Acid-sensing ion channels blockade attenuates pressor and sympathetic responses to skeletal muscle metaboreflex activation in humans

In animals, the blockade of acid-sensing ion channels (ASICs), cation pore-forming membrane proteins located in the free nerve endings of group IV afferent fibers, attenuates increases in arterial pressure (AP) and sympathetic nerve activity (SNA) during muscle contraction. Therefore, ASICs play a role in mediating the metabolic component (skeletal muscle metaboreflex) of the exercise pressor reflex in animal models. Here we tested the hypothesis that ASICs also play a role in evoking the skeletal muscle metaboreflex in humans, quantifying beat-by-beat mean AP (MAP; finger photoplethysmography) and muscle SNA (MSNA; microneurography) in 11 men at rest and during static handgrip exercise (SHG; 35% of the maximal voluntary contraction) and postexercise muscle ischemia (PEMI) before (B) and after (A) local venous infusion of either saline or amiloride (AM), an ASIC antagonist, via the Bier block technique. MAP (BAM +30 ± 6 vs. AAM +25 ± 7 mmHg, P = 0.001) and MSNA (BAM +14 ± 9 vs. AAM +10 ± 6 bursts/min, P = 0.004) responses to SHG were attenuated under ASIC blockade. Amiloride also attenuated the PEMI-induced increases in MAP (BAM +25 ± 6 vs. AAM +16 ± 6 mmHg, P = 0.0001) and MSNA (BAM +16 ± 9 vs. AAM +8 ± 8 bursts/min, P = 0.0001). MAP and MSNA responses to SHG and PEMI were similar before and after saline infusion. We conclude that ASICs play a role in evoking pressor and sympathetic responses to SHG and the isolated activation of the skeletal muscle metaboreflex in humans. NEW & NOTEWORTHY We showed that regional blockade of the acid-sensing ion channels (ASICs), induced by venous infusion of the antagonist amiloride via the Bier block anesthetic technique, attenuated increases in arterial pressure and muscle sympathetic nerve activity during both static handgrip exercise and postexercise muscle ischemia. These findings indicate that ASICs contribute to both pressor and sympathetic responses to the activation of the skeletal muscle metaboreflex in humans.

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Acid‐Sensing Ion Channels Blockade Attenuates Pressor and Sympathetic Responses to Skeletal Muscle Metaboreflex Activation in Humans

The FASEB Journal ◽

10.1096/fasebj.2019.33.1_supplement.860.2 ◽

2019 ◽

Vol 33 (S1) ◽

Author(s):

Igor Alexandre Fernandes ◽

Monique O Campos ◽

Daniel E Mansur ◽

João Mattos ◽

Adrielle Paiva ◽

...

Keyword(s):

Skeletal Muscle ◽

Ion Channels ◽

Muscle Metaboreflex ◽

Acid Sensing Ion Channels ◽

Sympathetic Responses

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Heart failure induces changes in acid-sensing ion channels in sensory neurons innervating skeletal muscle

The Journal of Physiology ◽

10.1113/jp270690 ◽

2015 ◽

Vol 593 (20) ◽

pp. 4575-4587 ◽

Cited By ~ 3

Author(s):

David D. Gibbons ◽

William J. Kutschke ◽

Robert M. Weiss ◽

Christopher J. Benson

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Ion Channels ◽

Sensory Neurons ◽

Acid Sensing Ion Channels

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Acid‐sensing ion channels (ASICs) in mouse skeletal muscle afferents are heteromers composed of ASIC1a, ASIC2, and ASIC3 subunits

The FASEB Journal ◽

10.1096/fj.12-220400 ◽

2012 ◽

Vol 27 (2) ◽

pp. 793-802 ◽

Cited By ~ 39

Author(s):

Mamta Gautam ◽

Christopher J. Benson

Keyword(s):

Skeletal Muscle ◽

Ion Channels ◽

Muscle Afferents ◽

Mouse Skeletal Muscle ◽

Acid Sensing Ion Channels

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Sympathetic Activation due to Limb Venous Distension Is Preserved during Muscle Metaboreceptor Stimulation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00305.2020 ◽

2021 ◽

Author(s):

Jian Cui ◽

Cheryl Blaha ◽

Urs A. Leuenberger ◽

Lawrence I. Sinoway

Keyword(s):

