Selective impairment of endothelium-dependent relaxations by prostaglandin endoperoxide

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.

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.

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.

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.