Linoleic Acid Induces Relaxation and Hyperpolarization of the Pig Coronary Artery

Abstract

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...

Low levels of linoleic acid and α-linolenic acid and high levels of arachidonic acid in plasma phospholipids are associated with hypertension

“…The possibility of detecting an association between LA and BP may be limited by imprecise measures of dietary LA, the sample size, and the degree of statistical control for potential confounders. However, consistent with the present results, animal studies indicate that LA may reduce the BP by serving as a substrate for vasoactive prostaglandins (29) and promote the relaxation of vascular smooth muscle cells (30). After adjusting for the confounding factors, logistic analysis indicated that higher quartiles of ALA, the essential n-3 PUFA, were associated with a lower prevalence of hypertension.…”

Plasma Saturated and Linoleic Fatty Acids Are Independently Associated With Blood Pressure

“…36 Animal studies suggest that 18:2n-6 may reduce blood pressure by serving as a substrate for vasoactive prostaglandins 11 and promote relaxation of vascular smooth muscle cells. 37 This study showed that plasma phospholipid total fatty acids and the proportions of saturated fatty acids and 18:2n-6 were independently associated with blood pressure and suggested that fatty acids are involved in blood pressure regulation. Additional studies are needed to determine whether these associations reflect cause-and-effect relations and whether blood pressure can decrease on a diet low in total and saturated fat and high in polyunsaturated 18:2n-6.…”

High-Fat Diet Elevates Blood Pressure and Cerebrovascular Muscle Ca 2+ Current

“…Our recent evidence demonstrates that linoleic acid, for example, can act as vascular smooth muscle hyperpolarizing factor by stimulating Na ϩ /K ϩ -ATPase activity. 16 In rabbit coronary VSMCs, longchain FAs were more effective than short-chain species in directly increasing maxi-K ϩ (BK) channel activity. 17 ⍀3-Polyunsaturated FAs (eg, eicosapentaenoic, docosahexaenoic) also inhibit receptor-mediated nonselective cationic currents in cultured A7r5 cells.…”