Analysis of responses to bradykinin in the pulmonary vascular bed of the cat
Responses to bradykinin (BK) were investigated in the pulmonary vascular bed of the cat under conditions of controlled pulmonary blood flow and constant left atrial pressure when lobar arterial pressure was elevated to a high steady level. Under elevated-tone conditions, BK caused dose-related decreases in lobar arterial pressure. After administration of Hoe-140, a BK B2-receptor antagonist, vasodilator responses to BK were reduced in a selective manner. Vasodilator responses to BK were unchanged by atropine, glibenclamide, meclofenamate, or bronchial occlusion, suggesting that responses are not dependent on the activation of muscarinic receptors or K(ATP)/+ channels, the release of vasodilator prostaglandins, or changes in bronchomotor tone. The nitric oxide (NO) synthase inhibitors N(ω)-nitro-L- arginine benzyl ester and N(ω)-nitro-L-arginine reduced vasodilator responses to BK in a selective manner, indicating that responses to BK are mediated in part by the release of NO. Methylene blue, an inhibitor of the activation of soluble guanylate cyclase, increased lobar arterial pressure and decreased responses to BK. The increases in lobar arterial pressure in response to methylene blue were partially reversed by the administration of superoxide dismutase, indicating that generation of O2/- may inactivate basally released NO. The duration of the response to BK was enhanced by the guanosine 3',5'-cyclic monophosphate (cGMP) phosphodiesterase inhibitor Zaprinast, suggesting that responses to BK involve increases in cGMP levels. Responses to BK were enhanced by captopril, indicating that BK is rapidly inactivated by kininase II in the lung. These results suggest that vasodilator responses to BK occur through activation of B2-receptors, which mediate NO release, the subsequent activation of soluble guanylate cyclase, and the elevation of cGMP levels in the pulmonary vascular bed.
DeWitt, BJ; Cheng, DY; McMahon, TJ; Nossaman, BD; Kadowitz, PJ
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