6-ketoprostaglandin-f1-alpha and 20-hydroxy-5-8-11-14-eicosatetraenoic-acid

Mediator contributions to hypoxic dilation of rat gracilis muscle resistance arteries were determined by measuring dilation, vascular smooth muscle hyperpolarization, and metabolite production after incremental hypoxia. Nitric oxide (NO) synthase inhibition abolished responses to mild hypoxia, whereas COX inhibition impaired responses to more severe hypoxia by 77%. Blocking 20-hydroxyeicosatetraenoic acid (20-HETE) impaired responses to moderate hypoxia. With only NO systems intact, responses were maintained with mild hypoxia (88% normal) mediated via K(Ca) channels. When only COX pathways were intact, responses to moderate-severe hypoxia were largely retained (79% of normal) mediated via K(ATP) channels. Vessel responses to moderate hypoxia were retained with only 20-HETE systems intact mediated via K(Ca) channels. NO production increased 5.6-fold with mild hypoxia; greater hypoxia was without further effect. With increased hypoxia, 20-HETE levels fell to 40% of control values. 6-keto-PGF(1alpha) levels were not altered with mild hypoxia, but increased 4.6-fold with severe hypoxia. These results suggest vascular reactivity to progressive hypoxia represents an integration of NO production (mild hypoxia), PGI(2) production (severe hypoxia), and reduced 20-HETE levels (moderate hypoxia).

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteries; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Epoprostenol; Hydroxyeicosatetraenoic Acids; Hypoxia; In Vitro Techniques; Male; Muscle, Skeletal; Nitric Oxide; Nitric Oxide Synthase; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Sprague-Dawley; Signal Transduction; Vascular Resistance; Vasodilation

Neutrophils respond to ischemic injury by infiltrating the myocardium via the vascular wall. During this process, neutrophils are activated and release inflammatory mediators. Some of these mediators are metabolites of arachidonic acid. We have reported that neutrophils metabolize arachidonic acid to 20-HETE, a cytochrome P450 metabolite. We investigated the effects of 20-HETE on coronary vascular tone by examining 20-HETE-induced changes in isometric tension in bovine coronary artery rings precontracted with the thromboxane-mimetic, U46619. 20-HETE relaxed precontracted coronary rings in a concentration-dependent manner (EC50 of 3 x 10(-7) mol/L). Pretreatment with indomethacin, a cyclooxygenase inhibitor, shifted the concentration-response curve to the right (EC50 of 1 x 10(-6) mol/L); maximal relaxations were not affected. This suggested that 20-HETE-induced relaxations were, in part, dependent on the cyclooxygenase pathway. Relaxations to 20-HETE were not significantly changed in endothelium-denuded rings. To determine whether metabolism of 20-HETE to a vasoactive compound might explain the relaxations caused by 20-HETE, rings of coronary artery were incubated with [3H] 20-HETE. The incubation buffer was extracted and the [3H] products resolved on reverse-phase HPLC. Both denuded and intact arteries failed to metabolize [3H] 20-HETE. To investigate whether 20-HETE-induced relaxations were related to release of prostacyclin, we measured the release of 6-keto PGF1alpha, the stable metabolite of prostacyclin, from bovine coronary arteries. 20-HETE (1 x 10(-6) mol/L) stimulated an increase in 6-keto PGF1alpha in intact vessels (908 +/- 138 pg/mL versus 1402 +/- 157 pg/mL, basal versus stimulated). Thus, 20-HETE-induced relaxations are due, in part, to the stimulation of the release of the dilatory prostanoid, prostacyclin.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Bradykinin; Cattle; Coronary Vessels; Epoprostenol; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Isometric Contraction; Muscle Tonus; Muscle, Smooth, Vascular; Vasodilation