Inotropic cardiac and vascular actions of [Ala7]angiotensin analogs.
Angiotensins I, II, and III are potent cardiac inotropic agents, but vasoconstrictor and steroidogenic activities compromise their use in conditions of cardiac dysfunction. This study examines the inotropic and vascular actions of [alanyl7]-substituted angiotensin analogs in field-stimulated rabbit left atria and isometrically contracting aortic strips. Angiotensin II increased cardiac contractility in a dose-dependent manner with an ED50 of 30 nM. Sarcosine substitution at the amino terminus of angiotensin II increased its potency 10-fold. Inhibition of converting enzyme with teprotide (10 microgram/ml) had no effect on contractile responses to angiotensin II or [Sar1]angiotensin II. [Ala7]Angiotensin II was a weaker cardiac stimulant than angiotensin II, but addition of teprotide enhanced its potency to that of angiotensin II. [Sar1, Ala7]Angiotensin II also was equipotent to [Sar1]angiotensin II in the presence of teprotide. The potency of angiotensin I as an inotropic agent (ED50 = 100 nM) was significantly less than that of angiotensin II, and the angiotensin I response was attenuated by teprotide. [Sar1, Ala7]Angiotensin I was a more effective inotropic agent following teprotide administration. These findings indicate that atrial converting enzyme metabolizes angiotensin I and the [Ala7] analogs of angiotensin I and II. Angiotensin II and [Sar1]angiotensin II had activities in aorta similar to those in atria. As previously reported for uterus, [Ala7]Angiotensin II was inactive in aorta whether teprotide was present or not. The decapeptides were equally potent in the aorta and atria. Sarcosine substitution at the NH2 terminus also was observed to attenuate cardiac selectivity. These data indicate that [Ala7]angiotensin analogs are cardioselective inotropic agents.
D000409:Alanine / Q000494:pharmacology; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000494:pharmacology; D000809:Angiotensins / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000187:drug effects; D006325:Heart Atria / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009842:Oligopeptides / Q000494:pharmacology; D011817:Rabbits; D013722:Teprotide; D014661:Vasoconstriction / Q000187:drug effects*
D000809:Angiotensins; D009842:Oligopeptides; D000804:Angiotensin II; D013722:Teprotide; D000409:Alanine