It is not known whether cerebral vasoprotective mechanisms in females include increased function of arterial K+ channels. We hypothesized that vasodilator responses mediated by activation of inwardly rectifying K+ (K(IR)) channels are greater in cerebral arteries of female versus male rats and that this is due to the effects of estrogen.Changes in basilar artery diameter were measured with a cranial window preparation in anesthetized Sprague-Dawley rats.K+ (5 and 10 mmol/L) caused greater vasodilatation in females (percent maximum, 21+/-3% and 58+/-7%, respectively) versus males (11+/-1% and 37+/-4%, respectively; P<0.05). In contrast, vasodilator responses to aprikalim (1 and 3 micromol/L) or acetylcholine (ACh, 1 and 10 micromol/L) did not differ between the genders. The selective K(IR) channel inhibitor barium ion (30 micromol/L) decreased basilar artery diameter in males but not females (-7+/-1% versus -2+/-1%, P<0.05) and selectively inhibited K+-induced vasodilatation by approximately 50% in both groups. Ovariectomy of female rats resulted in smaller vasodilator effects of K+, and chronic treatment of these rats with 17beta-estradiol (0.01 mg/kg per day for 7 days) normalized K+-induced vasodilatation. Furthermore, the selective M2 muscarinic ACh receptor antagonist methoctramine (1 micromol/L) increased responses to K+ in males to levels equivalent to responses in females but had no effect on responses to K+ in females.K+ is a more powerful vasodilator in the female versus male cerebral circulation. This difference is estrogen dependent and could be due to a lack of M2 muscarinic ACh receptor-induced inhibition of K(IR) channel activation by K+ in female cerebral arteries.