CYTOCHROME P450-DEPENDENT EFFECTS OF BRADYKININ IN THE RAT-HEART

1 Vasodilator responses to bradykinin (BK) in the rat heart are reported to be independent of NO and cyclo-oxygenase/lipoxygenase products of arachidonic acid (AA). 2 We verified that inhibition of NO synthase with L-nitroarginine (50 mu M) and cyclo-oxygenase with indomethacin (2.8 mu M) were without effect on vasodilator responses to BK (10-1000 ng) in the Langendorff rat heart preparation. 3 L-Nitroarginine elevated perfusion pressure, signifying a crucial role of NO in the maintenance of basal vasculature tone. 4 In hearts treated with L-nitroarginine to eliminate NO and elevate perfusion pressure, vasodilator responses were reduced by inhibitors of cytochrome P450 (P450), clotrimazole (1 mu M) and 7-ethoxyresorufin (1 mu M). 17-Octadecynoic acid (17-ODYA 2 mu M), a mechanism based inhibitor of P450-dependent metabolism of fatty acids, also reduced vasodilator responses to BK. 5 These results confirm that NO and prostaglandins do not mediate vasodilator responses to BK in the rat heart but suggest a major role for a P450-dependent mechanism via AA metabolism.