Fluoxetine Dilates Isolated Small Cerebral Arteries of Rats and Attenuates Constrictions to Serotonin, Norepinephrine, and a Voltage-Dependent Ca2+Channel Opener

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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 EC50of 7.7±1.0×10−6mol/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 (10−6to 3×10−5mol/L) significantly attenuated constrictions to serotonin (10−9to 10−5mol/L) and norepinephrine (10−9to 10−5mol/L). Increasing concentrations of Bay K 8644 (a voltage-dependent Ca2+channel opener, 10−10to 10−6mol/L) elicited constrictions, which were markedly reduced by 2×10−6and 10−5mol/L fluoxetine, whereas 3×10−5mol/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 Ca2+channel opener, as well as serotonin and norepinephrine, suggests that fluoxetine interferes with the Ca2+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.

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