Signal Transduction Underlying the Inhibitory Mechanism of Fluoxetine on Electrical Field Stimulation Response in Rat Ileal Smooth Muscle

Abstract

Fluoxetine (FLX), a well-known antidepressant drug under the class of selective serotonin reuptake inhibitor, exerts its action by inhibiting the reuptake of serotonin selectively. In some studies, it has been demonstrated that FLX relaxes the intestinal smooth muscle. In this study, we aimed at studying the signal transduction pathway underlying the muscle relaxation effect of FLX on electrically stimulated rat ileal muscle contraction. To investigate the possible mechanism involved, various antagonists were used. It was found that inhibition with L-N^G-nitroarginine methyl ester, ondansetron, GR113808 and bicuculline enhanced the relaxation effect of FLX. However, the effect of FLX was nullified under the presence of atropine, calcium channel modulator (calcium ionophore A23187), and potassium channel blockers (tetraethylammonium chloride, 4-aminopyridine and glybenclamide). Specific pathway-inhibiting antagonists, Y27632 (Rho-kinase inhibitor) and U73122 (phospholipase-C inhibitor) reversed the antagonistic effect of FLX, while ML-9 (myosin light chain kinase inhibitor) and chelerythrine (protein kinase C inhibitor) augmented the FLX-induced inhibition effect. Taken together, we concluded that FLX exerts the inhibitory effect on electric field stimulation response in rat ileal smooth muscle by the inhibition of muscarinic receptors, decrease of intracellular calcium level by inhibiting phospholipase C and opens the potassium channels.

Effects of selective serotonin reuptake inhibitors on motility of isolated fallopian tube

“…In addition to inhibition of serotonin reuptake that is common to all SSRIs, some of these antidepressants also have other effects, primarily at the level of smooth muscle cells and specificity of these effects is predominantly the result of significant differences in their chemical structures . The studies conducted on animal models have shown that fluoxetine causes dilatation of cerebral arterioles and skeletal muscle arterioles, as well as inhibition of the potassium‐induced contraction of the isolated uterine artery .…”

“…It is known that SSRIs relax intestinal smooth muscle cells . It is believed that SSRIs primarily achieve these effects acting on voltage‐dependent channels for sodium (Na + ), potassium (K + ) and calcium (Ca 2+ ) ions.…”

“…3 It is known that SSRIs relax intestinal smooth muscle cells. 6,7 It is believed that SSRIs primarily achieve these effects acting on voltage-dependent channels for sodium (Na + ), potassium (K + ) and calcium (Ca 2+ ) ions. Throughout the concentration range from 0.5 to 50 μmol/L (which includes concentrations necessary for main actions of SSRIs on central nervous system), fluoxetine and citalopram exhibit depressant effects on Ca 2+ and Na + channels, while at concentrations of 0.1-10 μmol/L they cause relaxation of vascular and intestinal smooth muscles.…”