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(Hypertension. 1995;26:1035-1040.)
© 1995 American Heart Association, Inc.

Articles

Prostacyclin Synthesis Elicited by Endothelin-1 in Rat Aorta Is Mediated by an ET_A Receptor via Influx of Calcium and Is Independent of Protein Kinase C

Harold M. Wright; Kafait U. Malik

From the Department of Pharmacology, College of Medicine, The University of Tennessee, Memphis.

Correspondence to K.U. Malik, PhD, DSc, Department of Pharmacology, College of Medicine, The University of Tennessee, 874 Union Ave, Memphis, TN 38163. E-mail kmalik@utmem1.utmem.edu.

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, was assessed in aortic rings exposed to endothelin receptor agonists in the presence and absence of selective ET_A and ET_B receptor antagonists. ET-1, which has equal affinity for both endothelin receptor subtypes, and ET-3, a preferential ET_B receptor agonist, enhanced 6-keto-PGF₁ synthesis in a time- and concentration-dependent manner. ET-1 was more potent than ET-3 in increasing 6-keto-PGF₁ synthesis. Moreover, the selective ET_B receptor agonists IRL-1620 and sarafotoxin S6c did not significantly increase 6-keto-PGF₁ synthesis. Furthermore, ET-1–induced 6-keto-PGF₁ synthesis was attenuated by an ET_A receptor antagonist, BQ-123, in a dose-dependent manner but not by an ET_B 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 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 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 ET_A receptor and is independent of protein kinase C.

Key Words: receptors • endothelin • prostaglandins • calcium • aorta

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