Acid-Sensing Ion Channels: Novel Mediators of Cerebral Vascular Responses.
Circ Res
; 125(10): 907-920, 2019 10 25.
Article
in En
| MEDLINE
| ID: mdl-31451088
ABSTRACT
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 ANDRESULTS:
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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Vasodilation
/
Cerebrovascular Circulation
/
Acid Sensing Ion Channels
/
Hypercapnia
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Circ Res
Year:
2019
Document type:
Article