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(Hypertension. 1996;28:76-82.)
© 1996 American Heart Association, Inc.

Articles

Mediators of Arachidonic Acid–Induced Relaxation of Bovine Coronary Artery

Phillip F. Pratt; Mark Rosolowsky; William B. Campbell

the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas.

Bovine coronary arteries relax in response to bradykinin, methacholine, sodium nitroprusside, isoproterenol, and arachidonic acid in a concentration-dependent manner. The relaxations to methacholine, bradykinin, and arachidonic acid are lost when endothelium is removed. Indomethacin, a cyclooxygenase inhibitor, attenuated the relaxations to methacholine, bradykinin, and arachidonic acid and shifted the EC₅₀ (control versus indomethacin) to each (1x10^-7 versus 3x10^-7 mol/L, 3x10^-10 versus 2x10^-9 mol/L, and 3x10^-7 versus 2x10^-6 mol/L, respectively). Nitro-L-arginine, a nitric oxide synthase inhibitor, also attenuated the relaxations to methacholine, bradykinin, and arachidonic acid and shifted the EC₅₀ (control versus nitro-L-arginine) to each (1x10^-7 versus 3x10^-7 mol/L, 3x10^-10 versus >10^-9 mol/L, and 3x10^-7 versus >10^-6 mol/L, respectively). The combination of indomethacin and nitro-L-arginine blunted the relaxations to these agents and also shifted the EC₅₀ values (control versus indomethacin plus nitro-L-arginine) to each (1x10^-7 versus 5x10^-7 mol/L, 3x10^-10 versus >10^-9 mol/L, and 3x10^-7 versus >10^-6 mol/L, respectively). Methacholine, bradykinin, and arachidonic acid stimulated the release of prostaglandin I₂, measured as 6-keto-PGF₁. Indomethacin, but not nitro-L-arginine, inhibited arachidonic acid–induced release of 6-keto-PGF₁. Vascular cGMP content was unchanged by arachidonic acid but was significantly elevated by bradykinin. Relaxations to prostaglandin I₂ and sodium nitroprusside, but not 8,9-epoxyeicosatrienoic acid or isoproterenol, were inhibited by nitro-L-arginine. We conclude that the endothelium-dependent relaxations to methacholine, bradykinin, and arachidonic acid are partly due to prostaglandin I₂ release. The remainder of the responses to these agents is due to the release of other relaxing factor or factors. Since bradykinin increased cGMP and nitro-L-arginine partially inhibited its relaxant effects, nitric oxide also appears to participate in the bradykinin-induced effect. Since the combination of indomethacin and nitro-L-arginine failed to completely block the relaxations to methacholine, bradykinin, and arachidonic acid, another endothelial factor must contribute to their vascular effects. Surprisingly, nitro-L-arginine attenuated the relaxations to arachidonic acid; however, L-arginine failed to reverse the effects of nitro-L-arginine on arachidonic acid–induced relaxations. In addition, arachidonic acid failed to increase cGMP. Nitro-L-arginine also reduced the responses to prostaglandin I₂ and sodium nitroprusside. These data indicate that these arginine analogues may have effects other than competitive inhibition of nitric oxide synthase.

Key Words: eicosanoids • endothelium • muscle, smooth, vascular • bradykinin • methacholine chloride • nitric oxide

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