Acetylcholine-induced endothelium-dependent contractions in the SHR aorta: the Janus face of prostacyclin.
In the spontaneously hypertensive rat (SHR) and aging Wistar-Kyoto rats (WKY), acetylcholine releases an endothelium-derived contracting factor (EDCF) produced by endothelial cyclooxygenase-1, which stimulates thromboxane A2 receptors (TP receptors) on vascular smooth muscle. The purpose of the present study was to identify this EDCF by measuring changes in isometric tension and the release of various prostaglandins by acetylcholine. In isolated aortic rings of SHR, U 46619, prostaglandin (PG) H2, PGF2alpha, PGE2, PGD2, prostacyclin (PGI2) and 8-isoprostane, all activate TP receptors of the vascular smooth muscle to produce a contraction (U 46619>>8-isoprostane=PGF2alpha=PGH2>PGE2=PGD2>PGI2). The contractions produced by PGH2 and PGI2 were fast and transient, mimicking endothelium-dependent contractions. PGI2 did not relax isolated aortic rings of WKY and SHR. Acetylcholine evoked the endothelium-dependent release of thromboxane A2, PGF2alpha, PGE2, PGI2 and most likely PGH2 (PGI2>>PGF2alpha>or=PGE2>TXA2>8-isoprostane, PGD2). Dazoxiben abolished the production of thromboxane A2, but did not influence the endothelium-dependent contractions to acetylcholine. The release of PGI2 was significantly larger in the aorta of SHR than in WKY, and the former was more sensitive to the contractile effect of PGI2 than the latter. The inhibition of PGI-synthase was associated with an increase in PGH2 spillover and the enhancement of acetylcholine-induced endothelium-dependent contractions. Thus, in the aorta of SHR and aging WKY, the endothelium-dependent contractions elicited by acetylcholine most likely involve the release of PGI2 with a concomitant contribution of PGH2.
Gluais
Pascale
P
Institut de Recherches Servier, 92150 Suresnes, France.
Lonchampt
Michel
M
Morrow
Jason D
JD
Vanhoutte
Paul M
PM
Feletou
Michel
M
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D009578:Nitrobenzenes / Q000494:pharmacology; D011453:Prostaglandins / Q000145:classification / Q000378:metabolism / Q000494:pharmacology; D044062:Prostaglandins I / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012459:Salicylates / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013928:Thromboxane A2 / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009578:Nitrobenzenes; D011453:Prostaglandins; D044062:Prostaglandins I; D012459:Salicylates; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; C401835:valerylsalicylate; C029166:dazoxiben; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000109:Acetylcholine; D007213:Indomethacin