K+ channel openers, cromakalim and Ki4032, inhibit agonist-induced Ca2+ release in canine coronary artery.
The effects of K+ channel openers, cromakalim and an acetoxyl derivative of KRN2391 (Ki4032), were studied on force of contraction, increases in intracellular calcium concentration ([Ca2+]i) measured by fura-2 and inositol 1,4,5-trisphosphate (IP3) production induced by the thromboxane A2 analogue, U46619, in canine coronary arteries. Upon single dose applications of U46619 at 300 nmol/l, phasic and tonic increases in [Ca2+]i and force were seen, which were almost abolished by cromakalim (10 mumol/l) and Ki4032 (100 mumol/l). In the absence of extracellular Ca2+, U46619 induced a transient increase in [Ca2+]i with a contraction. Cromakalim (0.01-10 mumol/l) and Ki4032 (0.1-100 mumol/l) concentration-dependently inhibited the increases in [Ca2+]i and contraction. The inhibitory effects of cromakalim and Ki4032 were blocked by the K+ channel blocker tetrabutylammonium (TBA) and counteracted by 20 mmol/l KCl-induced depolarization. Cromakalim and Ki4032 did not affect caffeine-induced Ca2+ release. Cromakalim reduced U46619-induced IP3 production significantly and TBA blocked this inhibitory effect. These results suggest that the hyperpolarization of the plasma membrane by K+ channel openers inhibits the production of IP3 and Ca2+ release from intracellular stores related to stimulation of the thromboxane A2 receptor.
Yamagishi
T
T
Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan.
Yanagisawa
T
T
Taira
N
N
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D019806:Cromakalim; D004285:Dogs; D004347:Drug Interactions; D015221:Potassium Channels / Q000187:drug effects*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors
D000959:Antihypertensive Agents; D001578:Benzopyrans; D015221:Potassium Channels; D011450:Prostaglandin Endoperoxides, Synthetic; D011725:Pyridines; D011758:Pyrroles; D014662:Vasoconstrictor Agents; D019806:Cromakalim; C074246:KI 4032; D002110:Caffeine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D002118:Calcium