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<0.01) 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<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. Therefore, we suggest that the positive inotropic effect of Ang I, in the presence of captopril, is not via a direct effect on either Ang I or Ang II receptors but most probably via conversion of Ang I to Ang II or another intermediate peptide that was mediated by an alternative converting enzyme. The positive inotropic effect of Ang I and, to a lesser extent, Ang II was accentuated in the myopathic compared with the normal hamster hearts; this finding suggests that Ang I conversion is increased in the diseased heart and that elevated levels of circulating Ang I during therapy with angiotensin convering enzyme inhibitors may be of direct benefit to the failing heart.