Blood Pressure ◽

Skeletal Muscle ◽

Healthy Subjects ◽

Sympathetic Nerve Activity ◽

Muscle Sympathetic Nerve Activity ◽

Muscle Afferents ◽

Sympathetic Activation ◽

Nerve Activity ◽

Post Exercise ◽

Muscle Metaboreflex

Venous saline infusions in an arterially occluded forearm evokes reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in humans (venous distension reflex). It is unclear if the inputs from metabolically sensitive skeletal muscle afferents (i.e. muscle metaboreflex) would modify venous distension reflex. We hypothesized that muscle metaboreceptor stimulation might augment the venous distension reflex. BP (Finapres), heart rate (ECG), and MSNA (microneurography) were assessed in 18 young healthy subjects. In trial A, saline (5% forearm volume) was infused into the veins of an arterially occluded arm (non-handgrip trial). In trial B, subjects performed 2 min static handgrip followed by post exercise circulatory occlusion (PECO) of the arm. During PECO, saline was infused into veins of the arm (handgrip trial). In trial A, the infusion increased MSNA and BP as expected (both P < 0.001). In trial B, handgrip significantly raised MSNA, BP and venous lactic acid concentrations. Venous saline infusion during PECO further raised MSNA and BP (both P < 0.001). The changes in MSNA (D8.6 ± 1.5 to D10.6 ± 1.8 bursts/min, P = 0.258) and mean arterial pressure (P = 0.844) evoked by the infusion during PECO were not significantly different from those in the non-handgrip trial. These observations indicate that venous distension reflex responses are preserved during sympathetic activation mediated by the muscle metaboreflex.

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Effect of adenosine receptor blockade with caffeine on sympathetic response to handgrip exercise in heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.281.3.h1312 ◽

2001 ◽

Vol 281 (3) ◽

pp. H1312-H1318 ◽

Cited By ~ 35

Author(s):

C. F. Notarius ◽

D. J. Atchison ◽

G. A. Rongen ◽

J. S. Floras

Keyword(s):

Heart Failure ◽

Sympathetic Nerve Activity ◽

Muscle Sympathetic Nerve Activity ◽

Normal Subjects ◽

Voluntary Contraction ◽

Receptor Blockade ◽

Handgrip Exercise ◽

Muscle Metaboreflex ◽

Sympathetic Response ◽

Isotonic Exercise

Adenosine (Ado) increases muscle sympathetic nerve activity (MSNA) reflexively. Plasma Ado and MSNA are elevated in heart failure (HF). We tested the hypothesis that Ado receptor blockade by caffeine would attenuate reflex MSNA responses to handgrip (HG) and posthandgrip ischemia (PHGI) and that this action would be more prominent in HF subjects than in normal subjects. We studied 12 HF subjects and 10 age-matched normal subjects after either saline or caffeine (4 mg/kg) infusion during isometric [30% of maximal voluntary contraction (MVC)] and isotonic (10%, 30%, and 50%) HG exercise, followed by 2 min of PHGI. In normal subjects, caffeine did not block increases in MSNA during PHGI after 50% HG. In HF subjects, caffeine abolished MSNA responses to PHGI after both isometric and 50% isotonic exercise ( P < 0.05) but MSNA responses during HG were unaffected. These findings are consistent with muscle metaboreflex stimulation by endogenous Ado during ischemic or intense nonischemic HG in HF and suggest an important sympathoexcitatory role for endogenous Ado during exercise in this condition.

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GABA A Receptors Modulate Muscle Sympathetic Nerve Activity and Pressor Responses to Skeletal Muscle Metaboreflex Activation in Humans

The FASEB Journal ◽

10.1096/fasebj.2019.33.1_supplement.860.11 ◽

2019 ◽

Vol 33 (S1) ◽

Author(s):

André L. Teixeira ◽

Igor A. Fernandes ◽

Lauro C. Vianna

Keyword(s):

Skeletal Muscle ◽

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Muscle Sympathetic Nerve Activity ◽

Nerve Activity ◽

Gaba A ◽

Muscle Metaboreflex ◽

Pressor Responses

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Acid-sensing ion channels contribute to the metaboreceptor component of the exercise pressor reflex

