Influence of fluoxetine and litoxetine on 5-HT4 receptor-mediated relaxation in the rat isolated oesophagus

The influence of two selective serotonin reuptake inhibitors (SSRIs), litox etine and fluoxetine, has been studied on 5-HT4 receptor-mediated relaxatio n in the rat isolated oesophageal muscularis mucosae, In carbachol-precontr acted oesophageal tissues, 5-hydroxytryptamine (5-HT) (0.1 nM-l mu M) induc ed concentration-dependent relaxations. Concentration-response curves were monophasic and reproducible. Litoxetine at concentrations without antimusca rinic properties (10 nM-1 mu M) caused concentration-dependent relaxations, which reduced carbachol tone up to 37%. Higher litoxetine concentrations ( 3 mu M-300 mu M) were associated with marked relaxation up to the abolition of carbachol tone. The overall curve profile of litoxetine was biphasic in nature with a high (10 nM-1 mu M) and a low (3 mu M-300 mu M) potency phas e. Unlike 5-HT, the second curve of litoxetine was not reproducible, with a reduction involving mainly the low potency phase. Compared to litoxetine, fluoxetine caused minimal relaxation (less than 10% at 1 mu M). Treatment o f rats with parachlorophenylalanine (pCPA: 375 mg kg per day, for two days) , to deplete endogenous 5-HT stores, did not modify the relaxant effect of 5-HT, while it significantly reduced the high potency phase of litoxetine. In tissues from untreated rats, this phase was reduced by the 5-HT4 recepto r antagonist GR 125487 (10 nM) to an extent similar (P = 0.20: ANOVA fur co ntinuous-by-class effects) to that induced by pCPA treatment. However, in t issues from pCPA treated animals GR 125487 (10 nM) exerted a slight but sig nificant antagonism of litoxetine response (P = 0.037: ANOVA for continuous -by-class effects) mainly involving the high potency phase. In tissues from untreated rats, litoxetine (1 mu M) increased the relaxant effects of 5-HT , while in tissues from pCPA treated animals it exerted a small but signifi cant depression of the maximal response to 5-HT, without changing its poten cy value. Fluoxetine (1 mu M) slightly, but significantly, antagonized the relaxant effect of 5-HT in an unsurmountable manner, In conclusion, litoxet ine up to 1 mu M relaxed the rat isolated oesophageal muscularis mucosae th rough a mechanism involving release of endogenous 5-HT, which in turn activ ates 5-HT4 receptors. However, based on results with GR 125487 in tissues f rom pCPA. treated rats, a small component of litoxetine-induced relaxation may involve a direct activation of 5-HT4 receptors. It is unlikely that blo ckade of 5-HT. reuptake can participate in the action of litoxetine, since fluoxetine, a 5-HT reuptake inhibitor equipotent to litoxetine, was ineffec tive in the same range of concentrations. The antimuscarinic activity of li toxetine, previously demonstrated in the isolated guinea-pig intestine, pla yed a role at concentrations greater than 1 mu M. The 5-HT-releasing action of litoxetine could account For the potentiation by litoxetine of 5-HT-ind uced relaxation in tissues from untreated rats, which was reversed by pCPA treatment. Under these conditions, litoxetine depressed relaxations to high 5-HT concentrations only. In tissues from untreated rats, fluoxetine sligh tly but unsurmountably antagonized 5-HT-induced relaxations, thus confirmin g previous observations in the guinea-pig small intestine. (C) Elsevier, Pa ris.