Role of ryanodine receptors in acidic pH‐induced dilation of brain parenchymal arterioles

Abstract

Ryanodine receptors (RyRs) are Ca2+ permeable channels in the sarcoplasmic reticulum. RyRs regulate vascular smooth muscle cell (VSMC) membrane potential through their localized Ca2+‐release events, termed Ca2+ sparks, which activate hyperpolarizing BK currents leading to vasodilation. This mechanism is clearly demonstrated by the non‐additive constrictions induced by RyR or BK channel blockers in pressurized pial arteries. However these blockers have little effect on the diameter of pressurized parenchymal arterioles (PAs) from the brain, even though functional BK channels and RyRs are present. At normal pH (7.4), VSMCs in pressurized PAs exhibit largely Ca2+ waves but not Ca2+ sparks. Alkaline pH has been shown to shift Ca2+ sparks to Ca2+ waves in pial arteries. Therefore, we hypothesized that acidic pH might dilate PAs by reshaping the intracellular Ca2+ dynamic from Ca2+ waves to Ca2+ sparks, thereby activating BK channels. As predicted, reducing extracellular pH from 7.4 to 7.0 dramatically decreased Ca2+ wave activity, and increased spark activity. Acidic pH caused a dilation of up to 70% of the maximal diameter, and this dilation was inhibited by about 60% by BK or RyR blockers. These findings suggest that RyRs play a major role in the acidic pH‐induced dilation of PAs through Ca2+ spark‐mediated activation of BK channels. Supported by AHA 09POST2290090 (FD) and the NIH HL095488, HL44455 and HL58231.