Infarct size reduction by AT1-receptor blockade through a signal cascade of AT2-receptor activation, bradykinin and prostaglandins in pigs

Objective. We studied the effect of the angiotensin II type 1 (AT(1))-receptor antagonist candesartan on infarct size resulting from regional myocardial ischemia in pigs. Background. The effects of AT(1)-receptor blockade on infarct size in different species remain controversial and its potential cardioprotective mechanisms are still unclear. In pigs, infarct development closely resembles that observed in humans. Methods. A total of 62 enflurane-anesthetized pigs underwent a protocol of 90-min low-bow ischemia and 120-min reperfusion. Systemic hemodynamics (micromanometer), regional myocardial function (sonomicrometry), regional myocardial blood how (microspheres) and infarct size (TTC [triphenyl tetrazolium chloride]-staining) were determined. Results. Left ventricular peak pressure decreased with candesartan (1 mg/kg i.v.) from 97 +/- 2 standard error of the mean (SEM) to 86 +/- 5 mm Hg and was then readjusted by aortic banding. In placebo pigs (n = 9), infarct size was 21.8 +/- 4.8% of the area at risk. Candesartan (n = 7) reduced infarct size to 9.7 a 2.5% (p < 0.05). Pretreatment with the AT,-receptor antagonist PD123319 (3 mu g/kg/min intracoronarily [i.c.]; n = 8), the bradykinin B-2-receptor antagonist HOE140 (0.01 mu g/kg/min i.c.; n = 8) or the cyclooxygenase inhibitor indomethacin (10 mg/kg i.v.; n 8) per se did not affect infarct size but did abolish the reduction of infarct size achieved by candesartan (PD123319 + candesartan (n = 7): 23.2 +/- 4.7%; HOE140 + candesartan (n = 7): 18.2 +/- 4.0%; indomethacin + candesartan (n = 8): 21.1 +/- 53%). Hemodynamics, regional myocardial blood flow during ischemia and the area at risk were comparable among all groups of pigs. Conclusions. Reduction of infarct size by the AT(1)-receptor antagonist candesartan in pigs involves angiotensin II type 2 receptor (AT(2)) activation, bradykinin and prostaglandins. (J Am Coil Cardiol 1998;32:1787-96) (C) 1998 by the American College of Cardiology.