sq-29548 and 15-hydroxy-5-8-11-13-eicosatetraenoic-acid

We examined the effects of diabetes on eicosanoid metabolism and endothelium-dependent relaxation in isolated aorta from alloxan-induced diabetic rabbits and that from normal rabbits incubated in increased concentrations (44 mM) of glucose in vitro for 6 h. Immunoreactive 15-hydroxyeicosatetraenoic acid (HETE) was assayed in the incubation media of isolated aortic segments. Basal and acetylcholine (ACh)-stimulated release of 15-HETE was significantly greater in aorta of diabetic animals as compared with those of normal rabbits. Incubation of aortic segments 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 endothelium than in segments without endothelium. Basal and ACh-stimulated release of 15-HETE was inhibited by indomethacin, a cyclooxygenase inhibitor. 15-HETE caused contractions of aortic rings that were inhibited by the prostaglandin H2 (PGH2) thromboxane A2 (TXA2) receptor blocker SQ-29548, but not by the TXA2 synthase inhibitor carbethoxyhexyl imidazole or indomethacin. Treatment of aortic rings with subthreshold concentrations of 15-HETE impaired ACh-induced relaxation; this was prevented by treatment with SQ-29548. Thus, abnormal release of endothelium-derived 15-HETE may play a role in endothelial cell dysfunction and increased vasoconstriction in diabetes by a mechanism that involves interaction with PGH2/TXA2 receptors.

Topics: Acetylcholine; Animals; Aorta, Abdominal; Bridged Bicyclo Compounds, Heterocyclic; Cytochrome P-450 Enzyme Inhibitors; Diabetes Mellitus, Experimental; Disease Models, Animal; Endothelium, Vascular; Fatty Acids, Unsaturated; Glucose; Hydrazines; Hydroxyeicosatetraenoic Acids; Imidazoles; Indomethacin; Male; Muscle Contraction; Muscle, Smooth, Vascular; Proadifen; Prostaglandin H2; Prostaglandins H; Rabbits; Radioimmunoassay; Superoxide Dismutase; Thromboxane A2