The contribution of guanylate cyclase stimulation and K+ channel opening to nicorandil-induced vasorelaxation depends on the conduit vessel and on the nature of the spasmogen.
Nicorandil, the specific K+ channel opener aprikalim, and the stimulant of guanylate cyclase, nitroglycerin, overcame in a concentration-dependent manner the sustained contractile responses evoked by KCl (10-25 mM) and norepinephrine (25-300 nM) in endothelium-denuded rings from rabbit aorta and pulmonary and mesenteric arteries. Nicorandil exhibited similar vasorelaxant potency (EC50, 1.6-3.1 microM) in all preparations investigated. The responses to nicorandil or nitroglycerin for pulmonary artery rings contracted with the two spasmogens and for aorta rings contracted with norepinephrine were not substantially modified by the K+ channel blocker glibenclamide at a concentration (1 microM) that displaced to the right the concentration-response curve to aprikalim obtained with these preparations. However, glibenclamide shifted to the right 2- to 3-fold the concentration-response curve obtained with nicorandil in aorta rings contracted with KCl and in mesenteric artery rings contracted with either KCl or norepinephrine, but not that obtained with nitroglycerin. Methylene blue (5-10 microM), an inhibitor of guanylate cyclase, displaced to the right the control concentration-response curves to nitroglycerin 3- to 21-fold and those to nicorandil 1.5- to 11-fold, but not those to aprikalim. In rabbit mesenteric artery rings, nicorandil both stimulated guanylate cyclase and opened K+ channels, regardless of whether KCl or norepinephrine was used to contract the vessels. However, nicorandil-induced relaxation of the pulmonary artery contracted with these spasmogens and the aorta contracted with norepinephrine was mediated almost entirely by the stimulation of guanylate cyclase, whereas the dual mechanism of action was again demonstrable when the latter vessel was contracted with KCl.(ABSTRACT TRUNCATED AT 250 WORDS)
Magnon
M
M
Rhône-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, Vitry-sur-Seine, France.
Durand
I
I
Cavero
I
I
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D004789:Enzyme Activation; D006162:Guanylate Cyclase / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology; D009119:Muscle Contraction / Q000187:drug effects; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D020108:Nicorandil; D005996:Nitroglycerin / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010847:Picolines / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011189:Potassium Chloride / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011714:Pyrans / Q000494:pharmacology; D011817:Rabbits; D014655:Vascular Resistance / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
D010847:Picolines; D015221:Potassium Channels; D011714:Pyrans; D014665:Vasodilator Agents; D009536:Niacinamide; D020108:Nicorandil; C061043:aprikalim; D011189:Potassium Chloride; D006162:Guanylate Cyclase; D005996:Nitroglycerin; D009638:Norepinephrine