Cytochrome P-450 metabolite of arachidonic acid mediates bradykinin-induced negative inotropic effect

This study focused on the mechanisms of the negative inotropic response to bradykinin (BK) in isolated rat hearts perfused at constant flow. BK (100 n M) significantly reduced developed left ventricular pressure (LVP) and the maximal derivative of systolic LVP by 20-22%. The cytochrome P-450 (CYP) in hibitors 1-aminobenzotriazole (1 mM and 100 muM) or proadifen (5 muM) aboli shed the cardiodepression by BK, which was not affected by nitric oxide and cyclooxygenase inhibitors (35 muM N-G-nitro-L-arginine methyl ester and 10 muM indomethacin, respectively). The CYP metabolite 14,15-epoxyeicosatrien oic acid (14,15-EET; 50 ng/ml) produced effects similar to those of BK in t erms of the reduction in contractility. After the coronary endothelium was made dysfunctional by Triton X-100 (0.5 mul), the BK-induced negative inotr opic effect was completely abolished, whereas the 14,15-EET-induced cardiod epression was not affected. In hearts with normal endothelium, after recove ry from 14,15-EET effects, BK reduced developed LVP to a 35% greater extent than BK in the control. In conclusion, CYP inhibition or endothelial dysfu nction prevents BK from causing cardiodepression, suggesting that, in the r at heart, endothelial CYP products mediate the negative inotropic effect of BK. One of these mediators appears to be 14,15-EET.