Endothelium-Dependent Contractions Are Associated With Both Augmented Expressionof Prostaglandin H Synthase-1 and Hypersensitivity to Prostaglandin H 2 in the SHR Aorta

Abstract

Abstract Prostaglandin H 2 (PGH 2 [endoperoxide]) is an immediate product of prostaglandin H (PGH) synthase activity (cyclooxygenase) and a likely candidate to mediate endothelium-dependent contractions evoked by acetylcholine in the aorta of the spontaneously hypertensive rat (SHR). Experiments were designed to investigate whether or not endothelium-dependent contractions were associated with an increased expression of PGH synthase, an augmented acetylcholine-induced release of PGH 2 , and/or a hypersensitivity of the smooth muscle to endoperoxides in SHR aorta compared with normotensive Wistar-Kyoto (WKY) aorta. In SHR aorta, endothelium-dependent contractions to acetylcholine were abolished by tenidap (10 −8 mol/L), a preferential PGH synthase-1 inhibitor, but slightly impaired by NS-398 (10 −6 mol/L), a preferential PGH synthase-2 inhibitor. PGH synthase-1 expression, which was evaluated by both reverse transcriptase–polymerase chain reaction and Western blotting, was about twofold greater in preparations with endothelium from SHR than from WKY rats. There was no difference in PGH synthase-1 expression between preparations with and those without endothelium in both strains. In SHR but not WKY aortas, acetylcholine (10 −5 mol/L, 5 minutes) caused a significant endothelium-dependent release of PGH 2 , as measured by gas chromatography/mass spectrometry. PGH 2 evoked more potent contractions in rings without endothelium from SHR than from WKY rats, whereas the thromboxane analogue U46619 and prostaglandin F 2α caused a comparable response in both preparations. These results show that endothelium-dependent contractions to acetylcholine in SHR aorta are associated with a greater expression of PGH synthase-1, a significant release of PGH 2 , and a hypersensitivity of the smooth muscle to the endoperoxide.