Serotonin reuptake inhibitors fluoxetine and citalopram relax intestinal smooth muscle

Selective serotonin reuptake inhibitor antidepressants (SSRIs) exert depres sant effects on cardiac myocytes and vascular smooth muscle cells by inhibi ting Ca2+ channels. We hypothesized that the SSRIs fluoxetine and citalopra m affect the contractile activity of intestinal smooth muscle by interferin g with Ca2+ entry and (or) signaling pathways. The effects of fluoxetine an d citalopram on contractions of guinea-pig ileum longitudinal muscle-myente ric plexus preparations (LMMP) were compared with the effects of the voltag e-operated Ca2+ channel inhibitors nifedipine and diltiazem. In a concentra tion-dependent manner, nifedipine, diltiazem, fluoxetine, and citalopram el icited relaxation of LMMPs contracted by electrical field stimulation (EC50 values of 4 x 10(7) M, 1.4 x 10(6) M, 1.4 x 10(5), and 6.8 x 10(6) M, resp ectively). Nifedipine, diltiazem, fluoxetine, and citalopram also relaxed L MMPs contracted with a depolarizing concentration of KCl (48 mM; EC50 value s of 1.8 x 10(8) M, 1.4 x 10(7) M, 3.7 x 10(6) M, and 6.3 x 10(6), respecti vely), a response that could be reversed by increasing the extracellular Ca 2+ concentration (2.5-30 mM). These data suggest that fluoxetine and citalo pram elicit relaxation of intestinal smooth muscle, likely by inhibiting Ca 2+ channel(s). This effect may be of clinical importance.