The sphingosine analog fingolimod ( FTY 720) enhances tone and contractility of rat gastric fundus smooth muscle

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Background 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 withFTY720, a sphingosine analog that is approved for the treatment of multiple sclerosis. The aim of this study was to characterize the effects ofFTY720 on rat gastric fundus smooth muscle under basal conditions and during activation induced by high‐K+solution. Methods Isometric contractions of isolated circular strips of gastric fundus smooth muscle were recorded using the organ bath method. The effects ofFTY720 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 ofFTY720 or vehicle are reported as % of the amplitude of an initial high‐K+contraction obtained under control conditions. Key Results From a concentration of 10 μmol L−1onwards,FTY720 increased the tone, reaching 8.9% ± 7.5% at 100 μmol L−1(P < .05). With indomethacin in the solution, the effects ofFTY720 were enhanced (32.1% ± 7.7%;P < .001). TheFTY720‐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. Conclusions & Inferences 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 thatFTY720 may increase gastric tone and contractility in patients.