      • some agonist activity

      • IV administration only

      •  less effective in lowering blood pressure compared to ACE inhibitors because:

        1. partial agonist properties

        2. ACE inhibitors enhance bradykinin vasodilation

Saralasin

• Receptor Blockers:

  • Losartan (Cozaar), valsartan:

    • competitive antagonist at AT₁ receptors

    • Effective orally

    • Antihypertensive effects comparable to those obtained with enalapril (ACE inhibitor)

    • no agonist activity

    • Clinical uses: Receptor Blockers

      1. hypertension

      2. congestive heart failure (possible)

Losartan

Kinins

• Overview:

  • Kinins: potent vasodilator peptides

  • Kinins formed from kininogens, catalyzed by kallikreins (or kininogenases)

  • kallikreins-kinin: similar to renin angiotensin system in certain respects

• Kallikreins:

  • Localization: kallikreins

    • plasma

    • tissues: kidneys, pancreas, intestine, salivary glands, sweat glands

    • serine proteases (catalytically similar to trypsin, chymotrypsin, thrombin, elastase, plasmin)

  • Kallikrein precursor:

    • Prekallikrein produced by the liver

    • Kallikreins in some glands exist as Prekallikreins

    • Prekallikrein is conveted to kallikrein

      • conversion catalyzed by: trypsin, Hageman factor, kallikrein itself (possibly)

• Kininogens:

  • Kininogens --precursors of kinins; kallikreins substrate

  • Localization-- kininogens:

    • plasma

      1. two forms:

         1. low molecular weight (LMW)kininogen

         2. high molecular weight (HMW) kininogen

      2.  HMW form (15-20% of total plasma kininogen) remains in the blood: substrate for plasma kallikrein

      3. LMW form: crosses capillary walls -- substrate for tissue kallikreins

    • lymph

    • interstitial fluid

     

• Tissue and plasma Kinin formation:

  • Three kinins:

    • bradykinin

    • lysylbradykinin

    • methionyllysylbradykinin

  • Bradykinin: released by plasma kallikreinin

  • Lysylbradykinin: released by glandular kallikrein

  • Methionyllysylbradykinin: released by pepsins and pepsin-like enzymes

  • Preferred substrate for plasma kallikrein:

    • HMW kininogen

  • Preferred substrate for tissue kallikrein:

    • LMW kininogen

  • Bradykinin: major plasma kinin

  • Lysylbradykinin: major urinary kinin

  • Methionyllysylbradykinin: found in acid urine (acid activates uropepsinogen, catalyzing release of methionyllysylbradykinin from urinary kininogens

• Kinins: Physiological Effects:

  • Cardiovascular

    • Vasodilation: vascular beds:

      • heart

      • kidney

      • intestine

      • skeletal muscle

      • liver

    • Mechanism of Action (possible): vasodilation

      1. direct effect of kinins on arteriolar, vascular smooth muscle

      2. mediated by nitric oxide (EDRF)

      3. mediated by vasodilator prostaglandins (PGE₂ and PGI₂)

    • Vasoconstriction: vascular beds

      • Venous smooth muscle

      • Mechanism of Action: vasoconstriction

        1. direct venous smooth muscle stimulation

        2. release of venoconstrictor prostaglandins (PGF_2-a )

      • Visceral smooth muscle

    • Blood Pressure Effects:

      • hypotensive response (brief)

      • reflex tachycardia, positive inotropism: increased cardiac output compensates

      • Arteriolar dilation:Mechanism of Action --

        1. increase in capillary bed pressure and flow

        2. promotes fluid transfer from blood to tissue (increased capillary permeability may occur because of endothelial cell contraction which widens intercellular junctions)

           1. increased venous pressure (following venous constriction) also promotes fluid transfer to tissue.

           2. Edema may result

  • Endocrine and Exocrine Gland Effects:

    • Prekallikreins and kallikreins present in:

      1. kidney

      2. pancreas

      3. intestine

      4. salivary glands

      5. sweat glands

    • Enzymes or kinins may diffuse from organs to blood, acting as local regulators of blood flow

    • Kinins may (because of smooth muscle effects) influence salivary and pancreatic ducts tone; and may influence gastrointestinal motility

    • Kinins affect transepithelial transport of:

      1. water

      2. electrolytes

      3. amino acids

      4. glucose

    • Kallikreins may be involved in physiological activation of prohormones, i.e. proinsulin and prorenin

  • Kinins and Inflammation:

    • Kallikreins and kinins: produce inflammatory symptoms

  • Kinins and Sensory Nerves:

    • potent pain-producing (intradermal application)

    • Mechanism of Action: stimulation of nociceptive afferents.