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

Objective. We studied the effect of the angiotensin II type 1 (AT1)-receptor antagonist candesartan on infarct size resulting from regional myocardial ischemi in pigs. Background. The effects of AT1-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. total of 62 enflurane-anesthetized pigs underwent protocol of 90-min low-flow ischemi and 120-min reperfusion. Systemic hemodynamics (micromanometer), regional myocardial function (sonomicrometry), regional myocardial blood flow (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 are at risk. Candesartan (n = 7) reduced infarct size to 9.7 ± 2.5% (p < 0.05). Pretreatment with the AT2-receptor antagonist PD123319 (3 μg/kg/min intracoronarily [i.c.]; n = 8), the bradykinin B2-receptor antagonist HOE140 (0.01 μg/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 ± 5.2%). Hemodynamics, regional myocardial blood flow during ischemi and the are at risk were comparable among all groups of pigs. Conclusions. Reduction of infarct size by the AT1-receptor antagonist candesartan in pigs involves angiotensin II type 2 receptor (AT2) activation, bradykinin and prostaglandins.