SELECTIVE IMPAIRMENT OF ENDOTHELIUM-DEPENDENT RELAXATIONS BY PROSTAGLANDIN ENDOPEROXIDE

Objective: Studies of aortas from hypertensive and diabetic rats and r abbits have demonstrated impairment of endothelium-dependent relaxatio ns, which were associated with increased release of endothelium-derive d thromboxane Az (TXA(2)). This implicates enhanced release of TXA(2) or its precursor prostanoid, prostaglandin endoperoxide (PGH(2)), or b oth, as factors mediating the endothelial cell dysfunction. Methods: T he interaction of vasoconstrictor prostanoids (PGH(2), PCF2 alpha and U-46619, a stable thromboxane-receptor agonist) and oxygen-derived fre e radicals with the release of nitric oxide was examined in isolated a ortas from Sprague-Dawley rats. Results: Exogenously applied PGH(2) or U-46619 caused concentration-dependent contractions of aortic rings, these contractions being blocked by the newly developed, potent and se lective PGH(2-) and TXA(2)-receptor antagonist BMS-180291, but not by inhibition of TXA synthase or cyclo-oxygenase (using dazoxiben and ind omethacin, respectively). In aortic rings contracted submaximally with phenylephrine, brief exposure to a subthreshold concentration of PGH( 2) caused impairment of acetylcholine- and ADP-induced, but not of nit roprusside-induced, relaxations. The impairment was restored towards n ormal by BMS-180291 or by superoxide dismutase (SOD), a superoxide ani on scavenger, but not by dazoxiben or indomethacin. in contrast, treat ment of aortic rings with U-46619 or PGF(2 alpha), did not impair the relaxations. Oxygen-derived free radicals generated by xanthine oxidas e caused contractions and impaired acetylcholine relaxations which wer e reversed by SOD but not by BMS-180291. Conclusions: These findings i ndicate that activation of PGH(2) receptors causes contractions and se lective impairment of endothelium-dependent relaxations by a mechanism involving generation of oxygen-derived free radicals in the endotheli um.