scholarly journals Identification of CaV channel types expressed in muscle afferent neurons

2013 ◽  
Vol 110 (7) ◽  
pp. 1535-1543 ◽  
Author(s):  
Renuka Ramachandra ◽  
Bassil Hassan ◽  
Stephanie G. McGrew ◽  
James Dompor ◽  
Mohamed Farrag ◽  
...  
Keyword(s):  
Charge Carrier ◽  
Muscle Afferents ◽  
Channel Blockers ◽  
Afferent Neurons ◽  
Group Iii ◽  
Exercise Pressor Reflex ◽  
Disease States ◽  
Increased Risk ◽  
Muscle Afferent ◽  
Voltage Dependent

Cardiovascular adjustments to exercise are partially mediated by group III/IV (small to medium) muscle afferents comprising the exercise pressor reflex (EPR). However, this reflex can be inappropriately activated in disease states (e.g., peripheral vascular disease), leading to increased risk of myocardial infarction. Here we investigate the voltage-dependent calcium (CaV) channels expressed in small to medium muscle afferent neurons as a first step toward determining their potential role in controlling the EPR. Using specific blockers and 5 mM Ba2+ as the charge carrier, we found the major calcium channel types to be CaV2.2 (N-type) > CaV2.1 (P/Q-type) > CaV1.2 (L-type). Surprisingly, the CaV2.3 channel (R-type) blocker SNX482 was without effect. However, R-type currents are more prominent when recorded in Ca2+ ( Liang and Elmslie 2001 ). We reexamined the channel types using 10 mM Ca2+ as the charge carrier, but results were similar to those in Ba2+. SNX482 was without effect even though ∼27% of the current was blocker insensitive. Using multiple methods, we demonstrate that CaV2.3 channels are functionally expressed in muscle afferent neurons. Finally, ATP is an important modulator of the EPR, and we examined the effect on CaV currents. ATP reduced CaV current primarily via G protein βγ-mediated inhibition of CaV2.2 channels. We conclude that small to medium muscle afferent neurons primarily express CaV2.2 > CaV2.1 ≥ CaV2.3 > CaV1.2 channels. As with chronic pain, CaV2.2 channel blockers may be useful in controlling inappropriate activation of the EPR.

scholarly journals Tetrodotoxin-resistant voltage-dependent sodium channels in identified muscle afferent neurons

2012 ◽  
Vol 108 (8) ◽  
pp. 2230-2241 ◽  
Author(s):  
Renuka Ramachandra ◽  
Stephanie Y. McGrew ◽  
James C. Baxter ◽  
Esad Kiveric ◽  
Keith S. Elmslie
Keyword(s):  
Sodium Channels ◽  
Cardiovascular Responses ◽  
Muscle Afferents ◽  
Exercise Group ◽  
Afferent Neurons ◽  
Group Iii ◽  
Group I ◽  
Muscle Afferent ◽  
Voltage Dependent ◽  
Extracellular Sodium

Muscle afferents are critical regulators of motor function (Group I and II) and cardiovascular responses to exercise (Group III and IV). However, little is known regarding the expressed voltage-dependent ion channels. We identified muscle afferent neurons in dorsal root ganglia (DRGs), using retrograde labeling to examine voltage-dependent sodium (NaV) channels. In patch-clamp recordings, we found that the dominant NaV current in the majority of identified neurons was insensitive to tetrodotoxin (TTX-R), with NaV current in only a few (14%) neurons showing substantial (>50%) TTX sensitivity (TTX-S). The TTX-R current was sensitive to a NaV1.8 channel blocker, A803467. Immunocytochemistry demonstrated labeling of muscle afferent neurons by a NaV1.8 antibody, which further supported expression of these channels. A portion of the TTX-R NaV current appeared to be noninactivating during our 25-ms voltage steps, which suggested activity of NaV1.9 channels. The majority of the noninactivating current was insensitive to A803467 but sensitive to extracellular sodium. Immunocytochemistry showed labeling of muscle afferent neurons by a NaV1.9 channel antibody, which supports expression of these channels. Further examination of the muscle afferent neurons showed that functional TTX-S channels were expressed, but were largely inactivated at physiological membrane potentials. Immunocytochemistry showed expression of the TTX-S channels NaV1.6 and NaV1.7 but not NaV1.1. NaV1.8 and NaV1.9 appear to be the dominant functional sodium channels in small- to medium-diameter muscle afferent neurons. The expression of these channels is consistent with the identification of these neurons as Group III and IV, which mediate the exercise pressor reflex.

