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.

We investigated the potential inhibitory effects of docosahexaenoic acid (DHA) on the contractions of guinea pig tracheal smooth muscles in response to U46619 (a thromboxane A 2 (TXA 2 ) mimetic) and prostaglandin F 2α (PGF 2α ) to examine whether this n-3 polyunsaturated fatty acid suppresses prostanoid-induced tracheal contractions. DHA (3 10 5 M) significantly suppressed tracheal contractions elicited by lower concentrations of U46619 (10 8 M) and PGF 2α (5 10 7 M) (vs. control), although it did not suppress the contractions induced by higher concentrations (U46619: 10 7 M; PGF 2α : 10 5 M). Supporting these findings, DHA (4 10 5 M/6 10 5 M) shifted the concentration-response curves for U46619 (10 9 -10 6 M) and PGF 2α (10 8 -10 5 M) to the right. However, the slope of the regression line in the Schild plot of DHA vs. U46619/ PGF 2α was larger than unity. The tracheal contractions induced by U46619 (10 8 M) and PGF 2α (5 10 7 M) were significantly suppressed by the prostanoid TP receptor antagonist SQ 29,548 (10 6 M) (vs. ethanol-treated). In contrast, DHA (4 10 5 M) did not show significant inhibitory effects on the contractions induced by acetylcholine (10 8 -10 4 M), histamine (10 8 -10 4 M), and leukotriene D 4 (10 11 -10 7 M) (vs. ethanol-treated). These findings indicate that DHA selectively suppresses tracheal contractions induced by U46619 and PGF 2α . Therefore, DHA may be a useful therapeutic agent against asthma associated with tracheal/bronchial hyperconstriction caused by prostanoids including TXA 2 and PGF 2α .

Docosahexaenoic acid (DHA) is an n-3 polyunsaturated fatty acid abundant in fish oil. Chronic administration of DHA has been reported to improve asthma due to its anti-inflammatory effects. However, the immediate effects of DHA on isolated tracheal smooth muscle (TSM) contractility have not been studied. In this study, we investigated the potential inhibitory effects of DHA on the guinea pig TSM contractions. DHA (3 × 10 −5 M) significantly inhibited TSM contractions induced by U46619 (a thromboxane A 2 (TXA 2 ) mimetic, 10 −8 M) and prostaglandin F 2α (PGF 2α , 5 × 10 −7 M). The TSM contractions induced by U46619 (10 −8 M) and PGF 2α (5 × 10 −7 M) were significantly inhibited by SQ 29,548 (a prostanoid TP receptor antagonist, 10 −6 M). DHA (4 × 10 −5 M/6 × 10 −5 M) shifted the concentration-response curves (CRCs) for U46619 and PGF 2α to the right in a concentration-dependent manner.However, the slope of the regression line in the Schild plot of DHA vs. U46619/PGF 2α was larger than unity. In contrast, DHA (4 × 10 −5 M) did not significantly affect the CRCs for acetylcholine, histamine, and leukotriene D 4 .These findings indicate that DHA selectively inhibit prostanoid TP receptor-mediated TSM contractions. DHA may have preventive and ameliorative effects on asthma attacks associated with TSM hyper-contraction caused by TXA 2 and PGF 2α .

Administration of a P2X4 receptor antagonist to asthma model mice improved asthma symptoms, suggesting that P2X4 receptor antagonists may be new therapeutics for asthma. However, the effects of these antagonists on tracheal/bronchial smooth muscle (TSM and BSM) have not been investigated. This study examined the effects of NP-1815-PX, a selective P2X4 receptor antagonist, on guinea pig TSM and BSM contractions. In epithelium-intact TSM, NP-1815-PX (10 5 M) strongly suppressed ATP-induced contractions. ATP-induced contractions were strongly suppressed by indomethacin (3 10 6 M) and ONO-8130 (a prostanoid EP 1 receptor antagonist, 10 7 M). ATP-induced contractions were partially suppressed by SQ 29,548 (a prostanoid TP receptor antagonist, 3 10 7 M), although the difference was not significant. In contrast, ATP-induced contractions were not affected by AL 8810 (a prostanoid FP receptor antagonist, 10 5 M) or L-798,106 (a prostanoid EP 3 receptor antagonist, 10 8 M). NP-1815-PX (10 5 -10 4 M) strongly suppressed U46619 (a TP receptor agonist)-and prostaglandin F 2α (PGF 2α )-induced epithelium-denuded TSM and BSM contractions, which were largely inhibited by SQ 29,548. Additionally, NP-1815-PX (10 5 -10 4 M) strongly suppressed the U46619-induced increase in intracellular Ca 2 concentrations in human TP receptor-expressing cells. However, NP-1815-PX (10 4 M) did not substantially inhibit the TSM/BSM contractions induced by carbachol, histamine, neurokinin A, or 50 mM KCl. These findings indicate that NP-1815-PX inhibits guinea pig TSM and BSM contractions mediated through the TP receptor, in addition to the P2X4 receptor, whose stimulation mainly induces EP 1 receptor-related mechanisms. Thus, these findings support the usefulness of NP-1815-PX as a therapeutic drug for asthma.