Abstract-Linoleic acid, a polyunsaturated C 18 fatty acid, is one of the major fatty acids in the coronary arterial wall. Although diets rich in linoleic acid reduce blood pressure and prevent coronary artery disease in both humans and animals, very little is known about its mechanism of action. We believed that its beneficial effects might be mediated by changes in vascular tone. We investigated whether linoleic acid induces relaxation of porcine coronary artery rings and the mechanism involved in this process. Linoleic acid and two of its metabolites, 13-hydroxyoctadecadienoic acid (13-HODE) and 13-hydroperoxyoctadecadienoic acid (13-HPODE), induced dose-dependent relaxation of prostaglandin (PG) F 2␣ -precontracted rings that was not affected by indomethacin (10 Ϫ5 mol/L), a cyclooxygenase inhibitor, or cinnamyl-3,4-dihydroxy-␣-cyanocinnamate (CDC; 10 Ϫ5 mol/L), a lipoxygenase inhibitor. Removal of endothelial cells had no effect on vasorelaxation, suggesting a direct effect on the vascular smooth muscle cells (VSMC). When rings were contracted with KCl, linoleic acid failed to induce relaxation. Although tetrabutylammonium (5ϫ10 Ϫ3 mol/L), a nonselective K ϩ channel blocker, slightly inhibited the relaxation caused by linoleic acid, glibenclamide (10 Ϫ6 mol/L), an ATP-sensitive K ϩ channel blocker, and charybdotoxin (7.5ϫ10-activated K ϩ channel blockers, had no effect. However, relaxation was completely blocked by ouabain (5ϫ10 Ϫ7 mol/L), a NaIn addition, linoleic acid (10 Ϫ6 mol/L) caused sustained hyperpolarization of porcine coronary VSMC (from -49.5Ϯ2.0 to -60.7Ϯ4.2 mV), which was also abolished by ouabain. We concluded that linoleic acid induces relaxation and hyperpolarization of porcine coronary VSMC via a mechanism that involves activation of the Na Key Words: linoleic acid Ⅲ nitric oxide Ⅲ prostaglandins Ⅲ endothelium-derived hyperpolarizing factorinoleic acid, a polyunsaturated C 18 fatty acid (18:2n-6), is one of the main essential fatty acids, and is one of the major fatty acids in the arterial wall, 1 which can be liberated by phospholipase activity.2,3 Linoleic acid is the principal precursor of arachidonic acid (20:4n-6), which is the substrate for synthesis of prostaglandins and thromboxane A 2 . Structurally related derivatives of arachidonic acid and linoleic acid have been demonstrated in blood vessels and related tissues. Linoleic acid can be enzymatically or nonenzymatically 4 converted to 13-HPODE, which can be further reduced to 13-HODE. Production of these hydro(per)oxy metabolites has been reported in aortas from rats, rabbits, and cows, 1 and unlike the fetal calf aorta 5 their formation is independent of cyclooxygenase activity. Lipoxygenation of linoleic acid resulted in 13-HODE formation in endothelial cells.6 Linoleic acid metabolites are formed in larger quantities than the corresponding arachidonic acid metabolites, 1 suggesting that they may be of biological significance.Several studies have suggested that hypertension and cardiovascular disease are caused in part by a relat...