Effects of SK&F 96365 and mefenamic acid on Ca2+ influx in stimulated endothelial cells and on endothelium-derived hyperpolarizing factor-mediated arterial hyperpolarization and relaxation.
This study was undertaken to assess how Ca2+ influx into endothelial cells via Ca2+-permeable nonselective cation channels (NSCCs) is important in vascular responses mediated by endothelium-derived hyperpolarizing factor (EDHF). In cultured porcine aortic endothelial cells, the sustained increases in the intracellular Ca2+ concentration ([Ca2+]i) elicited by bradykinin and cyclopiazonic acid, which were strongly dependent on the presence of extracellular Ca2+, were suppressed by the NSCC blockers, SK&F 96365 and mefenamic acid. In porcine coronary artery with intact endothelium, bradykinin elicited a rapid fall in the membrane potential, followed by sustained hyperpolarization with a slow decay. In the presence of SK&F 96365 or mefenamic acid, the peak amplitude was severely reduced and the decay phase of hyperpolarization to bradykinin was greatly accelerated, which was apparently similar to the response obtained in Ca2+-free medium. Cyclopiazonic acid caused sustained hyperpolarization in an extracellular Ca2+-dependent manner, an effect which was markedly diminished by SK&F 96365 and mefenamic acid. In rings of coronary artery precontracted with U46619, bradykinin and cyclopiazonic acid produced endothelium-dependent relaxations even in the presence of N(G)-nitro-L-arginine and indomethacin. SK&F 96365 and mefenamic acid significantly attenuated the relaxant responses. These results indicate that the increase in [Ca2+]i of endothelial cells due to Ca2+ entry via NSCCs plays a crucial role in the maintenance of the EDHF-mediated vascular responses.
Fukao
M
M
Department of Pharmacology, Hokkaido University, School of Medicine, Sapporo, Japan.
Watanabe
H
H
Takeuchi
K
K
Tomioka
H
H
Hattori
Y
Y
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016232:Endothelins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D008528:Mefenamic Acid / Q000494:pharmacology*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D002121:Calcium Channel Blockers; D016861:Cyclooxygenase Inhibitors; D016232:Endothelins; D007093:Imidazoles; D007211:Indoles; D014665:Vasodilator Agents; D008528:Mefenamic Acid; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D001920:Bradykinin; D002118:Calcium; C000543:cyclopiazonic acid