Background/Aims: Effects of docosahexaenoic acid (DHA) on blood vessel contractions to various constrictors were investigated in rat mesenteric artery and compared with those of eicosapentaenoic acid (EPA) and linoleic acid (LA). Methods: Tension changes in mesenteric ring segments were isometrically recorded. Results: On sustained contractions induced by a thromboxane A2 mimetic (U46619), DHA exerted a strong inhibitory effect. This inhibitory effect of DHA on U46619 appeared both in endothelium-intact and endothelium-denuded preparations. Although the inhibitory effect of DHA on prostaglandin F2α (PGF2α)-induced contractions was also significant, contractions to phenylephrine (PE) and high-KCI were not affected by DHA. As well as DHA, EPA strongly diminished U46619- and PGF2α-induced contractions without showing a substantial inhibition of PE- and high-KCl-induced contractions. By contrast, LA did not show any significant inhibitory effects on any contractions. The DHA-induced inhibitory actions exerted on U46619 and PGF2α also emerged if ring preparations were pretreated with this ω-3 polyunsaturated fatty acid (PUFA). Conclusion: DHA and EPA are found to more pronouncedly inhibit prostanoid receptor-mediated contractions than other constrictor responses of the mesenteric artery via endothelium-independent mechanisms. These inhibitory effects of ω-3 PUFAs on prostanoid receptor-mediated contractions may partly underlie the mechanisms by which these ω-3 PUFAs elicit protective actions against circulatory disorders.

Keywords:
Docosahexaenoic acid, Eicosapentaenoic acid, ω–3 polyunsaturated fatty acid, Thromboxane A2, Prostanoid receptor, Vascular smooth muscle
1.
Holub DJ, Holub BJ: Omega-3 fatty acids from fish oils and cardiovascular disease. Mol Cell Biochem 2004;263:217-225.
2.
Iso H, Kobayashi M, Ishihara J, Sasaki S, Okada K, Kita Y, Kokubo Y, Tsugane S; JPHC Study Group: Intake of fish and n-3 fatty acids and risk of coronary heart disease among Japanese: the Japan Public Health Center-Based (JPHC) Study Cohort I. Circulation 2006;113:195-202.
3.
León H, Shibata MC, Sivakumaran S, Dorgan M, Chatterley T, Tsuyuki RT: Effect of fish oil on arrhythmias and mortality: systematic review. BMJ 2008;337:a2931.
4.
Moreno JJ, Mitjavila MT: The degree of unsaturation of dietary fatty acids and the development of atherosclerosis (review). J Nutr Biochem 2003;14:182-195.
5.
Nakamura Y, Ueno Y, Tamaki S, Kadowaki T, Okamura T, Kita Y, Miyamatsu N, Sekikawa A, Takamiya T, El-Saed A, Sutton-Tyrrell K, Ueshima H: Fish consumption and early atherosclerosis in middle-aged men. Metabolism 2007;56:1060-1064.
6.
He K, Song Y, Daviglus ML, Liu K, van Horn L, Dyer AR, Goldbourt U, Greenland P: Fish consumption and incidence of stroke: a meta-analysis of cohort studies. Stroke 2004;35:1538-1542.
7.
Appel LJ, Miller ER 3rd, Seidler AJ, Whelton PK: Does supplementation of diet with ‘fish oil' reduce blood pressure? A meta-analysis of controlled clinical trials. Arch Intern Med 1993;153:1429-1438.
8.
Morris MC, Sacks F, Rosner B: Does fish oil lower blood pressure? A meta-analysis of controlled trials. Circulation 1993;88:523-533.
9.
Geleijnse JM, Giltay EJ, Grobbee DE, Donders AR, Kok FJ: Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. J Hypertens 2002;20:1493-1499.
10.
Kris-Etherton PM, Grieger JA, Etherton TD: Dietary reference intakes for DHA and EPA. Prostaglandins Leukot Essent Fatty Acids 2009;81:99-104.
11.
Engler MB: Vascular relaxation to omega-3 fatty acids: comparison to sodium nitroprusside, nitroglycerin, papaverine, and D600. Cardiovasc Drugs Ther 1992;6:605-610.
12.
Engler MB: Effects of omega-3, omega-6 and omega-9 fatty acids on vascular smooth muscle tone. Eur J Pharmacol 1992;215:325-328.
13.
Engler MB, Engler MM, Ursell PC: Vasorelaxant properties of n-3 polyunsaturated fatty acids in aortas from spontaneously hypertensive and normotensive rats. J Cardiovasc Risk 1994;1:75-80.
14.
Engler MB, Engler MM: Influence of aging on the relaxant responses to omega-3 fatty acids in Fischer 344 rat aorta. Gerontology 1996;42:25-35.
15.
Engler MB, Engler MM: Docosahexaenoic acid-induced vasorelaxation in hypertensive rats: mechanisms of action. Biol Res Nurs 2000;2:85-95.
16.
Otsuka K, Tanaka Y, Tanaka H, Koike K, Shigenobu K: Comparison of the inhibitory effects of docosahexaenoic acid (DHA) on U46619- and phenylephrine-induced contractions in guinea-pig aorta. Biol Pharm Bull 2005;28:1298-1300.
17.
Sato K, Chino D, Kobayashi T, Obara K, Miyauchi S, Tanaka Y: Selective and potent inhibitory effect of docosahexaenoic acid (DHA) on U46619-induced contraction in rat aorta. J Smooth Muscle Res 2013;49:63-77.
