SK&F 96365 inhibits histamine-induced formation of endothelium-derived relaxing factor in human endothelial cells.
Formation of endothelium-derived relaxing factor (EDRF) strictly correlates with the intracellular free Ca2+ ([Ca2+]i) concentration. We now demonstrate that the histamine-induced rise in [Ca2+]i of human umbilical vein endothelial cells is mostly due to activation of a membrane current which allows Ca2+ entry. This membrane current is sensitive to the novel inhibitor of agonist-induced Ca2+ entry, SK&F 96365, which blocked the histamine-induced sustained rise in [Ca2+]i, as well as 45Ca2+ uptake and membrane currents. Inhibition of the above cellular responses to histamine was accompanied by a considerable reduction of EDRF formation and release. Thus biosynthesis and release of EDRF from human umbilical vein endothelial cells significantly depend on agonist-induced Ca2+ entry involving receptor-operated Ca(2+)-permeable channels which can be blocked by SK&F 96365.
Graier
W F
WF
Institut für Pharmakologie und Toxikologie, Karl-Franzens-Universität Graz, Austria.
Groschner
K
K
Schmidt
K
K
Kukovetz
W R
WR
D002118:Calcium / Q000378:metabolism*; D002132:Calcium Radioisotopes; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D006632:Histamine / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D014471:Umbilical Veins
D002132:Calcium Radioisotopes; D007093:Imidazoles; D010975:Platelet Aggregation Inhibitors; D009569:Nitric Oxide; D006632:Histamine; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D002118:Calcium