Angiotensins and the failing heart. Enhanced positive inotropic response to angiotensin I in cardiomyopathic hamster heart in the presence of captopril.
We examined the hypothesis that the positive inotropic effect of angiotensin I (Ang I) may be retained in the presence of angiotensin converting enzyme inhibitors so that it may have a direct beneficial effect on the heart. Accordingly, isolated perfused hearts (Langendorff preparation) of 300-day-old cardiomyopathic hamsters (a model of spontaneous cardiomyopathy) and age-matched normal hamsters (controls) were infused with Ang I in the presence of captopril; propranolol was added to the perfusing medium to block catecholamine-mediated effects of angiotensins on the heart. Left ventricular developed pressure and the rate of increase in left ventricular developed pressure increased significantly (p less than 0.001) in both the cardiomyopathic and the normal hamster heart despite concomitant reduction in myocardial flow rate favoring a direct inotropic effect of Ang I in both normal and myopathic hearts; these changes were significantly higher by almost threefold in the cardiomyopathic than in the normal hamsters (p less than 0.01) and were blocked by the angiotensin II (Ang II) antagonist [Sar1,Thr8]Ang II. Comparing dose-left ventricular contractility response curves for Ang I and Ang II, ED50 for responses was identical in both normal and myopathic hearts, whereas peak responses to Ang II were double those to Ang I in normal hearts but were almost identical in the myopathic hearts. Binding of [125I]Ang II in six cardiomyopathic and four normal hamster hearts was of high affinity, but there was no evidence for Ang I-saturable high-affinity binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)
Hirakata
H
H
Department of Heart and Hypertension Research, Cleveland Clinic Foundation, OH 44195-5069.
Fouad-Tarazi
F M
FM
Bumpus
F M
FM
Khosla
M
M
Healy
B
B
Husain
A
A
Urata
H
H
Kumagai
H
H
D000803:Angiotensin I / Q000494:pharmacology*; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000809:Angiotensins / Q000502:physiology; D000818:Animals; D002216:Captopril / Q000494:pharmacology*; D002303:Cardiac Output, Low / Q000503:physiopathology*; D009202:Cardiomyopathies / Q000503:physiopathology*; D006224:Cricetinae; D004357:Drug Synergism; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D008647:Mesocricetus; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D000809:Angiotensins; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D000803:Angiotensin I; D002216:Captopril