K-CA CHANNEL ANTAGONISTS REDUCE NO DONOR-MEDIATED RELAXATION OF VASCULAR AND TRACHEAL SMOOTH-MUSCLE

Electrophysiological studies suggest that activation of large-conducta nce Ca-activated K channels (K-Ca) with nitric oxide (NO) causes hyper polarization and relaxation of smooth muscle. We determined whether K- Ca blockers decreased relaxation to the NO donors S-nitroso-N-acetylpe nicillamine (SNAP) and 3-morpholinosydnonimine-hydrochloride (SIN-1) i n isolated segments from main pulmonary artery (MPA), its left branch (LPA), aorta (Ao), carotid artery (CA), and trachea (Tr). NO donors ca used concentration-dependent relaxation of tissues precontracted with histamine whereas the inactive carrier molecule C88-3934 was without e ffect. The rank order profiles of SNAP and SIN-1 sensitivity were CA = Ao = MPA > LPA = Tr. Compared with histamine, 80 mM KCl precontractio n caused variable reductions in tissue sensitivity and maximum relaxat ion to SNAP. The K-Ca antagonists charybdotoxin, iberiotoxin, and tetr aethylammonium decreased sensitivity to SNAP and SIN-1 2- to 11-fold i n MPA, LPA, and Tr, with variable shifts in Ao and CA. The effect of i beriotoxin was not altered by removing the endothelium or epithelium. Furthermore, charybdotoxin or iberiotoxin did not alter basal or SNAP- stimulated guanosine 3',5'-cyclic monophosphate content. Glibenclamide , noxiustoxin, and leiurotoxin I, antagonists of ATP-dependent, delaye d rectifier, and small-conductance K-Ca channels, respectively, had no effect. In conclusion, antagonists of K-Ca decrease NO donor-mediated relaxation of pulmonary arterial and tracheal smooth muscle.