dinoprost and 15-hydroperoxy-5-8-11-13-eicosatetraenoic-acid

Selenium (Se) is an integral part of the Se-dependent glutathione peroxidase (Se-GSH-Px) catalytic domain. By modulating the cellular levels of fatty acid hydroperoxides, Se-GSH-Px can influence key enzymes of arachidonic acid cascade, in this case cyclooxygenase (COX) and lipoxygenase (LOX). To investigate this phenomenon, the effects of cellular Se status on the enzymatic oxidation of arachidonic acid were investigated in bovine mammary endothelial cells (BMEC), which were cultured in either Se-deficient (-Se) or Se-adequate (+Se) media. When stimulated with calcium ionophore A23187, BMEC produced eicosanoids of both COX and LOX pathways. Compared with the Se-adequate cells, the production of prostaglandin I(2) (PGI(2)), prostaglandin F(2) (PGF(2alpha)), and prostaglandin E(2) (PGE(2)) was significantly decreased in Se-deficient cells, whereas the production of thromboxane A(2) (TXA(2)) was markedly increased in the -Se BMEC cultures. Although the enzymatic oxidation of arachidonic acid by the LOX pathway was found to be relatively less than by the COX pathway, the BMEC cultured in -Se media produced significantly more 15-hydroperoxyeicosatetraenoic acid (15-HPETE) than the +Se cells produced. Based on these results, we postulate that cellular Se status plays an important regulatory role in the enzymatic oxidation of arachidonic acid by the COX and LOX pathways. The altered eicosanoid biosynthesis, especially the overproduction of 15-HPETE, in -Se BMEC may be one of the underlying biochemical phenomena responsible for vascular dysfunction during Se deficiency.

Topics: Animals; Arachidonic Acid; Calcimycin; Cattle; Cells, Cultured; Culture Media; Dinoprost; Dinoprostone; Eicosanoids; Endothelium, Vascular; Epoprostenol; Female; Leukotrienes; Lipid Peroxides; Lipoxygenase; Mammary Arteries; Oxidation-Reduction; Prostaglandin-Endoperoxide Synthases; Selenium; Thromboxane A2

The lipoxygenase product 15-hydroxyeicosatetraenoic acid (15-HETE) was shown to be the most important eicosanoid formed in the atherosclerotic rabbit aorta. The aim of the present study was to compare the effects of 15-HETE and its hydroperoxy precursor 15-HpETE with those of other vasoconstrictor and vasodilator agents in arteries from rabbits fed either a control or a cholesterol-rich diet for 16 and 30 weeks. 5-Hydroxytryptamine (5-HT) aggregated platelets and thrombin caused contractions of isolated rabbit aortas. The contractile responses elicited by platelets from control animals were similar to those evoked by platelets from atherosclerotic rabbits. After 16 weeks of hypercholesterolemia, the contractile responses were either augmented (5-HT), unchanged (platelets) or reduced (thrombin). After 30 weeks of hypercholesterolemia, the responses to all contractile agents used had decreased. In both aortas and pulmonary arteries the endothelium-dependent relaxations to the calcium ionophore, A23167, and to acetylcholine were progressively lost and the endothelium-independent relaxations to nitroglycerin were reduced by the progressing hypercholesterolemia. The 15-lipoxygenase metabolites contracted the isolated thoracic aorta and pulmonary artery from control rabbits and to a lesser extent those of the cholesterol-fed rabbits. After raising the tone in these vessels with prostaglandin F2 alpha PGF2 alpha) or noradrenaline, 15-HpETE induced relaxations which were not significantly influenced by the development of fatty streaks. Our data illustrate that the contractions of the blood vessel wall to 15-HETE, like those to other vasoconstrictors, are markedly reduced by developing atherosclerosis. In contrast, the relaxations to 15-HpETE in the rabbit arteries remain unaltered after 16 to 30 weeks of hypercholesterolemia. This is unlike the reactions to other vasodilators, which are markedly reduced.

Topics: Acetylcholine; Animals; Arachidonate 15-Lipoxygenase; Arteriosclerosis; Calcimycin; Dinoprost; Hydroxyeicosatetraenoic Acids; Hypercholesterolemia; In Vitro Techniques; Leukotrienes; Lipid Peroxides; Male; Muscle, Smooth, Vascular; Nitroglycerin; Platelet Aggregation; Rabbits; Thrombin; Vasoconstrictor Agents; Vasodilator Agents

The 15-hydroperoxy metabolite of arachidonic acid (15-hydroperoxyeicosatetraenoic acid; 15-HPETE) and its hydroxyderivative 15-hydroxyeicosatetraenoic acid (15-HETE) are known to evoke contractions in a variety of isolated blood vessels. In this study, segments of isolated canine coronary, splenic, femoral and renal arteries were exposed to 15-HETE and 15-HPETE; both metabolites induced small basal relaxations followed by contractions at higher concentrations. The contractions were augmented by indomethacin and could be blocked by the thromboxane A2 receptor antagonists BM13177 and BM13505. In vessels in which the tone was raised with prostaglandin F2 alpha, both 15-lipoxygenase metabolites evoked marked relaxations, which were in part dependent on the presence of the endothelium. When the segments were contracted with norepinephrine or increased KCl concentration, 15-HETE and 15-HPETE induced relaxations followed by additional contractions. The relaxations to the fatty acid derivatives were not inhibited by BM13505. In tissues without endothelium, the relaxations to 15-HETE and 15-HPETE were completely blocked by indomethacin; in tissues with endothelium, indomethacin only partly inhibited the relaxations to 15-HETE, whereas the drug did not interfere with the relaxing effects of 15-HPETE. Our experiments indicate that in isolated canine arteries 15-lipoxygenase metabolites of arachidonic acid can 1) induce contractions, most likely by direct activation of thromboxane A2 receptors on smooth muscle cells, and 2) evoke relaxations that are in part endothelium dependent; the endothelium-independent part of the relaxations was inhibited by indomethacin. Thus, the relaxations to these metabolites seem to occur via the release of an endothelium-derived relaxing factor and via production of a cyclooxygenase metabolite.

Topics: Animals; Arachidonate 15-Lipoxygenase; Arachidonic Acid; Arachidonic Acids; Arteries; Coronary Vessels; Cyclooxygenase Inhibitors; Dinoprost; Dogs; Dose-Response Relationship, Drug; Endothelium; Femoral Artery; Hydroxyeicosatetraenoic Acids; Indomethacin; Leukotrienes; Lipid Peroxides; Muscle Contraction; Muscle Relaxation; Receptors, Prostaglandin; Receptors, Thromboxane; Renal Artery; Splenic Artery