A study of the mediators involved in the protection induced by exogenous kinins in the isolated rat heart

Abstract

The aim of this study was to determine whether endothelium-derived mediators and the endocannabinoid system were involved in the cardioprotective effects induced by exogenous kinins, namely bradykinin and its active metabolites, des-Arg 9-bradykinin. Isolated rat hearts were submitted to a 20-min stabilisation period, followed by 90 min of low-flow ischemia (flow rate, 0.6 ml min −1) before a 60-min reperfusion period. Perfusion of bradykinin (BK, 30 nM) or des-Arg 9-bradykinin (DBK, 30 nM) was initiated 1 min before the ischemia and maintained during the entire ischemic period. Perfusion with BK reduced infarct size, when measured at the end of the 60-min reperfusion. This effect was blocked by the B 2-receptor antagonist, HOE140 (30 nM). Likewise, DBK reduced infarct size, effect that was blocked by the B 1-receptor antagonist (30 nM Lys 0-Leu 8-DBK). The cardioprotective effect of both BK and DBK was abolished by the cannabinoid CB 1-receptor antagonist (1 μM SR141716A), but not by the CB 2-receptor antagonist (1 μM SR144528). Neither the NO synthase inhibitor, N-nitro- l-arginine (NNLA, 30 μM), the COX inhibitor, indomethacin (2.8 μM), nor the CYP450 inhibitor, clotrimazole (1 μM), prevented the cardioprotective effect of the kinins. However, a combined treatment with those three inhibitors abolished completely the ability of BK and DBK to reduce infarct size. In conclusion, exogenously administered BK and DBK exert a protective effect against ischemia in an isolated heart model. Endothelium-derived mediators such as nitric oxide, prostanoids, and endothelium-derived hyperpolarizing factor, as well as an SR141716A-sensitive mediator, appear to be involved in this beneficial effect.