A study of the mediators involved in the protection induced by exogenous kinins in the isolated rat heart.
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 B2-receptor antagonist, HOE140 (30 nM). Likewise, DBK reduced infarct size, effect that was blocked by the B1-receptor antagonist (30 nM Lys(0)-Leu(8)-DBK). The cardioprotective effect of both BK and DBK was abolished by the cannabinoid CB1-receptor antagonist (1 microM SR141716A), but not by the CB2-receptor antagonist (1 microM SR144528). Neither the NO synthase inhibitor, N-nitro-L-arginine (NNLA, 30 microM), the COX inhibitor, indomethacin (2.8 microM), nor the CYP450 inhibitor, clotrimazole (1 microM), 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.
Lagneux
Caroline
C
Faculté de pharmacie, Université de Montréal, CP 6128, succursale Centre-ville, Montréal, QC, Canada H3C3J7.
Adam
Albert
A
Lamontagne
Daniel
D
D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors; D043885:Receptor, Cannabinoid, CB2 / Q000037:antagonists & inhibitors
D002316:Cardiotonic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C024626:bradykinin, des-Arg(9)-; D019001:Nitric Oxide Synthase; D011451:Prostaglandin-Endoperoxide Synthases; D001920:Bradykinin