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The inhibitory effects of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and linoleic acid (LA) on the contractions induced by five prostanoids and U46619 (a TP receptor agonist) were examined in guinea pig gastric fundus smooth muscle (GFSM). Tension changes were isometrically measured, and the mRNA expression of prostanoid receptors was measured by RT‐qPCR. DHA and EPA significantly inhibited contractions induced by the prostanoids and U46619, whereas LA inhibited those induced by prostaglandin D 2 and U46619. The mRNA expression levels of the prostanoid receptors were TP ≈ EP 3 >> FP > EP 1 . The inhibition by DHA, EPA, and LA was positively correlated with that by SQ 29,548 (a TP receptor antagonist) but not with that by L‐798,106 (an EP 3 receptor antagonist). DHA and EPA suppressed high KCl‐induced contractions by 35% and 25%, respectively, and the contractions induced by the prostanoids and U46619 were suppressed by verapamil, a voltage‐dependent Ca 2+ channel (VDCC) inhibitor, by 40%–85%. Although LA did not suppress high KCl‐induced contractions, it suppressed U46619‐induced contractions in the presence of verapamil. However, LA did not show significant inhibitory effects on U46619‐induced Ca 2+ increases in TP receptor‐expressing cells. In contrast, LA inhibited U46619‐induced contractions in the presence of verapamil, which was also suppressed by SKF‐96365 (a store‐operated Ca 2+ channel [SOCC] inhibitor). These findings suggest that the TP receptor and VDCC are targets of DHA and EPA to inhibit prostanoid‐induced contractions of guinea pig GFSM, and SOCCs play a significant role in LA‐induced inhibition of U46619‐induced contractions.

Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are n-3 polyunsaturated fatty acids (PUFAs), and are abundant in fish oil. These n-3 PUFAs have been reported to improve the lower gastrointestinal (LGI) disorders such as ulcerative colitis and Crohn's disease through their anti-inflammatory effects. However, there are few studies on the effect of n-3 PUFAs on motility of the LGI tract, such as the ileum and colon, the parts frequently affected by these inflammatory disorders. To elucidate the effects of DHA and EPA on the LGI tract motility, we performed comparative evaluation of their effects and linoleic acid (LA), an n-6 PUFA, on contractions in the ileal and colonic longitudinal smooth muscles (LSMs) isolated from guinea pigs. In the ileal and colonic LSMs, DHA and EPA (3 10 5 M each) significantly inhibited contractions induced by acetylcholine (ACh), histamine, and prostaglandin (PG) F 2α (vs. control), and these effects are stronger than that of LA (3 10 5 M). In the colonic LSMs, DHA and EPA also significantly inhibited contractions induced by PGD 2 (vs. control). In addition, DHA and EPA significantly inhibited CaCl 2 -induced ileal and colonic LSM contractions in Ca 2 -free 80 mM-KCl solution (vs. control). Any ileal and colonic LSM contractions induced by ACh, histamine, PGF 2α , and CaCl 2 were completely suppressed by verapamil (10 5 M), a voltage-gated/dependent Ca 2 channel (VGCC/VDCC) inhibitor. These findings suggest that DHA and EPA could improve the abnormal contractile functions of the LGI tract associated with inflammatory diseases, partly through inhibition of VGCC/VDCC-dependent ileal and colonic LSM contractions.

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DHA and EPA, which are n-3 polyunsaturated fatty acids (PUFAs), has been reported to improve LGI disorders such as ulcerative colitis and Crohn's disease through their anti-inflammatory effects. However, there are few studies on the effects of these PUFAs on the motilities of LGI tracts such as ileum and colon, in which these inflammatory disorders frequently occur. In order to clarify the effects of DHA and EPA on LGI tract motilities, we examined their effects on the contractions of ileal and colonic longitudinal smooth muscles (SMs) isolated from the guinea pig, by comparing them with those of an n-6 PUFA, linoleic acid (LA). In both ileal and colonic SMs, DHA and EPA (3 × 10 −5 M each) significantly inhibited any contractions due to acetylcholine (ACh), histamine, and prostaglandin (PG) F 2α , and these inhibitory effects were more potent than those of LA. DHA and EPA also significantly inhibited CaCl 2induced contractions constructed in Ca 2+ -free high-KCl solution. Any contractions induced by ACh, histamine, and PGF 2α were completely suppressed by verapamil (10 −5 M). These findings suggest that DHA and EPA could suppressLGI tracts' contractile functions excessively enhanced in association with inflammatory diseases partly through inhibition of voltage-gated Ca 2+ channel-dependent ileal and colonic SM contractions.

DHA is a typical n-3 polyunsaturated fatty acid (n-3 PUFA), and numerous epidemiological and clinical studies have shown that its intake exerts beneficial preventive effects against various cardiovascular diseases. Although possible vascular relaxation induced by DHA seems to be a mechanism underlying its cardioprotective effects, few pharmacological studies have been reported to evidence this idea. In this regard, we found that in the isolated rat thoracic aortae and mesenteric arteries, DHA shows acute and selective suppressive effects against prostanoid receptor-mediated contraction, which may partly underly its cardiovascular protective effects. In this study, we examined the possibility that DHA also shows selective suppressive effects vs. prostanoid receptor-mediated contractions in coronary and cerebral arteries. In both porcine coronary and cerebral arteries, DHA (~3 × 10 −5 M) inhibited U46619-and PGF 2α -induced contractions more potently than high (80 mM)-KCl-induced contraction.These findings suggest that DHA strongly and selectively suppresses prostanoid receptor-mediated contraction in both coronary and cerebral arteries, which suggests that this n-3 PUFA is also significant in preventing the occurrence of coronary and cerebral spasm due to contractile prostaglandins.

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Eicosapentaenoic acid (EPA) is an n-3 polyunsaturated fatty acid (PUFA) found in fish oil. We recently showed that docosahexaenoic acid (DHA), another n-3 PUFA, potently inhibited pig basilar and coronary artery contractions induced by U46619 (a TP receptor agonist) and prostaglandin (PG) F 2α . We also showed that prostanoid TP receptors are potential targets for DHA. In this study, we investigated whether EPA, like DHA, suppresses contractions of pig basilar and coronary arteries induced by U46619 and PGF 2α through inhibition of the TP receptor.EPA suppressed both U46619-and PGF 2α -induced pig basilar and coronary contractions in a concentrationdependent manner without affecting 80 mM KCl-induced contractions. U46619-/PGF 2α -induced contractions in both arteries were completely/largely suppressed by SQ 29,548 (a TP receptor antagonist). In addition, EPA suppressed U46619-/PGF 2α -induced increases in intracellular Ca 2+ concentrations ([Ca 2+ ] i ) in human TP receptoroverexpressing 293T cells, whereas it showed only a slight effect on PGF 2α -induced [Ca 2+ ] i increases in human FP receptor-overexpressing 293T cells. These findings suggest that EPA strongly suppresses TP-receptor-mediated contractions of pig basilar and coronary arteries, which can be partially attributed to its inhibitory effects on the TP receptor.