scholarly journals NaV1.9 channels in muscle afferent neurons and axons

2018 ◽  
Vol 120 (3) ◽  
pp. 1032-1044 ◽  
Author(s):  
Tyler L. Marler ◽  
Andrew B. Wright ◽  
Kristina L. Elmslie ◽  
Ankeeta K. Heier ◽  
Ethan Remily ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Muscle Activity ◽  
Muscle Blood Flow ◽  
Small Diameter ◽  
Muscle Afferents ◽  
Inactivation Kinetics ◽  
Afferent Neurons ◽  
Internal Solution ◽  
Group Iii ◽  
Muscle Afferent

The exercise pressor reflex (EPR) is activated by muscle contractions to increase heart rate and blood pressure during exercise. While this reflex is beneficial in healthy individuals, the reflex activity is exaggerated in patients with cardiovascular disease, which is associated with increased mortality. Group III and IV afferents mediate the EPR and have been shown to express both tetrodotoxin-sensitive (TTX-S, NaV1.6, and NaV1.7) and -resistant (TTX-R, NaV1.8, and NaV1.9) voltage-gated sodium (NaV) channels, but NaV1.9 current has not yet been demonstrated. Using a F−-containing internal solution, we found a NaV current in muscle afferent neurons that activates at around −70 mV with slow activation and inactivation kinetics, as expected from NaV1.9 current. However, this current ran down with time, which resulted, at least in part, from increased steady-state inactivation since it was slowed by both holding potential hyperpolarization and a depolarized shift of the gating properties. We further show that, following NaV1.9 current rundown (internal F−), application of the NaV1.8 channel blocker A803467 inhibited significantly more TTX-R current than we had previously observed (internal Cl−), which suggests that NaV1.9 current did not rundown with that internal solution. Using immunohistochemistry, we found that the majority of group IV somata and axons were NaV1.9 positive. The majority of small diameter myelinated afferent somata (putative group III) were also NaV1.9 positive, but myelinated muscle afferent axons were rarely labeled. The presence of NaV1.9 channels in muscle afferents supports a role for these channels in activation and maintenance of the EPR. NEW & NOTEWORTHY Small diameter muscle afferents signal pain and muscle activity levels. The muscle activity signals drive the cardiovascular system to increase muscle blood flow, but these signals can become exaggerated in cardiovascular disease to exacerbate cardiac damage. The voltage-dependent sodium channel NaV1.9 plays a unique role in controlling afferent excitability. We show that NaV1.9 channels are expressed in muscle afferents, which supports these channels as a target for drug development to control hyperactivity of these neurons.

scholarly journals Functional expression of α7-nicotinic acetylcholine receptors by muscle afferent neurons

2014 ◽  
Vol 112 (6) ◽  
pp. 1549-1558 ◽  
Author(s):  
James C. Baxter ◽  
Renuka Ramachandra ◽  
Dustin R. Mayne ◽  
Keith S. Elmslie
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Functional Expression ◽  
Muscle Afferents ◽  
Group Iv ◽  
Afferent Neurons ◽  
Sprague Dawley ◽  
Group Iii ◽  
Muscle Afferent ◽  
Exercise Induced

