Fluoxetine dilates isolated small cerebral arteries of rats and attenuatesconstrictions to serotonin, norepinephrine, and a voltage-dependent Ca2+ channel opener

Background and Purpose-Recent clinical observations question that the antid epressant effect of fluoxetine (Prozac) can be explained solely with seroto nin reuptake inhibition in the central nervous system, We hypothesized that fluoxetine affects the tone of vessels and thereby modulates cerebral bloo d flow. Methods-A small branch of rat anterior cerebral artery (195 +/- 15 mu m in diameter at 80 mm Hg perfusion pressure) was isolated, cannulated, and pres surized (at 80 mm Hg), and changes in diameter were measured by videomicros copy. Results-Fluoxetine dilated small cerebral arteries with an EC50 of 7.7 +/- 1.0 x 10(-6) mol/L, a response that was not affected by removal of the endo thelium or application of 4-aminopyridine (an inhibitor of aminopyridine-se nsitive K+ channels), glibenclamide (an inhibitor of ATP-sensitive K+ chann els), or tetraethylammonium (a nonspecific inhibitor of K+ channels). The p resence of fluoxetine (10(-6) to 3 x 10(-5) mol/L) significantly attenuated constrictions to serotonin (10(-9) to 10(-5) mol/L) and norepinephrine (10 (-9) to 10(-5) mol/L), Increasing concentrations of Bay K 8644 (a voltage-d ependent Ca2+ channel opener, 10(-10) to 10(-6) mol/L) elicited constrictio ns, which were markedly reduced by 2 x 10(-6) and 10(-5) mol/L fluoxetine, whereas 3 x 10(-5) mol/L fluoxetine practically abolished the responses. Conclusions-Fluoxetine elicits substantial dilation of isolated small cereb ral arteries, a response that is not mediated by endothelium-derived dilato r factors or activation of K+ channels. The finding that fluoxetine inhibit s constrictor responses to Ca2+ channel opener, as well as serotonin and no repinephrine, suggests that fluoxetine interferes with the Ca2+ signaling m echanisms in the vascular smooth muscle. We speculate that fluoxetine incre ases cerebral blood flow in vivo, which contributes to its previously descr ibed beneficial actions in the treatment of mental disorders.