Short-term regulation of endothelin receptor-mediated phosphoinositide hydrolysis and arachidonic acid release in A7r5 smooth-muscle cells.
In this study, the short-term regulation of endothelin-1-(ET-1) induced phosphoinositide (PI) hydrolysis and arachidonic acid release were investigated in cultured rat aortic smooth-muscle cells. ET-1, but not the ETB-selective peptide sarafotoxin (SFX) S6c, induced a dose-dependent increase in [3H]inositol phosphate release (EC50 = 0.4 +/- 0.1 nM). ET-3 stimulated this response only at concentrations > 0.1 microM. The ETA receptor antagonist BQ-123 inhibited ET-1-induced PI turnover, with an IC50 value of 97 +/- 15 nM. Pre-exposure of intact cells to ET-1 resulted in a 72% and 73% reduction in the ability of ET-1 or SFX S6b, respectively, to stimulate [3H]inositol phosphate release, without affecting the response to vasopressin. In contrast, PI turnover induced by ET-1 or SFX S6b was only slightly lowered, by 28% and 22%, after a 30-min preincubation period with SFX S6b. ET-1, but not SFX S6c, also stimulated [3H]arachidonic acid release by two-fold (EC50 = 3 +/- 0.8 nM). Pretreatment of intact cells with neomycin or phorbol-12-myristate-13-acetate resulted in a 49% and 44% inhibition of ET-1-induced [3H]inositol phosphate accumulation but did not decrease ET-1-stimulated [3H]arachidonic acid release, suggesting that these responses are separately regulated events in these cells.
Cioffi
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CL
Research Department, Ciba-Geigy Corporation, Summit, New Jersey 07901.
Garay
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D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D002478:Cells, Cultured; D016232:Endothelins / Q000494:pharmacology; D006868:Hydrolysis; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D017466:Receptors, Endothelin / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D001095:Arachidonic Acids; D016232:Endothelins; D010716:Phosphatidylinositols; D017466:Receptors, Endothelin; D014665:Vasodilator Agents; D014757:Viper Venoms; C057354:sarafotoxins s6