Myocardial Protection by Preconditioning of Heart With Losartan, an Angiotensin II Type 1–Receptor Blocker

Abstract

Background —Ischemic preconditioning (PC) represents a state-of-the-art technique for myocardial preservation. Although certain intracellular mediators have been shown to play a role in PC, the exact nature of the trigger for PC is not known. Our previous study demonstrated that intracellular bradykinin released from the heart during ischemia/reperfusion plays a role in myocardial preservation. This study was undertaken to further examine the mechanism of bradykinin-mediated PC. Methods and Results —Since the bradykinin B 2 receptor is likely to provide cardioprotection by blocking angiotensin II formation, we determined the effects of an angiotensin II type 1 (AT 1 ) receptor blocker, losartan, and a bradykinin B 2 receptor blocker, HOE 140, on myocardial protection. Isolated rat hearts were perfused initially by the Langendorff mode with Krebs-Henseleit buffer (KHB) for 15 minutes in the absence (control) or presence of losartan (4.5 μmol/L) and/or HOE 140 (10 μmol/L). After conversion to the working mode for 10 minutes (baseline), randomly assigned control and experimental hearts were subjected to 30 minutes of normothermic global ischemia followed by 2 hours of reperfusion. Myocardial function, infarct size, cardiomyocyte apoptosis, and amount of bradykinin/angiotensin released from the hearts were measured at baseline and during reperfusion while in the working mode. Significant postischemic ventricular recovery was demonstrated by improved developed pressure and aortic flow and reduced myocardial infarct size and apoptotic cell death with losartan, whereas the reverse was true for HOE 140. The functional recovery and infarct size–lowering ability of losartan were partially blocked and the antiapoptotic function of losartan was completely blocked by HOE 140. Conclusions —The results document that losartan reduced whereas HOE 140 increased myocardial ischemia/reperfusion injury by blocking AT 1 and bradykinin B 2 receptors, respectively, suggesting a role of the bradykinin B 2 receptor in PC. Losartan provided cardioprotection through both bradykinin-dependent and bradykinin-independent mechanisms.