Docosahexaenoic acid and eicosapentaenoic acid strongly inhibit prostanoid TP receptor‐dependent contractions of guinea pig gastric fundus smooth muscle

Abstract

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.

Inhibitory mechanisms of docosahexaenoic acid on carbachol-, angiotensin II-, and bradykinin-induced contractions in guinea pig gastric fundus smooth muscle

“…Against these contractions, we showed that DHA exhibited inhibitory activity that was partly attributed to its competitive antagonism versus TP receptors; the p A 2 value of DHA versus U46619 was calculated to be 5.13 17 , which was equivalent to the value of 5.16 obtained in porcine coronary artery 10 . Functional inhibition of voltage-dependent Ca 2+ channels (VDCCs) was also assumed to be partly responsible for the DHA-induced suppression of GFSM contractions by U46619 and prostanoids 17 . Furthermore, the functional inhibition of VDCCs was shown to be involved in the DHA inhibitory actions on GP ileal/colonic longitudinal SM contractions induced by some prostanoids 18 .…”

“…We previously reported that DHA suppressed GP GFSM contractions induced by U46619 (a TXA 2 mimetic) and prostanoids 17 . In the present study, we showed that DHA significantly suppressed the maximum contractions induced by CCh/Ang II/BK, although this unsaturated fatty acid showed a significant inhibition only against BK when contractions were assessed by AUC (Fig.…”

“…We have proposed TP receptor antagonism and functional inhibition of VDCCs as the mechanisms by which DHA produces immediate inhibitory activity against SM contractions induced by a TP receptor agonist/prostanoids and non-prostanoid agonists 8 – 11 , 17 , 18 . In addition, we now show that inhibition of SOCC-mediated Ca 2+ influx is a new mechanism responsible for the DHA-induced inhibition of SM contractions (Supplementary Fig.…”

“…TP receptors play an important role in the contractile regulations of not only tonic SMs including blood vessel and tracheal SMs, but also phasic SMs including gastrointestinal tract SM 14 – 16 . For instance, we reported that TP receptors play a significant role in the contractions induced by U46619 and some prostanoids in gastric fundus (GF) SM (GFSM) in guinea pig (GP) 17 . Against these contractions, we showed that DHA exhibited inhibitory activity that was partly attributed to its competitive antagonism versus TP receptors; the p A 2 value of DHA versus U46619 was calculated to be 5.13 17 , which was equivalent to the value of 5.16 obtained in porcine coronary artery 10 .…”

“…For instance, we reported that TP receptors play a significant role in the contractions induced by U46619 and some prostanoids in gastric fundus (GF) SM (GFSM) in guinea pig (GP) 17 . Against these contractions, we showed that DHA exhibited inhibitory activity that was partly attributed to its competitive antagonism versus TP receptors; the p A 2 value of DHA versus U46619 was calculated to be 5.13 17 , which was equivalent to the value of 5.16 obtained in porcine coronary artery 10 . Functional inhibition of voltage-dependent Ca 2+ channels (VDCCs) was also assumed to be partly responsible for the DHA-induced suppression of GFSM contractions by U46619 and prostanoids 17 .…”