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00328.2009 ◽

2009 ◽

Vol 297 (1) ◽

pp. H443-H449 ◽

Cited By ~ 31

Author(s):

Jennifer L. McCord ◽

Hirotsugu Tsuchimochi ◽

Marc P. Kaufman

Keyword(s):

Skeletal Muscle ◽

Ion Channels ◽

Pressor Response ◽

Triceps Surae ◽

Exercise Pressor Reflex ◽

Acid Sensing Ion Channels ◽

Pressor Responses ◽

Static Contraction ◽

Pressor Reflex ◽

Triceps Surae Muscles

The exercise pressor reflex is evoked by both mechanical and metabolic stimuli arising in contracting skeletal muscle. Recently, the blockade of acid-sensing ion channels (ASICs) with amiloride and A-316567 attenuated the reflex. Moreover, amiloride had no effect on the mechanoreceptor component of the reflex, prompting us to determine whether ASICs contributed to the metaboreceptor component of the exercise pressor reflex. The metaboreceptor component can be assessed by measuring mean arterial pressure during postcontraction circulatory occlusion when only the metaboreceptors are stimulated. We examined the effects of amiloride (0.5 μg/kg), A-317567 (10 mM, 0.5 ml), and saline (0.5 ml) on the pressor response to and after static contraction while the circulation was occluded in 30 decerebrated cats. Amiloride ( n = 11) and A-317567 ( n = 7), injected into the arterial supply of the triceps surae muscles, attenuated the pressor responses both to contraction while the circulation was occluded and to postcontraction circulatory occlusion (all, P < 0.05). Saline ( n = 11), however, had no effect on the pressor responses to contraction while the circulation was occluded or to postcontraction circulatory occlusion (both, P > 0.79). Our findings led us to conclude that ASICs contribute to the metaboreceptor component of the exercise pressor reflex.

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Effect of concentric and eccentric muscle actions on muscle sympathetic nerve activity

Journal of Applied Physiology ◽

10.1152/jappl.1999.86.2.558 ◽

1999 ◽

Vol 86 (2) ◽

pp. 558-563 ◽

Cited By ~ 21

Author(s):

Dario I. Carrasco ◽

Michael D. Delp ◽

Chester A. Ray

Keyword(s):

Sympathetic Nerve ◽

Sympathetic Nerve Activity ◽

Muscle Sympathetic Nerve Activity ◽

Lactate Concentration ◽

Blood Lactate Concentration ◽

Nerve Activity ◽

Endurance Time ◽

Muscle Metaboreflex ◽

Muscle Ischemia ◽

Muscle Actions

The purpose of this study was to determine the effects of concentric (Con) and eccentric (Ecc) muscle actions on leg muscle sympathetic nerve activity (MSNA). Two protocols were utilized. In protocol 1, eight subjects performed Con and Ecc arm curls for 2 min, with a resistance representing 50% of one-repetition maximum for Con curls. Heart rate (HR) and mean arterial pressure (MAP) were greater ( P < 0.05) during Con than during Ecc curls. Similarly, the MSNA was greater ( P < 0.05) during Con than during Ecc curls. In protocol 2, eight different subjects performed Con and Ecc arm curls to fatigue, followed by postexercise muscle ischemia, by using the same resistance as in protocol 1. Endurance time was significantly greater for Ecc than for Con curls. The increase in HR, MAP, and MSNA was greater ( P < 0.05) during Con than during Ecc curls. However, when the data were normalized as a function of endurance time, the differences in HR, MAP, and MSNA between Con and Ecc curls were no longer present. HR, MAP, and MSNA responses during postexercise muscle ischemia were similar for Con and Ecc curls. Con curls elicited greater increase ( P < 0.05) in blood lactate concentration than did Ecc curls. In summary, Con actions contribute significantly more to the increase in cardiovascular and MSNA responses during brief, submaximal exercise than do Ecc actions. However, when performed to a similar level of effort (i.e., fatigue), Con and Ecc muscle actions elicit similar cardiovascular and MSNA responses. These results indicate that the increase in MSNA during a typical bout of submaximal dynamic exercise is primarily mediated by the muscle metaboreflex, which is stimulated by metabolites produced predominantly during Con muscle action.

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