Serotonin reuptake inhibitor fluoxetine decreases arteriolar myogenic toneby reducing smooth muscle [Ca2+](i)

Previous studies showed that the serotonin reuptake inhibitor (SSRI) antide pressant fluoxetine (Prozac) dilates skeletal muscle and cerebral arteriole s independent of the endothelium. We hypothesized that fluoxetine affects t he contractile activity of arteriolar smooth muscle by interfering with Ca2 + signaling pathways. The effects of fluoxetine on pressure-induced tone of isolated rat skeletal muscle arterioles (similar to 110 mu m) were investi gated by videomicroscopy. Changes in smooth muscle [Ca2+](i) were measured simultaneously by the fura-2 ratiometric method. Elevation of intraluminal pressure (from 20 to 120 mm Hg) increased (by similar to 20%) the smooth mu scle calcium fluorescence ratio (R-Ca) and resulted in a significant myogen ic constriction (similar to 40%). Fluoxetine and nifedipine significantly d ecreased R-Ca (by similar to 30%) and abolished pressure-induced arteriolar tone (EC50, 3.1 x 10(-6) and 6.0 x 10(-9) M, respectively). Constrictions to the L-type Ca2+ channel opener Bay K 8644 also were inhibited and abolis hed by increasing doses of fluoxetine (3 x 10(-6) and 10(-5) M, respectivel y), In the presence of 10(-5) M fluoxetine, a concentration that elicited s ubmaximal (similar to 80%) dilation, elevation of extracellular Ca2+ concen tration (from 2.5 to 15 mM) normalized R-Ca and restored arteriolar myogeni c tone. Thus, fluoxetine reduces [Ca2+](i) and tone of arteriolar smooth mu scle, likely by interfering with Ca2+ entry. We speculate that the "calcium antagonist" effect of fluoxetine may be an additional element in the thera peutic actions of this drug.