The sphingosine analog fingolimod (FTY720) enhances tone and contractility of rat gastric fundus smooth muscle.

Abstract

Sphingosine and its metabolite sphingosine phosphate (S1P) regulate a multitude of biological functions, including the contractile state of smooth. Gastrointestinal side effects have been reported in patients treated with FTY720, a sphingosine analog that is approved for the treatment of multiple sclerosis. The aim of this study was to characterize the effects of FTY720 on rat gastric fundus smooth muscle under basal conditions and during activation induced by high-K+ solution. Isometric contractions of isolated circular strips of gastric fundus smooth muscle were recorded using the organ bath method. The effects of FTY720 or vehicle were recorded under control conditions and in the presence of indomethacin, L-NAME, HA-1100, nifedipine, JTE-013, and suramin. Tone and contractions recorded in the presence of FTY720 or vehicle are reported as % of the amplitude of an initial high-K+ contraction obtained under control conditions. From a concentration of 10μmol L-1 onwards, FTY720 increased the tone, reaching 8.9%±7.5% at 100μmol L-1 (P<.05). With indomethacin in the solution, the effects of FTY720 were enhanced (32.1%±7.7%; P<.001). The FTY720-induced increase in tone was abolished in the absence of extracellular Ca2+ and reduced by nifedipine, HA-1100, JTE-013, and suramin. Furthermore, FTY720 increased high-K+ contractions in the presence of indomethacin. FTY720 increases tone and contractile responses to depolarization in gastric fundus smooth muscle by triggering calcium entry and calcium sensitization in a S1P receptor-dependent manner. Taken together, the experimental results presented in this work suggest that FTY720 may increase gastric tone and contractility in patients.