PARACRINE SYSTEMS IN THE CARDIOPROTECTIVE EFFECT OF ANGIOTENSIN-CONVERTING ENZYME-INHIBITORS ON MYOCARDIAL-ISCHEMIA REPERFUSION INJURY IN RATS

After transient episodes of ischemia, benefits of thrombolytic or angi oplastic therapy may be limited by reperfusion injury. Angiotensin-con verting enzyme inhibitors protect the heart against ischemia/reperfusi on injury, an effect mediated by kinins. We examined whether the prote ctive effect of the angiotensin-converting enzyme inhibitor ramiprilat on myocardial ischemia/reperfusion is due to kinin stimulation of pro staglandin and/or nitric oxide release. The left anterior descending c oronary artery of Lewis inbred rats was occluded for 30 minutes, follo wed by 120 minutes of reperfusion. Immediately before reperfusion rats were treated with vehicle, ramiprilat, or the angiotensin II type 1 r eceptor antagonist losartan. We tested whether pretreatment with the k inin receptor antagonist Hoe 140, the nitric oxide synthase inhibitor N-G-nitro-L-arginine methyl ester, or the cyclooxygenase inhibitor ind omethacin blocked the effect of ramiprilat on infarct size and reperfu sion arrhythmias. In controls, infarct size as a percentage of the are a at risk was 79+/-3%; ramiprilat reduced this to 49+/-4% (P<.001), bu t losartan had little effect (74+/-6%, P=NS). Pretreatment with Hoe 14 0, N-G-nitro-L-arginine methyl ester, or indomethacin abolished the be neficial effect of ramiprilat. Compared with the 30-minute ischemia/12 0-minute reperfusion group, nonreperfused hearts with 30 minutes of is chemia had significantly smaller infarct size as a percentage of the a rea at risk, whereas in the 150-minute ischemia group it was significa ntly larger. This suggests that reperfusion caused a significant part of the myocardial injury, but it also suggests that compared with prol onged ischemia, reperfusion salvaged some of the myocardium. Ventricul ar arrhythmias mirrored the changes in infarct size. Thus, angiotensin -converting enzyme inhibitors protect the myocardium against ischemia/ reperfusion injury and arrhythmias; these beneficial effects are media ted primarily by a kinin-prostaglandin-nitric oxide pathway, not inhib ition of angiotensin II formation.