Inhibitory effects of docosahexaenoic acid (DHA) on blood vessel contractions induced by various constrictor stimulants were investigated in the rat thoracic aorta. The inhibitory effects of DHA were also compared with those of eicosapentaenoic acid (EPA) and linoleic acid (LA). DHA exhibited a strong inhibitory effect on the sustained contractions induced by U46619, a TXA2 mimetic. This inhibitory effect of DHA was not affected by removal of the endothelium or by treatment with either indomethacin or Nω-nitro-l-arginine. DHA also significantly diminished PGF2α-induced contraction but did not show any appreciable inhibitory effects on the contractions to both phenylephrine (PE) and high-KCl. Similarly, EPA exhibited significant inhibitory effects against the contractions induced by both U46619 and PGF2α without substantially affecting either PE- or high-KCl-induced contractions. However, both DHA and EPA generated more potent inhibitions against contractions induced by U46619 than those by PGF2α. In contrast, LA did not show significant inhibitory effects against any contractions, including those induced by U46619. The present findings suggest that DHA and EPA elicit more selective inhibition against blood vessel contractions that are mediated through stimulation of prostanoid receptors than those through α-adrenoceptor stimulation or membrane depolarization. Although DHA and EPA have similar inhibitory potencies against prostanoid receptor-mediated contractions, they had a more potent inhibition against TXA2 receptor (TP receptor)-mediated contractions than against PGF2α receptor (FP receptor)-mediated responses. Selective inhibition by either DHA or EPA of prostanoid receptor-mediated blood vessel contractions may partly underlie the mechanisms by which these ω-3 polyunsaturated fatty acids exert their circulatory-protective effects.
Docosahexaenoic acid (DHA) shows more pronounced relaxation when blood vessel is contracted with prostanoid receptor agonists than other stimulants. The present study was carried out to obtain information on the mechanisms underlying prostanoid receptor-selective relaxant action of DHA, particularly focusing on the possible roles for K channels and its CYP epoxygenase (EOX) metabolites. In endothelium-denuded rat thoracic aorta, DHA (10 5 M) almost completely relaxed U46619 (a thromboxane A 2 (TP) receptor agonist)-contracted muscle without substantially affecting noradrenaline (NA)-induced contraction. DHA-induced relaxation was not affected by a large conductance, calcium-and voltage-activated K (BK) channels inhibitor iberiotoxin (IbTX, 10 7 M) but was almost abolished by high-KCl (8 10 2 M) or 10 2 M tetraethylammonium (TEA) which non-selectively inhibits K channel activity. DHA also prominently relaxed U46619-contracted aorta even in the presence of CYP inhibitors (SKF525A or miconazole, each at 10 5 M). However, in the presence of these CYP inhibitors, the relaxant action of DHA was not affected by 10 2 M TEA. In supporting a significant role for CYP EOX metabolites in the blood vessel relaxation to DHA, 16,17-epoxy docosapentaenoic acid (16,17-EpDPE), but not 19,20-EpDPE, showed a potent relaxation in U46619-contracted aorta, and this action was significantly attenuated by 10 2 M TEA. The present findings suggest that the relaxant action of DHA shown in the rat aorta contracted through the stimulation with TP receptor is generated by DHA itself and its CYP EOX metabolites. The relaxant effect of DHA metabolites seems to be partly triggered by the activation of K channels though the role for BK channel is insignificant.Key words docosahexaenoic acid (DHA); blood vessel relaxation; rat aorta; thromboxane A 2 receptor (TP receptor); CYP epoxygenase (EOX) Intake of fish or fish oil as a supplement is known to protect against cardiovascular disorders including coronary heart diseases, 1-3) atherosclerosis 4,5) and stroke. 6) Epidemiological studies have also indicated dietary fish oil has a blood pressure-lowering effect in hypertensive patients though this effect is weak or not observed in normotensive individuals. 7-9)These cardiovascular-protective effects of fish oil are probably attributed to docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the major n-3 polyunsaturated fatty acids (PUFAs) contained in fish oil, which show anti-inflammatory effects, reduction of platelet aggregation and of plasma triglycerides, 10,11) and so on. Of these two n-3 PUFAs, DHA may be superior to EPA as a cardiovascular protector since DHA produces more favorable improving effects on abnormal lipid profile, 12) thrombosis risk 13) and ambulatory blood pressure. 14)Although it remains poorly understood how DHA exerts its beneficial actions on the cardiovascular systems, its cardiovascular-protective effects may be partly attributed to blood vessel relaxant effects. As to this issue, we previously found out DHA more s...
Background/Aims: To investigate the potential inhibitory effects of 18 clinically available antidepressants on acetylcholine (ACh)-induced contractions in guinea pig urinary bladder smooth muscle (UBSM) in order to predict whether they may induce voiding impairment. Methods: Concentration-response curves for ACh-induced contractions in guinea pig UBSM strips were obtained in the absence or presence of selected antidepressants. When inhibitory effects indicated competitive antagonism, pA2 values against ACh were calculated and compared to plausible antidepressant blood concentrations. Results: ACh-induced contraction was antagonized competitively within clinical dose ranges by tricyclic antidepressants (imipramine, amitriptyline, trimipramine, clomipramine, nortriptyline, and amoxapine), maprotiline (a tetracyclic antidepressant), and mirtazapine (a noradrenergic and specific serotonergic antidepressant). ACh-induced contraction was also significantly inhibited by mianserin (a tetracyclic antidepressant), paroxetine and sertraline (serotonin-selective reuptake inhibitors, SSRIs), and duloxetine (a serotonin noradrenaline (norepinephrine) reuptake inhibitor, SNRI), albeit at concentrations that substantially exceeded clinically achievable blood levels. However, ACh-induced contractions were not significantly affected by fluvoxamine and escitalopram (SSRIs), milnacipran (an SNRI), trazodone (a serotonin 5-HT2A receptor antagonist), sulpiride (a dopamine D2 receptor antagonist), or aripiprazole (a dopamine partial agonist). Conclusion: These findings suggest that in addition to tricyclics, some relatively novel antidepressants such as mirtazapine can induce voiding impairment, attributed to diminished UBSM contractility from the inhibition of muscarinic receptors in the UBSM.
1Vasodilating effects of prostaglandin E1 incorporated in lipid microspheres (lipo-PGE1) were compared with those of prostaglandin E1 (PGE1) or its cyclodextrin clathrated preparation (PGE1-CD) on plantar skin blood flow in rats treated with tetrodotoxin and N(G)-nitro-L-arginine (L-NNA). Tetrodotoxin (50 microg/kg, i.v.) could totally inhibit the pressor response to electrical stimulation of the spinal cord, and the reflex tachycardia due to the depressor response to acetylcholine. Furthermore, L-NNA (30 mg/kg, i.v.) was used to counteract the lowering of the systemic blood pressure and peripheral vascular tone by elimination of sympathetic nerve activity, and to maintain the arterial blood pressure at the control level. Lipo-PGE1 increased plantar skin blood flow 4 to 6 times more potently than PGE1-CD or PGE1 in the treated rats. Furthermore, lipo-PGE1 increased plantar skin blood flow about 3 times more selectively than PGE1-CD. We also assessed several vasodilators, including terbutaline, nitroprusside, nicardipine, and papaverine in tetrodotoxin- and L-NNA-treated rats. However, none of them could selectively increase plantar blood flow despite the prominent depressor responses achieved. These results suggest that PGE1 preparations, especially lipo-PGE1 could potently and selectively increase plantar skin blood flow in rats treated with tetrodotoxin and L-NNA.
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.
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