18.
Sato K, Chino D, Nishioka N, Kanai K, Aoki M, Obara K, Miyauchi S, Tanaka Y: Pharmacological evidence showing significant roles for potassium channels and CPY epoxygenase metabolites in the relaxant effects of docosahexaenoic acid on the rat aorta contracted with U46619. Biol Pharm Bull 2014;37:1-10.
19.
Mistry M, Nasjletti A: Role of TXA2 in the pathogenesis of severe angiotensin II-salt hypertension. Adv Prostaglandin Thromboxane Leukot Res 1989;19:207-210.
20.
Francois H, Athirakul K, Mao L, Rockman H, Coffman TM: Role for thromboxane receptors in angiotensin-II-induced hypertension. Hypertension 2004;43:364-369.
21.
Tanaka Y, Tang G, Takizawa K, Otsuka K, Eghbali M, Song M, Nishimaru K, Shigenobu K, Koike K, Stefani E, Toro L: Kv channels contribute to nitric oxide- and atrial natriuretic peptide-induced relaxation of a rat conduit artery. J Pharmacol Exp Ther 2006;317:341-354.
22.
Lawson DL, Mehta JL, Saldeen K, Mehta P, Saldeen TG: Omega-3 polyunsaturated fatty acids augment endothelium-dependent vasorelaxation by enhanced release of EDRF and vasodilator prostaglandins. Eicosanoids 1991;4:217-223.
23.
Hirafuji M, Machida T, Hamaue N, Minami M: Cardiovascular protective effects of n-3 polyunsaturated fatty acids with special emphasis on docosahexaenoic acid. J Pharmacol Sci 2003;92:308-316.
24.
Li X, Hong S, Li PL, Zhang Y: Docosahexaenoic acid-induced coronary arterial dilation: actions of 17S-hydroxy docosahexaenoic acid on K+ channel activity. J Pharmacol Exp Ther 2011;336:891-899.
25.
Yanagisawa A, Lefer AM: Vasoactive effects of eicosapentaenoic acid on isolated vascular smooth muscle. Basic Res Cardiol 1987;82:186-196.
26.
Asano M, Nakajima T, Iwasawa K, Hazama H, Omata M, Soma M, Yamashita K, Okuda Y: Inhibitory effects of ω-3 polyunsaturated fatty acids on receptor-mediated non-selective cation currents in rat A7r5 vascular smooth muscle cells. Br J Pharmacol 1997;120:1367-1375.
27.
Bunting S, Gryglewski R, Moncada S, Vane JR: Arterial walls generate from prostaglandin endoperoxides a substance (prostaglandin X) which relaxes strips of mesenteric and coeliac arteries and inhibits platelet aggregation. Prostaglandins 1976;12:897-913.
28.
Palmer RM, Ferrige AG, Moncada S: Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524-526.
29.
Taylor SG, Weston AH: Endothelium-derived hyperpolarizing factor: a new endogenous inhibitor from the vascular endothelium. Trends Pharmacol Sci 1988;9:272-274.
30.
Narumiya S, Sugimoto Y, Ushikubi F: Prostanoid receptors: structures, properties, and functions. Physiol Rev 1999;79:1193-1226.
31.
Takayama K, Yuhki K, Ono K, Fujino T, Hara A, Yamada T, Kuriyama S, Karibe H, Okada Y, Takahata O, Taniguchi T, Iijima T, Iwasaki H, Narumiya S, Ushikubi F: Thromboxane A2 and prostaglandin F2α mediate inflammatory tachycardia. Nat Med 2005;11:562-566.
32.
Abeywardena MY, Head RJ: Longchain n-3 polyunsaturated fatty acids and blood vessel function. Cardiovasc Res 2001;52:361-371.
33.
Swann PG, Venton DL, Le Breton GC: Eicosapentaenoic acid and docosahexaenoic acid are antagonists at the thromboxane A2/prostaglandin H2 receptor in human platelets. FEBS Lett 1989;243:244-246.
34.
McLennan P, Howe P, Abeywardena M, Muggli R, Raederstorff D, Mano M, Rayner T, Head R: The cardiovascular protective role of docosahexaenoic acid. Eur J Pharmacol 1996;300:83-89.
35.
Lai LH, Wang RX, Jiang WP, Yang XJ, Song JP, Li XR, Tao G: Effects of docosahexaenoic acid on large-conductance Ca2+-activated K+ channels and voltage-dependent K+ channels in rat coronary artery smooth muscle cells. Acta Pharmacol Sin 2009;30:314-320.
36.
Wang RX, Chai Q, Lu T, Lee HC: Activation of vascular BK channels by docosahexaenoic acid is dependent on cytochrome P450 epoxygenase activity. Cardiovasc Res 2011;90:344-352.
37.
Hoshi T, Wissuwa B, Tian Y, Tajima N, Xu R, Bauer M, Heinemann SH, Hou S: Omega-3 fatty acids lower blood pressure by directly activating large-conductance Ca2+-dependent K+ channels. Proc Natl Acad Sci USA 2013;110:4816-4821.
38.
Agbor LN, Walsh MT, Boberg JR, Walker MK: Elevated blood pressure in cytochrome P4501A1 knockout mice is associated with reduced vasodilation to omega-3 polyunsaturated fatty acids. Toxicol Appl Pharmacol 2012;264:351-360.
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