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(Hypertension. 1998;31:1290-1298.)
© 1998 American Heart Association, Inc.

Scientific Contributions

Role of Ca²⁺-Activated K⁺ Channels in the Protective Effect of ACE Inhibition Against Ischemic Myocardial Injury

Koichi Node; Masafumi Kitakaze; Hiroaki Kosaka; Tetsuo Minamino; Hidezo Mori; ; Masatsugu Hori

From the First Departments of Medicine (K.N., M.K., T.M., M.H.) and of Physiology (H.K.), Osaka University School of Medicine, and the Department of Physiology, Tokai University, Isehara (H.M.), Japan.

Abstract—Angiotensin-converting enzyme (ACE) inhibitors increase the production of nitric oxide (NO) and prostacyclin and open Ca²⁺-activated K⁺ channels. The effects of these actions of ACE inhibitors on infarct size were investigated in open-chest dogs subjected to myocardial ischemia and reperfusion. Infarct size was assessed 6 hours after the onset of reperfusion, subsequent to 90 minutes of occlusion of the left anterior descending coronary artery. The ACE inhibitor cilazaprilat was administered into the coronary artery 10 minutes before coronary occlusion, and infusion was continued until 1 hour after reperfusion. The bradykinin and NO concentrations in coronary venous blood 10 minutes after the onset of reperfusion were significantly higher in dogs treated with cilazaprilat (3 µg · kg^-1 · min^-1) than in control animals. Although there were no significant differences in collateral flow during ischemia, infarct size in the cilazaprilat group was smaller than that in the control group (15.1±3.0% versus 46.7±4.2% of the area at risk, P<0.0001). The infarct size–limiting effect of cilazaprilat was partially reduced by either N^G-nitro-L-arginine methyl ester (an inhibitor of NO synthase) or iberiotoxin (a blocker of Ca²⁺-activated K⁺ channels) and was abolished by N^G-nitro-L-arginine methyl ester plus iberiotoxin. Indomethacin (an inhibitor of cyclooxygenase) had no effect on the beneficial action of cilazaprilat. Inhibition of ACE thus reduced myocardial infarct size, an effect that was mediated by NO and the opening of Ca²⁺-activated K⁺ channels in canine hearts.

Key Words: angiotensin-converting enzyme • nitric oxide • potassium channels • prostacyclin • bradykinin • infarction

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