15-HYDROXYEICOSATETRAENOIC ACID AND DIABETIC ENDOTHELIAL DYSFUNCTION IN RABBIT AORTA

We examined the effects of diabetes on eicosanoid metabolism and endot helium-dependent relaxation in isolated aorta from alloxan-induced dia betic rabbits and that from normal rabbits incubated in increased conc entrations (44 mM) of glucose in vitro for 6 h. Immunoreactive 15-hydr oxyeicosatetraenoic acid (HETE) was assayed in the incubation media of isolated aortic segments. Basal and acetylcholine (ACh)-stimulated re lease of 15-HETE was significantly greater in aorta of diabetic animal s as compared with those of normal rabbits. Incubation of aortic segme nts from normal rabbits in increased concentrations of glucose caused a significant increase in basal and ACh-stimulated release of 15-HETE; and the release was significantly greater in aortic segments with end othelium than in segments without endothelium. Basal and ACh-stimulate d release of 15-HETE was inhibited by indomethacin, a cyclooxygenase i nhibitor. 15-HETE caused contractions of aortic rings that were inhibi ted by the prostaglandin H-2 (PGH(2)) thromboxane A(2) (TXA(2)) recept or blocker SQ-29548, but not by the TXA(2) synthase inhibitor carbetho xyhexyl imidazole or indomethacin. Treatment of aortic rings with subt hreshold concentrations of 15-HETE impaired ACh-induced relaxation; th is was prevented by treatment with SQ-29548. Thus, abnormal release of endothelium-derived 15-HETE may play a role in endothelial cell dysfu nction and increased vasoconstriction in diabetes by a mechanism that involves interaction with PGH(2)/TXA(2) receptors.