EFFECTS OF THE NITRIC OXIDE-DONOR, GEA-3175, ON GUINEA-PIG AIRWAYS

This investigation characterized the smooth muscle relaxing effect of a novel nitric oxide (NO)-releasing substance, GEA 3175 (1,2,3,4-oxatr iazolium, methylphenyl)-5-[[(4-methylphenyl)sulfonyl]amino], hydroxide inner salt) on guinea-pig trachea. GEA 3175 caused a concentration-de pendent relaxation of tracheal smooth muscle precontracted with acetyl choline. This effect was reversed by both okadaic acid, an inhibitor o f serine/threonine-specific phosphatases, and iberiotoxin, an inhibito r of Ca2+-activated K+ channels. Furthermore, GEA 3175 had a relaxatio n potency similar to that of the commonly used NO-donor, S-nitroso-N-a cetyl-penicillamine. On the contractile response provoked by electrica l field stimulation, GEA 3175 induced a long-lasting relaxation which persisted even after repeated washing. The relaxing effect of GEA 3175 was associated with rises in guanosine 3':5'-cyclic monophosphate (cG MP). In time course studies, cGMP continued to increase with incubatio n time after stimulation with GEA 3175 and there was a significant ele vation of cGMP even after washing. In contrast, incubation with S-nitr oso-N-acetyl-penicillamine caused a transient rise in cGMP. The presen t investigation showed that GEA 3175 evokes long-lasting effects on co ntractile responses and cGMP levels in guinea-pig trachea. Our results indicate that the relaxing effect of GEA 3175 occurs through a mechan ism involving phosphatases and iberiotoxin-sensitive K+ channels. (C) 1997 Elsevier Science B.V.