title: Prostacyclin synthesis elicited by endothelin-1 in rat aorta is mediated by an ETA receptor via influx of calcium and is independent of protein kinase C.
abstract: The purpose of this study was to characterize the receptor(s) and second messenger systems involved in prostacyclin (prostaglandin [PG] I2) synthesis elicited by endothelin (ET)-1 in the rat aorta. PGI2 synthesis, measured as immunoreactive 6-keto-PGF1 alpha, was assessed in aortic rings exposed to endothelin receptor agonists in the presence and absence of selective ETA and ETB receptor antagonists. ET-1, which has equal affinity for both endothelin receptor subtypes, and ET-3, a preferential ETB receptor agonist, enhanced 6-keto-PGF1 alpha synthesis in a time- and concentration-dependent manner. ET-1 was more potent than ET-3 in increasing 6-keto-PGF1 alpha synthesis. Moreover, the selective ETB receptor agonists IRL-1620 and sarafotoxin S6c did not significantly increase 6-keto-PGF1 alpha synthesis. Furthermore, ET-1-induced 6-keto-PGF1 alpha synthesis was attenuated by an ETA receptor antagonist, BQ-123, in a dose-dependent manner but not by an ETB receptor antagonist, BQ-788. Depletion of extracellular Ca2+ or addition of Ca2+ channel blockers (nifedipine, verapamil, SK&F 96365) attenuated ET-1-mediated 6-keto-PGF1 alpha synthesis, while a Ca2+ channel agonist, S(-)-Bay K 8644, potentiated this effect of ET-1. Selective protein kinase C inhibitors (bisindolylmaleimide I, calphostin C) did not alter ET-1-induced 6-keto-PGF1 alpha synthesis. These data suggest that PGI2 synthesis elicited by ET-1 in the rat aorta is mediated primarily through influx of extracellular Ca2+ via activation of an ETA receptor and is independent of protein kinase C.
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D001011:Aorta / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology / Q000502:physiology*; D004789:Enzyme Activation; D011464:Epoprostenol / Q000096:biosynthesis*; D066298:In Vitro Techniques; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000187:drug effects / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C074308:sovateltide; D015121:6-Ketoprostaglandin F1 alpha; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D011464:Epoprostenol; D011493:Protein Kinase C; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium