Myocardial protection by preconditioning of heart with losartan, an angiotensin II type 1-receptor blocker - Implication of bradykinin-dependent and bradykinin-independent mechanisms

Background-Ischemic preconditioning (PC) represents a state-of-the-art tech nique 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 bradyki nin released from the heart during ischemia/reperfusion plays a role in myo cardial preservation. This study was undertaken to further examine the mech anism 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 ef fects of an angiotensin II type 1 (AT(1)) receptor blocker, losartan, and a bradykinin B-2 receptor blocker, HOE 140, on myocardial protection. Isolat ed rat hearts were perfused initially by the Langendorff mode with Krebs-He nseleit buffer (KHB) for 15 minutes in the absence (control) or presence of losartan (4.5 mu mol/L) and/or HOE 140 (10 mu mol/L). After conversion to the working mode for 10 minutes (baseline), randomly assigned control and e xperimental hearts were subjected to 30 minutes of normothermic global isch emia followed by ?, hours of reperfusion. Myocardial function, infarct size , cardiomyocyte apoptosis, and amount of bradykinin/angiotensin released fr om the hearts were measured at baseline and during reperfusion while in the working mode. Significant postischemic ventricular recovery was demonstrat ed by improved developed pressure and aortic flow and reduced myocardial in farct 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 losar tan was completely blocked by HOE 140. Conclusions-The results document that losartan reduced whereas HOE 140 incr eased myocardial ischemia/reperfusion injury by blocking AT, and bradykinin Bz receptors, respectively, suggesting a role of the bradykinin B-2 recept or in PC. Losartan provided cardioprotection through both bradykinin-depend ent and bradykinin-independent mechanisms.