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-oxatriazolium, 3-(3-chloro-2-methylphenyl)-5-[[(4-methylphenyl)sulfonyl]amino], hydroxide inner salt) on guinea-pig trachea. GEA 3175 caused a concentration-dependent relaxation of tracheal smooth muscle precontracted with acetylcholine. This effect was reversed by both okadaic acid, an inhibitor of serine/threonine-specific phosphatases, and iberiotoxin, an inhibitor of Ca2+-activated K+ channels. Furthermore, GEA 3175 had a relaxation potency similar to that of the commonly used NO-donor, S-nitroso-N-acetyl-penicillamine. On the contractile response provoked by electrical 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 (cGMP). In time course studies, cGMP continued to increase with incubation time after stimulation with GEA 3175 and there was a significant elevation of cGMP even after washing. In contrast, incubation with S-nitroso-N-acetyl-penicillamine caused a transient rise in cGMP. The present investigation showed that GEA 3175 evokes long-lasting effects on contractile responses and cGMP levels in guinea-pig trachea. Our results indicate that the relaxing effect of GEA 3175 occurs through a mechanism involving phosphatases and iberiotoxin-sensitive K+ channels.
Johansson Rydberg
I G
IG
Department of Medicine and Care, Faculty of Health Sciences, LinköpingUniversity, Sweden.
Andersson
R G
RG
Grenegård
M
M
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019319:Okadaic Acid / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D026902:Potassium Channel Blockers; D014132:Trachea / Q000187:drug effects* / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology*
D004791:Enzyme Inhibitors; C093084:GEA 3175; D010455:Peptides; D026902:Potassium Channel Blockers; D014230:Triazoles; D019319:Okadaic Acid; D009569:Nitric Oxide; C064719:iberiotoxin; D010749:Phosphoprotein Phosphatases; D006152:Cyclic GMP; D000109:Acetylcholine