Role of soluble guanylyl cyclase in the relaxations to a nitric oxide donor and to nonadrenergic nerve stimulation in guinea pig trachea and human bronchus

Abstract

The effect of the novel, selective, soluble guanylyl cyclase inhibitor 1 H-[1,2,4]oxadiazolol[4,3-a]quinoxalin-1-one (ODQ) on the nitric oxide component of the nonadrenergic, noncholinergic relaxation in guinea pig trachea was examined. Relaxant responses to field stimulation (1-16 Hz, 8 V, 1 ms for 15 s) in the presence of indomethacin (3 microM), atropine (1 microM), propranolol (1 microM), alpha-chymotrypsin (2 U/ml) and histamine (3 microM) were partially inhibited by 0.1 microM ODQ and almost abolished by 1 microM ODQ. In addition, relaxations to the nitric oxide donor 3-morpholinosyndnonimine-N-ethylcarbamide were partially inhibited by 0.1 microM ODQ and abolished by 1 microM ODQ. Relaxations to 3-morpholinosyndnonimine-N-ethylcarbamide in human bronchus were also substantially inhibited by ODQ (1-10 microM). By contrast, relaxations elicited by the stable 3',5'-cyclic monophosphate analog 8-bromoguanosine-3',5'-cyclic monophosphate and by isoproterenol were unaffected by 1 microM ODQ in guinea pig trachea and by 10 microM ODQ in human bronchus. These results suggest that relaxant responses to endogenously released or exogenously added nitric oxide in guinea pig trachea and human bronchus are mediated via the activation of soluble guanylyl cyclase and the formation of guanosine-3',5'-cyclic monophosphate.