Comparison of effects of angiotensin-converting enzyme inhibition with those of angiotensin II receptor antagonism on functional and metabolic recovery in postischemic working rat heart as studied by [31P] nuclear magnetic resonance.
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.
Werrmann
J G
JG
Merck Research Laboratories, Rahway, New Jersey 07065.
Cohen
S M
SM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000284:Administration, Oral; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000627:therapeutic use*; D017706:Lisinopril / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D011725:Pyridines; C083194:L 158338; D000255:Adenosine Triphosphate; D017706:Lisinopril