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

Frank M Faraci; Rebecca J Taugher; Cynthia Lynch; Rong Fan; Subhash Gupta; John A Wemmie

doi:10.1161/CIRCRESAHA.119.315024

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

Journal article

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

Frank M Faraci, Rebecca J Taugher, Cynthia Lynch, Rong Fan, Subhash Gupta and John A Wemmie

Circulation research, Vol.125(10), pp.907-920

10/25/2019

DOI: 10.1161/CIRCRESAHA.119.315024

PMID: 31451088

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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 (CO 2 ), 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 CO 2 -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 CO 2 -evoked and acid-evoked behaviors, we hypothesized that ASIC1A might also mediate microvascular responses to CO 2 . Methods and Results: To test this hypothesis, we genetically and pharmacologically manipulated ASIC1A and assessed effects on CO 2 -induced dilation of cerebral arterioles in vivo. Effects of inhalation of 5% or 10% CO 2 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 CO 2 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 CO 2 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 CO 2 -induced nitric oxide production and vasodilation. With these findings, ASIC1A emerges as major regulator of microvascular tone.

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Title: Subtitle: Acid-Sensing Ion Channels: Novel Mediators of Cerebral Vascular Responses
Creators: Frank M Faraci - From the Departments of Internal Medicine (F.M.F., C.L.), Department of Veterans Affairs Medical Center, Francois M. Abboud Cardiovascular Center, Papajohn Biomedical Institute, Carver College of Medicine, University of Iowa, Iowa City., Pharmacology (F.M.F.), Department of Veterans Affairs Medical Center, Francois M. Abboud Cardiovascular Center, Papajohn Biomedical Institute, Carver College of Medicine, University of Iowa, Iowa City
Rebecca J Taugher - Psychiatry (R.J.T., R.F., S.G., J.A.W.), Department of Veterans Affairs Medical Center, Francois M. Abboud Cardiovascular Center, Papajohn Biomedical Institute, Carver College of Medicine, University of Iowa, Iowa City
Cynthia Lynch - From the Departments of Internal Medicine (F.M.F., C.L.), Department of Veterans Affairs Medical Center, Francois M. Abboud Cardiovascular Center, Papajohn Biomedical Institute, Carver College of Medicine, University of Iowa, Iowa City
Rong Fan - Psychiatry (R.J.T., R.F., S.G., J.A.W.), Department of Veterans Affairs Medical Center, Francois M. Abboud Cardiovascular Center, Papajohn Biomedical Institute, Carver College of Medicine, University of Iowa, Iowa City
Subhash Gupta - Psychiatry (R.J.T., R.F., S.G., J.A.W.), Department of Veterans Affairs Medical Center, Francois M. Abboud Cardiovascular Center, Papajohn Biomedical Institute, Carver College of Medicine, University of Iowa, Iowa City
John A Wemmie - Psychiatry (R.J.T., R.F., S.G., J.A.W.), Department of Veterans Affairs Medical Center, Francois M. Abboud Cardiovascular Center, Papajohn Biomedical Institute, Carver College of Medicine, University of Iowa, Iowa City
Resource Type: Journal article
Publication Details: Circulation research, Vol.125(10), pp.907-920
DOI: 10.1161/CIRCRESAHA.119.315024
PMID: 31451088
NLM abbreviation: Circ Res
ISSN: 0009-7330
eISSN: 1524-4571
Language: English
Date published: 10/25/2019
Academic Unit: Molecular Physiology and Biophysics; Psychiatry; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Neurosurgery; Internal Medicine
Record Identifier: 9984066136402771

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