title: The relaxant action of nicorandil in bovine tracheal smooth muscle.
abstract: The relaxant mechanisms of nicorandil were examined by comparing its effects with those of sodium nitroprusside and cromakalim in bovine tracheal smooth muscle. In preparations contracted with methacholine (0.3 μ mol/l) or high K(+)(40 mmol/l), nicorandil and sodium nitroprusside caused concentration-dependent relaxations. Their relaxant effects on high K(+) -contracted preparations were smaller than those on methacholine-contracted muscle. Cromakalim relaxed methacholine-contracted preparations, whereas it had no effect on high K(+) -contracted muscle. The inhibitor of soluble guanylyl cyclase 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 5 mol/l) completely prevented the relaxation induced by lower concentrations ( <30 μ mol/l) of nicorandil,whereas it partially attenuated relaxation caused by higher concentrations. The ATP-sensitive K(+) (K(ATP)) channel blocker glibenclamide only partially attenuated the relaxant responses to nicorandil (at 100 and 300 μ mol/l). Combination treatment with ODQ and glibenclamide almost completely prevented nicorandil-induced relaxations. The large-conductance Ca2(+) -activated K(+) channel (Maxi K(+) channel) inhibitor iberiotoxin significantly prevented the relaxations induced by lower concentrations (3 and 10 μ mol/l) of nicorandil. The preventive effect of iberiotoxin was markedly enhanced under the blockade of K(ATP) channels with glibenclamide. These results suggest that nicorandil relaxes bovine tracheal smooth muscle through 2 mechanisms: opening of K(ATP) channels and activation of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway. Nicorandil may also activate Maxi K(+) channels, possibly through the NO-cGMP pathway, and the interaction of K ATP channels and Maxi K(+) channels may affect the relaxant effect of nicorandilin bovine tracheal smooth muscle.
authors.affiliation: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo, Japan.
authors.forename: Motonari
authors.initials: M
authors.lastname: Yunoki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakahara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Moriuchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Kunio
authors.initials: K
authors.lastname: Ishii
mesh_terms: D000818:Animals; D002417:Cattle; D019806:Cromakalim / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D020108:Nicorandil / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010455:Peptides; D011810:Quinoxalines; D014665:Vasodilator Agents; D019806:Cromakalim; D009599:Nitroprusside; D020108:Nicorandil; C064719:iberiotoxin; D006162:Guanylate Cyclase; D005905:Glyburide