Nanomolar therapeutic concentrations of statins rapidly induce cerebral artery vasoconstriction by stimulating L-type calcium channels.

All commonly prescribed statins have been reported to cause reversible memory loss within weeks of therapy, though the exact molecular mechanism remains unknown. However, whether therapeutic concentrations of statins can directly regulate the contractility of resistance cerebral arteries that control cerebrovascular perfusion remains unexplored. Here, we examined the acute vascular effects of statins on rat cerebral arteries and the underlying molecular mechanisms. Our pressure myography data demonstrate that, at therapeutically-relevant nanomolar concentrations, statins produced a robust and rapid vasoconstriction, appearing within 2-3 min of drug application. Interestingly, such vasoconstriction was largely absent in female rat cerebral arteries. Endothelial denudation or mevalonate supplementation did not alter statin-induced vasoconstriction, suggesting an endothelium- and cholesterol-independent mechanism. In contrast, such vasoconstriction was abolished upon removal of extracellular Ca2+, pharmacological blockade of the smooth muscle cell voltage-gated Ca2+ channel, CaV1.2, or siRNA knockdown of CaV1.2 - all of which reduced [Ca2+]i, indicating that Ca2+ entry through CaV1.2 plays a critical role in cerebral artery vasoconstriction. Arterial biotinylation revealed that acute statin exposure did not alter the surface expression, distribution, or function of CaV1.2 channels. Altogether, our data unveil an unexpected role of statins in rapidly inducing constriction of resistance cerebral arteries by directly stimulating CaV1.2 in smooth muscle cells. These findings offer a plausible explanation for statin-associated reversible memory impairment, its mitigation by calcium channel blockers, and why such effects may not be observed in all subjects, particularly those concurrently taking antihypertensive agents.