Acid-Sensing Ion Channels: Novel Mediators of Cerebral Vascular Responses.

RATIONALE:Precise regulation of cerebral blood flow is critical for normal brain function. Insufficient cerebral blood flow contributes to brain dysfunction and neurodegeneration. Carbon dioxide (CO₂), via effects on local acidosis, is one of the most potent regulators of cerebral blood flow. Although a role for nitric oxide in intermediate signaling has been implicated, mechanisms that initiate CO₂-induced vasodilation remain unclear. OBJECTIVE:Acid-sensing ion channel-1A (ASIC1A) is a proton-gated cation channel that is activated by extracellular acidosis. Based on work that implicated ASIC1A in the amygdala and bed nucleus of the stria terminalis in CO₂-evoked and acid-evoked behaviors, we hypothesized that ASIC1A might also mediate microvascular responses to CO₂. METHODS AND RESULTS:To test this hypothesis, we genetically and pharmacologically manipulated ASIC1A and assessed effects on CO₂-induced dilation of cerebral arterioles in vivo. Effects of inhalation of 5% or 10% CO₂ on arteriolar diameter were greatly attenuated in mice with global deficiency in ASIC1A (Asic1a^-/-) or by local treatment with the ASIC inhibitor, psalmotoxin. Vasodilator effects of acetylcholine, which acts via endothelial nitric oxide synthase were unaffected, suggesting a nonvascular source of nitric oxide may be key for CO₂ responses. Thus, we tested whether neurons may be the cell type through which ASIC1A influences microvessels. Using mice in which Asic1a was specifically disrupted in neurons, we found effects of CO₂ on arteriolar diameter were also attenuated. CONCLUSIONS:Together, these data are consistent with a model wherein activation of ASIC1A, particularly in neurons, is critical for CO₂-induced nitric oxide production and vasodilation. With these findings, ASIC1A emerges as major regulator of microvascular tone.

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