Serotonin reuptake inhibitor, fluoxetine, dilates isolated skeletal musclearterioles. Possible role of altered Ca2+ sensitivity

1 Inhibitors of serotonin reuptake in the central nervous system, such as f luoxetine, may also affect the function of vascular tissues. Thus, we inves tigated the effect of fluoxetine on the vasomotor responses of isolated, pr essurized arterioles of rat gracilis muscle (98 +/- 4 mu m in diameter at 8 0 mmHg perfusion pressure). 2 We have found that increasing concentrations of fluoxetine dilated arteri oles up to 155 +/- 5 mu m with an EC50 of 2.5 +/- 0.5 x 10(-6) M. 3 Removal of the endothelium, application of 4-aminopyridine (4-AP, an inhi bitor of aminopyridine sensitive K+ channels), or use of glibenclamide (an inhibitor of ATP-sensitive K+ channels) did not affect the vasodilator resp onse to fluoxetine. 4 In the presence of 10(-6), 2 x 10(-6) or 10(-5) M fluoxetine noradrenalin e (NA, 10(-9)-10(-5) M) and 5-hydroxytryptamine (5-MT, 10(-9)-10(-5) M)-ind uced constrictions were significantly attenuated resulting in concentration -dependent parallel rightward shifts of their dose-response curves (pA(2) = 6.1 +/- 0.1 and 6.9 +/- 0.1, respectively). 5 Increasing concentrations of Ca2+ (10(-4)-3 x 10(-2) M) elicited arteriol ar constrictions (up to similar to 30%), which were markedly reduced by 2x 10(-6) M fluoxetine, whereas 10(-5) M fluoxetine practically abolished thes e responses. 6 In conclusion, fluoxetine elicits substantial dilations of isolated skele tal muscle arterioles, a response which is not mediated by 4-AP- and ATP-se nsitive Ki channels or endothelium-derived dilator factors. The findings th at fluoxetine had a greater inhibitory effect on Ca2+ elicited constriction s than on responses to NA and 5-HT suggest that fluoxetine may inhibit Ca2 channel(s) or interfere with the signal transduction by Ca2+ in the vascul ar smooth muscle cells.