Enhanced maximal exercise capacity, vasodilation to electrical muscle contraction, and hind limb vascular density in ASIC1a null mice

Drummond, Heather A.; Xiang, Lusha; Chade, Alejandro; Hester, Robert L.

doi:10.14814/phy2.13368

Cited by 4 publications

(6 citation statements)

References 67 publications

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“…ASIC1a expressed in cardiac muscle afferents contributes to myocardial ischemic-reperfusion injury ( Redd et al, 2021 ). In skeletal muscle afferents, ASIC1a participates in the exercise pressor reflex ( Ducrocq et al, 2020 ), consistent with findings that ASIC1a opposes functional hyperemia and exercise capacity in the skeletal muscle circulation ( Drummond et al, 2017 ). However, this effect of ASIC1a was not mediated by reducing the ability of vessels to dilate, but rather ASIC1a appears to limit vascular recruitment in the hind limb skeletal muscle bed ( Drummond et al, 2017 ).…”

Section: Discussionsupporting

confidence: 85%

Acid-sensing ion channel 1a activates IKCa/SKCa channels and contributes to endothelium-dependent dilation

Garcia

Naik

Resta

et al. 2022

Journal of General Physiology

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Acid-sensing ion channel 1a (ASIC1a) belongs to a novel family of proton-gated cation channels that are permeable to both Na+ and Ca2+. ASIC1a is expressed in vascular smooth muscle and endothelial cells in a variety of vascular beds, yet little is known regarding the potential impact of ASIC1a to regulate local vascular reactivity. Our previous studies in rat mesenteric arteries suggest ASIC1a does not contribute to agonist-induced vasoconstriction but may mediate a vasodilatory response. The objective of the current study is to determine the role of ASIC1a in systemic vasodilatory responses by testing the hypothesis that the activation of endothelial ASIC1a mediates vasodilation of mesenteric resistance arteries through an endothelium-dependent hyperpolarization (EDH)-related pathway. The selective ASIC1a antagonist psalmotoxin 1 (PcTX1) largely attenuated the sustained vasodilatory response to acetylcholine (ACh) in isolated, pressurized mesenteric resistance arteries and ACh-mediated Ca2+ influx in freshly isolated mesenteric endothelial tubes. Similarly, basal tone was enhanced and ACh-induced vasodilation blunted in mesenteric arteries from Asic1a knockout mice. ASIC1a colocalizes with intermediate- and small-conductance Ca2+-activated K+ channels (IKCa and SKCa, respectively), and the IKCa/SKCa-sensitive component of the ACh-mediated vasodilation was blocked by ASIC1a inhibition. To determine the role of ASIC1a to activate IKCa/SKCa channels, we measured whole-cell K+ currents using the perforated-patch clamp technique in freshly isolated mesenteric endothelial cells. Inhibition of ASIC1a prevented ACh-induced activation of IKCa/SKCa channels. The ASIC1 agonist, α/β-MitTx, activated IKCa/SKCa channels and induced an IKCa/SKCa-dependent vasodilation. Together, the present study demonstrates that ASIC1a couples to IKCa/SKCa channels in mesenteric resistance arteries to mediate endothelium-dependent vasodilation.

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Section: Discussionsupporting

confidence: 85%

Acid-sensing ion channel 1a activates IKCa/SKCa channels and contributes to endothelium-dependent dilation

Garcia

Naik

Resta

et al. 2022

Journal of General Physiology

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“…Fourth, ASIC1a is located on vascular smooth muscle cells and when activated caused vasoconstriction (17). This mechanism raised the possibility that the reduced exercise pressor reflex found following ASIC1a blockade was the result of a local vasodilation that increased arterial blood flow to the triceps surae muscles, thereby washing out hydrogen ions.…”

Section: Methodological Considerations and Limitsmentioning

confidence: 99%

“…Control for ASIC1a on vascular smooth muscle cells. ASIC1a has been found on vascular smooth muscle cells, and when stimulated by hydrogen ions, these cells will cause vasoconstriction (17). To determine if ASIC1a blockade reduced the exercise pressor reflex by increasing blood flow and washing out metabolic byproducts of contraction, we statically contracted the triceps surae muscles and measured their arterial blood flow by placing a Transonic flow probe around the popliteal artery.…”

