Serotonin Reuptake Inhibitor, Fluoxetine, Dilates Isolated Skeletal Muscle Arterioles. Possible Role of Altered Ca2+ Sensitivity

1. Inhibitors of serotonin reuptake in the central nervous system, such as fluoxetine, may also affect the function of vascular tissues. Thus, we investigated the effect of fluoxetine on the vasomotor responses of isolated, pressurized arterioles of rat gracilis muscle (98 +/- 4 microns in diameter at 80 mmHg perfusion pressure). 2. We have found that increasing concentrations of fluoxetine dilated arterioles up to 155 +/- 5 microns with an EC50 of 2.5 +/- 0.5 x 10(-6) M. 3. Removal of the endothelium, application of 4-aminopyridine (4-AP, an inhibitor of aminopyridine sensitive K+ channels), or use of glibenclamide (an inhibitor of ATP-sensitive K+ channels) did not affect the vasodilator response to fluoxetine. 4. In the presence of 10(-6), 2 x 10(-6) or 10(-5) M fluoxetine noradrenaline (NA, 10(-9)-10(-5) M) and 5-hydroxytryptamine (5-HT, 10(-9)-10(-5)M)-induced constrictions were significantly attenuated resulting in concentration-dependent parallel rightward shifts of their dose-response curves (pA2 = 6.1 +/- 0.1 and 6.9 +/- 0.1, respectively). 5. Increasing concentrations of Ca2+ (10(-4) 3 x 10(-2) M) elicited arteriolar constrictions (up to approximately 30%), which were markedly reduced by 2 x 10(-6)M fluoxetine, whereas 10(-5)M fluoxetine practically abolished these responses. 6. In conclusion, fluoxetine, elicits substantial dilations of isolated skeletal muscle arterioles, a response which is not mediated by 4-AP- and ATP-sensitive K+ channels or endothelium-derived dilator factors. The findings that fluoxetine had a greater inhibitory effect on Ca2+ elicited constrictions 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 vascular smooth muscle cells.