15-Hydroxyeicosatetraenoic acid and diabetic endothelial dysfunction in rabbit aorta.
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.
Tesfamariam
B
B
Robert Dawson Evans Department of Clinical Research, Boston University School of Medicine, MA 02118, USA.
Brown
M L
ML
Cohen
R A
RA
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D065607:Cytochrome P-450 Enzyme Inhibitors; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005231:Fatty Acids, Unsaturated; D005947:Glucose / Q000494:pharmacology*; D006834:Hydrazines / Q000494:pharmacology; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000503:physiopathology; D011335:Proadifen / Q000494:pharmacology; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000494:pharmacology; D011817:Rabbits; D011863:Radioimmunoassay; D013482:Superoxide Dismutase / Q000494:pharmacology; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000494:pharmacology
D019086:Bridged Bicyclo Compounds, Heterocyclic; D065607:Cytochrome P-450 Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D006893:Hydroxyeicosatetraenoic Acids; D007093:Imidazoles; D011463:Prostaglandins H; D044262:Prostaglandin H2; D013928:Thromboxane A2; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; C045749:SQ 29548; D011335:Proadifen; D013482:Superoxide Dismutase; D005947:Glucose; D000109:Acetylcholine; D007213:Indomethacin