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(Hypertension. 1998;31:237.)
© 1998 American Heart Association, Inc.

Scientific Contributions

20-HETE Relaxes Bovine Coronary Arteries Through the Release of Prostacyclin

Phillip F. Pratt; John R. Falck; Komandla M. Reddy; Jason B. Kurian; William B. Campbell

From the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin; and the Department of Biochemistry (J.R.F., K.M.R.), University of Texas, Southwestern Medical Center, Dallas, Texas.

Reprint requests to William B. Campbell, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226

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 PGF₁, the stable metabolite of prostacyclin, from bovine coronary arteries. 20-HETE (1 x 10^-6 mol/L) stimulated an increase in 6-keto PGF₁ 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.

Key Words: neutrophils • cytochrome P₄₅₀ • coronary artery • prostacyclin • endothelium • cyclooxygenase

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