Nursing Pharmacology Chapter 24:  Vasoactive Peptides

• Primary determinants of renin-angiotensin system activity:

   

  • "Renin Angiotensin Aldosterone System"

    "This animation focuses on the renin angiotensin aldosterone system (RAAS), a classic endocrine system that helps to regulate long-term blood pressure and extracellular volume in the body." MechanismsMedicine:  https://www.youtube.com/watch?v=bY6IWVgFCrQ

  •  

     

    Renin-Angiotensin System

    Rad A "The renin-angiotensin system (RAS) or the renin-angiotensin-aldosterone system (RAAS)" "Start reading this schematic from the left, where it says 'Decrease in renal perfusion (juxtaglomerular apparatus).'  Alternative, the RAAS can also be activated by low NaCl concentration in the macula densa or by sympathetic activation." http://en.wikipedia.org/wiki/File:Renin-angiotensin-aldosterone_system.png

  • 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 which is sensitive to luminal chloride concentration changes.

      2. Renal vascular receptor associated with afferent arterioles.

         • Stretch receptor

           • Less stretch promotes increased renin release.

           • More stretch by contrast, decreases 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 β₁ 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.  β-adrenergic receptor agonists (isoproterenol (Isuprel))

           3.  α-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, an AT₁ receptor blocker)

• Angiotensinogen

  • Renin acts on angiotensinogen protein substrate to form angiotensin I

    • 

  • 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

  • Converting enzyme is localized on vascular endothelial cell luminal surfaces.

• Angiotensinase

  • Catabolizes (degrades) angiotensin II.

  • Enzyme localization: vascular beds (except pulmonary)

  • Most angiotensin II metabolites are inactive with the exception:[des-ASP]-angiotensin II.

Reid, I.A., Vasoactive Peptides, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 287-303.