Mechanism for the postive inotropic effect of angiotensin II on isolated cardiac muscle.
Angiotensin II (A II) and analogues were tested for their ability to restore electrical and mechanical activity to cardiac muscle preparations in which the fast Na+ channels had been inactivated by partial depolarization (22-27 mM K+) or by tetrodotoxin (TTX). The partially depolarized or TTX-blocked preparations were chosen because under these conditions electrical and mechanical responses are primarily Ca2+ -dependent. In depolarized rabbit right atria, A II restored spontaneous mechanical and electrical activity (measured by both intracellular and extracellular recording techniques). The frequency of action potential discharge was concentration-dependent; the threshold concentration of A II was 10(-10) M, the ED50 was 8 X 10(-9) M, and the maximum effect was observed at 5 X 10(-8) M. In contrast, depolarized guinea pig atria were insensitive to A II, Sar1-angiotensin II, and des-Asp1-angiotensin II, even at concentrations as high as 10(-5) M. Rabbit papillary muscle (TTX-blocked), embryonic (18-day) chick heart (partially depolarized) and chick heart reaggregates (TTX-blocked) responded similarly to rabbit atria in that A II (9.6 X 10(-7) M) restored both electrical and mechanical activity. We found that in these preparations the action of A II was unaffected by propranolol (5.0 X 10(-6) M to 5.0 X 10(-5) M) but was blocked by Mn2+ (10(-3) M), D-600 (1 X 10(-7) g/ml) and the specific A II antagonists Sar1-Ala8-angiotensin II (P-113) (5.0 X 10(-5) M) and Sar1-Ile8-angiotensin II (5.28 X 10(-5) M). We conclude that the positive inotropic effect of A II on the myocardium is due to its ability to increase transmembrane ion movements in or through the cell membrane. The ability of Mn2+ and D-600 to block this effect suggests that this ion movement is via the so-called "slow channels."
D000200:Action Potentials / Q000187:drug effects; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D002642:Chick Embryo; D004837:Epinephrine / Q000494:pharmacology; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D066298:In Vitro Techniques; D008345:Manganese / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009638:Norepinephrine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011817:Rabbits; D013268:Stimulation, Chemical; D013779:Tetrodotoxin / Q000494:pharmacology
D000804:Angiotensin II; D008345:Manganese; D013779:Tetrodotoxin; D011433:Propranolol; D009638:Norepinephrine; D004837:Epinephrine