Acidosis Dilates Brain Parenchymal Arterioles by Conversion of Calcium Waves to Sparks to Activate BK Channels

Abstract

Rationale: 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. One important mechanism to dilate cerebral (pial) arteries is by activation of large-conductance, calcium-sensitive potassium (BK Ca ) channels by local Ca 2+ signals (Ca 2+ sparks) through ryanodine receptors (RyRs). However, the role of this pathway in the brain microcirculation is not known. Objective: The objectives of this study were to determine the mechanism by which acidosis dilates brain parenchymal arterioles (PAs) and to elucidate the roles of RyRs and BK Ca channels in this response. Methods and Results: Internal diameter and vascular smooth muscle cell Ca 2+ signals were measured in isolated pressurized murine PAs, using imaging techniques. In physiological pH (7.4), vascular smooth muscle cells exhibited primarily RyR-dependent Ca 2+ waves. Reducing external pH from 7.4 to 7.0 in both normocapnic and hypercapnic conditions decreased Ca 2+ wave activity, and dramatically increased Ca 2+ spark activity. Acidic pH caused a dilation of PAs which was inhibited by about 60% by BK Ca channel or RyR blockers, in a nonadditive manner. Similarly, dilator responses to acidosis were reduced by nearly 60% in arterioles from BK Ca channel knockout mice. Dilations induced by acidic pH were unaltered by inhibitors of K ATP channels or nitric oxide synthase. Conclusions: These results support the novel concept that acidification, by converting Ca 2+ waves to sparks, leads to the activation of BK Ca channels to induce dilation of cerebral PAs.