Section: Control Experimentsmentioning

confidence: 99%

ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex in rats

Ducrocq

Kim

Estrada

et al. 2020

American Journal of Physiology-Heart and Circulatory Physiology

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The role of the acid-sensing ion channel 1a (ASIC1a) in evoking the exercise pressor reflex is unknown, despite the fact that ASIC1a is opened by decreases in pH in the physiological range. This fact prompted us to test the hypothesis that ASIC1a plays an important role in evoking the exercise pressor reflex in decerebrated rats with freely perfused hindlimb muscles. To test this hypothesis, we measured the effect of injecting two ASIC1a blockers into the arterial supply of the triceps surae muscles on the reflex pressor responses to four maneuvers, namely 1) static contraction of the triceps surae muscles (i.e., the exercise pressor reflex), 2) calcaneal tendon stretch, 3) intra-arterial injection of lactic acid, and 4) intra-arterial injection of diprotonated phosphate. We found that the 2 ASIC1a blockers, psalmotoxin-1 (200 ng/kg) and mambalgin-1 (6.5 μg/kg), decreased the pressor responses to static contraction as well as the peak pressor responses to injection of lactic acid and diprotonated phosphate. In contrast, neither ASIC1a blocker had any effect on the pressor responses to tendon stretch. Importantly, we found that ASIC1a blockade significantly decreased the pressor response to static contraction after a latency of at least 8 s. Our results support the hypothesis that ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex. NEW & NOTEWORTHY The role played by acid-sensing ion channel 1a (ASIC1a) in evoking the exercise pressor reflex remains unknown. In decerebrated rats with freely perfused femoral arteries, blocking ASIC1a with psalmotoxin-1 or mambalgin-1 significantly attenuated the pressor response to static contraction, lactic acid, and diprotonated phosphate injection but had no effect on the pressor response to stretch. We conclude that ASIC1a plays a key role in evoking the exercise pressor reflex by responding to contraction-induced metabolites, such as protons.

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“…ASICs have been shown to contribute to cardiovascular homeostasis via sensory signaling from arterial baroreceptors and peripheral chemoreceptor afferent sensory neurons (1). However, recent studies provide evidence that ASICs also exist in several nonneural tissues, including vascular smooth muscle cells (12,17,20,28), although the functional roles of ASICs within the vasculature remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

Loss of acid-sensing ion channel 2 enhances pulmonary vascular resistance and hypoxic pulmonary hypertension

Detweiler

Herbert

Garcia

et al. 2019

Journal of Applied Physiology

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Acid-sensing ion channels (ASICs) are voltage-insensitive cation channels that contribute to cellular excitability. We previously reported that ASIC1 in pulmonary artery smooth muscle cells (PASMC) contribute to pulmonary vasoreactivity and vascular remodeling during the development of chronic hypoxia (CH)-induced pulmonary hypertension. However, the roles of ASIC2 and ASIC3 in regulation of pulmonary vasoreactivity and the development of CH-induced pulmonary hypertension are unknown. We tested the hypothesis that ASIC2 and ASIC3 contribute to increased pulmonary vasoreactivity and development of CH-induced pulmonary hypertension using ASIC2- and ASIC3-knockout (−/−) mice. In contrast to this hypothesis, we found that ASIC2−/− mice exhibit enhanced CH-induced pulmonary hypertension compared with WT and ASIC3−/− mice. This response was not associated with a change in ventilatory sensitivity or systemic cardiovascular function but was instead associated with direct changes in pulmonary vascular reactivity and pulmonary arterial morphology in ASIC2−/− mice. This increase in reactivity correlated with enhanced pulmonary arterial basal tone, elevated basal PASMC [Ca2+] and store-operated calcium entry (SOCE) in PASMC from ASIC2−/− mice. This increase in PASMC [Ca2+] and vasoreactivity was dependent on ASIC1-mediated Ca2+ influx but was not contingent upon an increase in ASIC1 mRNA or protein expression in PASMC from ASIC2−/− mice. Together, the results from this study demonstrate an important role for ASIC2 to regulate pulmonary vascular reactivity and for ASIC2 to modulate the development of CH-induced pulmonary hypertension. These data further suggest that loss of ASIC2 enhances the contribution of ASIC1 to overall pulmonary vascular reactivity. NEW & NOTEWORTHY This study demonstrates that loss of ASIC2 leads to increased baseline pulmonary vascular resistance, enhanced responses to a variety of vasoconstrictor stimuli, and greater development of hypoxic pulmonary hypertension. Furthermore, these results suggest that loss of ASIC2 enhances the contribution of ASIC1 to pulmonary vascular reactivity.

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Enhanced maximal exercise capacity, vasodilation to electrical muscle contraction, and hind limb vascular density in ASIC1a null mice

Cited by 4 publications

References 67 publications

Acid-sensing ion channel 1a activates IKCa/SKCa channels and contributes to endothelium-dependent dilation

Acid-sensing ion channel 1a activates IKCa/SKCa channels and contributes to endothelium-dependent dilation

ASIC1a plays a key role in evoking the metabolic component of the exercise pressor reflex in rats

Loss of acid-sensing ion channel 2 enhances pulmonary vascular resistance and hypoxic pulmonary hypertension

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