To assess the role of
angiotensin II (AII) in development of myocardial injury during
ischemia and reperfusion, the effects of short-term treatment with the
angiotensin-converting enzyme (
ACE) inhibitor lisinopril were compared with the effects of short-term treatment with
L-158,338, an AII antagonist, in isolated working rat heart. Myocardial function was assessed and correlated with simultaneous measurement of high-energy
phosphate metabolism and intracellular pH by [31P] nuclear magnetic resonance (NMR) before, during, and after global
ischemia. Hearts from rats treated with 1 mg/kg
lisinopril in vivo recovered substantially more function than those of controls (p < 0.001), whereas 50 ng/ml (0.11 microM)
lisinopril in vitro had no effect on functional recovery. A dose-dependent increase in functional recovery was observed in rat heart treated with 0.3, 1, or 3 mg/kg
L-158,338 in vivo (p < 0.005). Treatment with 50 ng/ml (0.12 microM)
L-158,338 in vitro also resulted in increased functional recovery (p < 0.02). Significantly milder
acidosis during
ischemia and significantly increased coronary flow were characteristic of the improved functional recovery exhibited by the groups treated with either
lisinopril or
L-158,338 in vivo. Treatment with
L-158,338 in vitro caused significantly increased coronary flow during reperfusion as compared with either its control group or with
lisinopril treatment in vitro. High-energy
phosphate metabolism was essentially unchanged by any treatment regimen. AII antagonism alone resulted in a degree of improvement in functional recovery comparable to that observed with oral
ACE inhibitor treatment.