Influence of fluoxetine and litoxetine on 5‐HT4receptor‐mediated relaxation in the rat isolated oesophagus
Authors: Lucchelli Adele , Santagostino‐Barbone Maria Grazia , Masoero Elisabetta , Baiardi Paola , Tonini Marcello 
Published: August 2009

Abstract—The influence of two selective serotonin reuptake inhibitors (SSRIs), litoxetine and fluoxetine, has been studied on 5‐HT4receptor‐mediated relaxation in the rat isolated oesophageal muscularis mucosae. In carbachol‐precontracted oesophageal tissues, 5‐hydroxytryptamine (5‐HT) (0.1 nM‐1 μM) induced concentration‐dependent relaxations. Concentration‐response curves were monophasic and reproducible. Litoxetine at concentrations without antimuscarinic properties (10 nM‐1 μM) caused concentration‐dependent relaxations, which reduced carbachol tone up to 37%. Higher litoxetine concentrations (3 μM‐300 μM) 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 μM) and a low (3 μM‐300 μM) potency phase. 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 μM). Treatment of rats with parachlorophenylalanine (pCPA: 375 mg kg−1per 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‐HT4receptor antagonist GR 125487 (10 nM) to an extent similar (P = 0.20: ANOVA for continuous‐by‐class effects) to that induced by pCPA treatment. However, in tissues from pCPA treated animals GR 125487 (10 nM) exerted a slight but significant 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 μM) increased the relaxant effects of 5‐HT, while in tissues from pCPA treated animals it exerted a small but significant depression of the maximal response to 5‐HT, without changing its potency value. Fluoxetine (1 μM) slightly, but significantly, antagonized the relaxant effect of 5‐HT in an unsurmountable manner. In conclusion, litoxetine up to 1 μM relaxed the rat isolated oesophageal muscularis mucosae through a mechanism involving release of endogenous 5‐HT, which in turn activates 5‐HT4receptors. However, based on results with GR 125487 in tissues from pCPA treated rats, a small component of litoxetine‐induced relaxation may involve a direct activation of 5‐HT4receptors. It is unlikely that blockade of 5‐HT reuptake can participate in the action of litoxetine, since fluoxetine, a 5‐HT reuptake inhibitor equipotent to litoxetine, was ineffective in the same range of concentrations. The antimuscarinic activity of litoxetine, previously demonstrated in the isolated guinea‐pig intestine, played a role at concentrations greater than 1 μM. The 5‐HT‐releasing action of litoxetine could account for the potentation by litoxetine of 5‐HT‐induced 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 slightly but unsurmountably antagonized 5‐HT‐induced relaxations, thus confirming previous observations in the guinea‐pig small intestine.