Role of Arachidonic Acid

Bradykinin-induced relaxation of precontracted, porcine coronary artery (PCA) rings is mediated by distinctly different endothelium-derived relaxing factors depending on the contractile agent used. Thus when contracted with KC1, bradykinin-induced relaxation of PCA rings is mediated solely by nitric oxide (NO), whereas when contracted with the thromboxane mimetic U46619, a small component of the relaxation is attributable to NO and a large component is attributable to a non-NO mechanism that is independent of cyclooxygenase activity. We hypothesized that the non-NO component was mediated by arachidonic acid (AA) or by a non-cyclooxygenase product of AA metabolism. Bradykinininduced relaxations of PCA rings precontracted with U46619 in the presence of indomethacin (10 /imol/L) were moderately attenuated by the NO synthase inhibitor W-nitro-L-arginine methyl ester (L-NAME, 100 fxmolfL), whereas when precontracted with KC1, L-NAME abolished the relaxations. AA produced endothelium-dependent relaxations of rings preconThe concept of the vascular endothelium as a fundamental participant in circulatory control is rapidly evolving.In addition to several vasoconstricting agents,at least two vasorelaxing substances of vascular endothelial origin have been identified: prostaglandin I2 (PGI2), 6 a product of cyclooxygenase-mediated arachidonic acid metabolism, and nitric oxide (NO), or a closely related compound, which is produced by the action of NO synthase on L-arginine. More recently, endothelium-dependent relaxations of several vascular tissues have been reported to occur through a mechanism(s) distinct from one involving either cyclooxygenase or NO synthase. Thus relaxation of isolated porcine coronary arterial (PCA) rings to bradykinin, for example, persisted despite inhibition of both cyclooxygenase and NO synthase. It was proposed that this relaxation was mediated by an endothelium-derived hyperpolarizing factor. Bradykinin activates phospholipase A2, 1718 purportedly through receptor-mediated increases in intracellular calcium. The activation of phospholipase A2 results in hydrolysis of tissue phospholipids, in turn releasing fatty acids, including arachidonic acid.Arachidonic From the Departments of Internal Medicine (N.L.W., S.NJ., C.A.B., R.S.S., A.J.L.) and Pharmacological and Physiological Science (A.H.S., A.J.L.), Saint Louis (Mo) University School of Medicine. Correspondence to Neal L. Weintraub, MD, Saint Louis University, School of Medicine, Division of Clinical Pharmacology, Rm M205, 1402 S Grand Blvd, St Louis, MO 63104. traded with U46619 that were unaffected by L-NAME, whereas AA did not relax rings precontracted with KC1. In rings precontracted with U46619, in the presence of L-NAME and indomethacin the phospholipase inhibitors quinacrine (50 fimolfL) and 4-bromophenacyl bromide (10 jtmol/L) attenuated bradykininbut not AA-induced relaxations. Inhibitors of both lipoxygenase (BW 755c [100 /imol/L] and nafazatrom [20 /xmol/L]) and cytochrome P-450 (proadifen [10 iimol/L] and clotrimazole [10 /xmol/L]) pathways did not eliminate bradykininor AA-induced relaxations, although clotrimazole partially attenuated AA-induced relaxations. These findings suggest that bradykinin-induced relaxation of PCA rings is mediated by AA through a mechanism that is not dependent on cyclooxygenase, lipoxygenase, or cytochrome P-450 pathways. (Hypertension. 1994;23[part 2]:976-981.)