Evidence that the mechanism of the inhibitory action of pinacidil in rat and guinea-pig smooth muscle differs from that of glyceryl trinitrate.
The effects of pinacidil have been compared with those of glyceryl trinitrate (GTN) using the aorta and portal vein of the rat and the trachealis and taenia caeci of the guinea-pig. In aorta, both pinacidil and GTN inhibited responses to noradrenaline and showed some selective inhibition of contractions to 20 mM K+. Responses to 80 mM K+ were little affected. In trachealis, both pinacidil and GTN inhibited spontaneous tone and selectively relaxed spasms to 20 mM K+. Responses to 80 mM K+ were unaffected. In portal vein, pinacidil completely inhibited spontaneous electrical and mechanical activity. GTN reduced the amplitude of tension waves and extracellularly-recorded discharges, but increased the frequency of spontaneous electrical and mechanical activity. In portal vein, pinacidil inhibited contractions to noradrenaline and selectively inhibited responses to 20 mM K+. GTN had little inhibitory effect on responses to either noradrenaline or K+. In portal veins loaded with 86Rb as a K+-marker, pinacidil significantly increased the 86Rb efflux rate coefficient whilst GTN had no effect on 86Rb exchange. In taenia caeci, both pinacidil and GTN inhibited the spontaneous tone of the preparation. These inhibitory effects were not antagonized by apamin. It is concluded that pinacidil and GTN do not share a common relaxant mechanism. Evidence has been obtained that pinacidil exerts its inhibitory effects by the opening of apamin-insensitive, 86Rb-permeable K+ channels.
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000187:drug effects; D002432:Cecum / Q000187:drug effects; D005260:Female; D006146:Guanidines / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects*; D005996:Nitroglycerin / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D020110:Pinacidil; D011169:Portal Vein / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D011868:Radioisotopes / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012413:Rubidium / Q000378:metabolism; D014132:Trachea / Q000187:drug effects
D000959:Antihypertensive Agents; D006146:Guanidines; D011868:Radioisotopes; D011189:Potassium Chloride; D020110:Pinacidil; D005996:Nitroglycerin; D012413:Rubidium; D009638:Norepinephrine