Selective impairment of endothelium-dependent relaxations by prostaglandin endoperoxide.
OBJECTIVE: Studies of aortas from hypertensive and diabetic rats and rabbits have demonstrated impairment of endothelium-dependent relaxations, which were associated with increased release of endothelium-derived thromboxane A2 (TXA2). This implicates enhanced release of TXA2 or its precursor prostanoid, prostaglandin endoperoxide (PGH2), or both, as factors mediating the endothelial cell dysfunction. METHODS: The interaction of vasoconstrictor prostanoids (PGH2, PGF2 alpha and U-46619, a stable thromboxane-receptor agonist) and oxygen-derived free radicals with the release of nitric oxide was examined in isolated aortas from Sprague-Dawley rats. RESULTS: Exogenously applied PGH2 or U-46619 caused concentration-dependent contractions of aortic rings, these contractions being blocked by the newly developed, potent and selective PGH2- and TXA2-receptor antagonist BMS-180291, but not by inhibition of TXA synthase or cyclo-oxygenase (using dazoxiben and indomethacin, respectively). In aortic rings contracted submaximally with phenylephrine, brief exposure to a subthreshold concentration of PGH2 caused impairment of acetylcholine- and ADP-induced, but not of nitroprusside-induced, relaxations. The impairment was restored towards normal by BMS-180291 or by superoxide dismutase (SOD), a superoxide anion scavenger, but not by dazoxiben or indomethacin. In contrast, treatment of aortic rings with U-46619 or PGF2 alpha did not impair the relaxations. Oxygen-derived free radicals generated by xanthine oxidase caused contractions and impaired acetylcholine relaxations which were reversed by SOD but not by BMS-180291. CONCLUSIONS: These findings indicate that activation of PGH2 receptors causes contractions and selective impairment of endothelium-dependent relaxations by a mechanism involving generation of oxygen-derived free radicals in the endothelium.[1]References
- Selective impairment of endothelium-dependent relaxations by prostaglandin endoperoxide. Tesfamariam, B. J. Hypertens. (1994) [Pubmed]
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