Acetylcholine-induced endothelium-dependent contractions in the SHR aorta: the Janus face of prostacyclin.
Journal: 2006/February - British Journal of Pharmacology
ISSN: 0007-1188
Abstract:
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.
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Br J Pharmacol 146(6): 834-845

Acetylcholine-induced endothelium-dependent contractions in the SHR aorta: the Janus face of prostacyclin

Institut de Recherches Servier, 92150 Suresnes, France
Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, U.S.A.
Department of Pharmacology, Faculty of Medicine, Hong Kong, China
Author for correspondence: moc.srgten.rf@uotelef.lehcim
Received 2005 May 31; Revised 2005 Jul 12; Accepted 2005 Aug 11.

Abstract

  1. 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.

  2. In isolated aortic rings of SHR, U 46619, prostaglandin (PG) H2, PGF2α, PGE2, PGD2, prostacyclin (PGI2) and 8-isoprostane, all activate TP receptors of the vascular smooth muscle to produce a contraction (U 46619≫8-isoprostane=PGF2α=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.

  3. Acetylcholine evoked the endothelium-dependent release of thromboxane A2, PGF2α, PGE2, PGI2 and most likely PGH2 (PGI2≫PGF2α⩾PGE2>TXA2>8-isoprostane, PGD2). Dazoxiben abolished the production of thromboxane A2, but did not influence the endothelium-dependent contractions to acetylcholine.

  4. 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.

  5. 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.

Keywords: Endothelium-dependent contractions, TP receptors, spontaneously hypertensive rat, prostaglandins, endoperoxide, prostacyclin
Abstract

Acknowledgments

We thank M. Gaudin and M. Germain for technical assistance. Dr J. Morrow was supported by NIH grants DK48831, GM15431, CA77839, RR00095.

Acknowledgments

Abbreviations

COXcyclooxygenase
EDCFendothelium-derived contracting factor(s)
NOSnitric oxide synthase
L-NAN-nitro-L-arginine
SHRspontaneously hypertensive rat
PGH2prostaglandin H2
PGI2prostacyclin
WKYWistar–Kyoto rats
Abbreviations
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