Fluoxetine Dilates Isolated Small Cerebral Arteries of Rats and Attenuates Constrictions to Serotonin, Norepinephrine, and a Voltage-Dependent Ca 2+ Channel Opener

Abstract

Background and Purpose —Recent clinical observations question that the antidepressant effect of fluoxetine (Prozac) can be explained solely with serotonin reuptake inhibition in the central nervous system. We hypothesized that fluoxetine affects the tone of vessels and thereby modulates cerebral blood flow. Methods —A small branch of rat anterior cerebral artery (195±15 μm in diameter at 80 mm Hg perfusion pressure) was isolated, cannulated, and pressurized (at 80 mm Hg), and changes in diameter were measured by videomicroscopy. Results —Fluoxetine dilated small cerebral arteries with an EC 50 of 7.7±1.0×10 −6 mol/L, a response that was not affected by removal of the endothelium or application of 4-aminopyridine (an inhibitor of aminopyridine-sensitive K + channels), glibenclamide (an inhibitor of ATP-sensitive K + channels), or tetraethylammonium (a nonspecific inhibitor of K + channels). The presence of fluoxetine (10 −6 to 3×10 −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-dependent Ca 2+ channel opener, 10 −10 to 10 −6 mol/L) elicited constrictions, which were markedly reduced by 2×10 −6 and 10 −5 mol/L fluoxetine, whereas 3×10 −5 mol/L fluoxetine practically abolished the responses. Conclusions —Fluoxetine elicits substantial dilation of isolated small cerebral arteries, a response that is not mediated by endothelium-derived dilator factors or activation of K + channels. The finding that fluoxetine inhibits constrictor responses to Ca 2+ channel opener, as well as serotonin and norepinephrine, suggests that fluoxetine interferes with the Ca 2+ signaling mechanisms in the vascular smooth muscle. We speculate that fluoxetine increases cerebral blood flow in vivo, which contributes to its previously described beneficial actions in the treatment of mental disorders.