Medical Pharmacology Chapter 24:  Vasoactive Peptides

• 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

• Renin-Angiotensin Inhibitors

  • 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 β-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)

       

      • The vasoconstrictive effects of the renin-angiotensin can be mitigated by either limiting the formation of angiotensin II by angiotensin-converting enzyme inhibitors (ACE inhibitors) or by blocking angiotensin II effects at the level of the receptor by angiotensin receptor blockers.272 The angiotensin II receptor is a G protein system that involves Gq/11 mediated activation of phospholipase C.303 The resultant increase in cytosolic Ca2+ levels. Elevation in cytosolic Ca2+ causes various cellular responses including enhanced protein kinase C activity. ACE inhibitors are especially useful in managing hypertension in individuals with heart failure and in chronic renal disease. ACE inhibitors are furthermore indicated in managing hypertension in patients who have suffered significant myocardial infarction and in stroke patients, when combined with thiazide-type diuretic drugs. Examples of ACE inhibitors include captopril (Capoten), enalapril (Vasotec) and ramipril (Altace). Some angiotensin II antagonists include losartan (Cozaar), valsartan (Diovan) and irbesartan (Avapro).272

        Rashidi A Rahman M  Wright Jr JI Chapter 70.  Diagnosis and Treatment of Hypertension in Hurst's The Heart, 12th edition (eds, Fuster V O'Rourke RA Wash RA Poole-Wilson P; associate eds: King II SB Roberts R Nash IS Prystowsky EN; Editors of the online edition:  senior editors:  Walsh RA and Simon DI; associate Editors;  Hoit BD Fang JC Costa M), 2008, on-line edition.

      •  

        Angiotensin-Converting Enzyme Inhibitors (ACE inhibitors)

        Angiotensin Converting Enzyme Inhibitors	Trade Names
        Benazepril	Lotensin
        Captopril	Capoten
        Enalapril	Vasotec
        Fosinopril	Monopril
        Lisinopril	Prinivil
        Moexipril	Univasc
        Perindopril	Aceon
        Quinapril	Accupril
        Ramipril	Altace
        Trandolapril	Mavik

      • Seventh report of the joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7), U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute. 2004 http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.htm .

    • 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

• Receptor Blockers

  • Losartan (Cozaar), valsartan:

    •  

      Angiotensin-II Receptor Blockers

      Angiotensin II Receptor Antagonist	Trade Name
      Candesartan	Atacand
      Eprosartan	Teveten
      Irbesartan	Avapro
      Losartan	Cozaar
      Olmesartan	Benicar
      Telmisartan	Micardis
      Valsartan	Diovan

    • Seventh report of the joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7), U.S. Department of Health and Human Services, National Institutes of Health, National Heart, Lung and Blood Institute. 2004 http://www.nhlbi.nih.gov/guidelines/hypertension/jnc7full.htm

    • 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)

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