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Acidosis is a powerful vasodilator signal in the brain circulation. However, the mechanisms by which this response occurs are not well understood, particularly in the cerebral microcirculation. Ryanodine receptors (RyRs) are Ca2+ permeable channels in the sarcoplasmic reticulum. They dilate cerebral (pial) arteries by activation of large-conductance, calcium-sensitive potassium (BKCa) channels by local Ca2+ signals (Ca2+ sparks). This mechanism is clearly demonstrated by the non-additive constrictions induced by RyR or BKCa channel blockers in pressurized pial arteries. Nevertheless, these blockers have little effect on the diameter of pressurized parenchymal arterioles (PAs) from the brain, even though functional BKCa channels and RyRs are present. To determine the mechanism by which acidosis dilates brain PAs and to elucidate the roles of RyRs and BKCa channels in this response, internal diameter and vascular smooth muscle cell Ca2+ signals were measured in isolated pressurized murine PAs, using imaging techniques. At physiological pH (7.4) vascular smooth muscle cells exhibited largely Ca2+ waves but not Ca2+ sparks. Reducing external pH from 7.4 to 7.0 in both normocapnic and hypercapnic conditions decreased Ca2+wave activity, and dramatically increased Ca2+ spark activity. Acidic pH caused a dilation of PAs which was inhibited by about 60% in a non-additive manner by BKCa channel blocker (1 µM paxilline) or RyR blocker (ryanodine 10 µM). Similarly, dilator responses to acidosis were reduced by nearly 60% in arterioles from BKCa channel knockout mice. Dilations induced by acidic pH were unaltered by inhibitors of KATP channels (1 µM glibenclamide) or nitric oxide synthase (100 µM LNAME). These results support the novel concept that acidification, by converting Ca2+ waves to sparks, leads to the activation of BKCa channels to induce dilation of cerebral PAs. [ABSTRACT FROM AUTHOR]