The exercise pressor reflex (EPR) is generated by group III and IV muscle afferents during exercise to increase cardiovascular function. Muscle contraction is triggered by ACh, which is metabolized into choline that could serve as a signal of exercise-induced activity. We demonstrate that ACh can induce current in muscle afferents neurons isolated from male Sprague-Dawley rats. The nicotinic ACh receptors (nAChRs) appear to be expressed by some group III-IV neurons since capsaicin (TRPV1) and/or ATP (P2X) induced current in 56% of ACh-responsive neurons. α7- And α4β2-nAChRs have been shown to be expressed in sensory neurons. An α7-nAChR antibody stained 83% of muscle afferent neurons. Functional expression was demonstrated by using the specific α7-nAChR blockers α-conotoxin ImI (IMI) and methyllycaconitine (MLA). MLA inhibited ACh responses in 100% of muscle afferent neurons, whereas IMI inhibited ACh responses in 54% of neurons. Dihydro-β-erythroidine, an α4β2-nAChR blocker, inhibited ACh responses in 50% of muscle afferent neurons, but recovery from block was not observed. Choline, an α7-nAChR agonist, elicited a response in 60% of ACh-responsive neurons. Finally, we demonstrated the expression of α7-nAChR by peripherin labeled (group IV) afferent fibers within gastrocnemius muscles. Some of these α7-nAChR-positive fibers were also positive for P2X3 receptors. Thus choline could serve as an activator of the EPR by opening α7-nAChR expressed by group IV (and possible group III) afferents. nAChRs could become pharmacological targets for suppressing the excessive EPR activation in patients with peripheral vascular disease.

Gadolinium attenuates exercise pressor reflex in cats

2001 ◽  
Vol 280 (5) ◽  
pp. H2153-H2161 ◽  
Author(s):  
Shawn G. Hayes ◽  
Marc P. Kaufman
Keyword(s):  
Pressor Response ◽  
Oxygen Demand ◽  
Muscle Afferents ◽  
Triceps Surae ◽  
Mechanical Stimuli ◽  
Group Iii ◽  
Exercise Pressor Reflex ◽  
Static Contraction ◽  
Pressor Reflex ◽  
Triceps Surae Muscles

The exercise pressor reflex, which arises from the contraction-induced stimulation of group III and IV muscle afferents, is widely believed to be evoked by metabolic stimuli signaling a mismatch between blood/oxygen demand and supply in the working muscles. Nevertheless, mechanical stimuli may also play a role in evoking the exercise pressor reflex. To determine this role, we examined the effect of gadolinium, which blocks mechanosensitive channels, on the exercise pressor reflex in both decerebrate and α-chloralose-anesthetized cats. We found that gadolinium (10 mM; 1 ml) injected into the femoral artery significantly attenuated the reflex pressor responses to static contraction of the triceps surae muscles and to stretch of the calcaneal (Achilles) tendon. In contrast, gadolinium had no effect on the reflex pressor response to femoral arterial injection of capsaicin (5 μg). In addition, gadolinium significantly attenuated the responses of group III muscle afferents, many of which are mechanically sensitive, to both static contraction and to tendon stretch. Gadolinium, however, had no effect on the responses of group IV muscle afferents, many of which are metabolically sensitive, to either static contraction or to capsaicin injection. We conclude that mechanical stimuli arising in contracting skeletal muscles contribute to the elicitation of the exercise pressor reflex.

P2 antagonist PPADS attenuates responses of thin fiber afferents to static contraction and tendon stretch

2006 ◽  
Vol 290 (3) ◽  
pp. H1214-H1219 ◽  
Author(s):  
Angela E. Kindig ◽  
Shawn G. Hayes ◽  
Ramy L. Hanna ◽  
Marc P. Kaufman
Keyword(s):  
Pyridoxal Phosphate ◽  
Discharge Rate ◽  
Muscle Afferents ◽  
Group Iv ◽  
Disulfonic Acid ◽  
Group Iii ◽  
Exercise Pressor Reflex ◽  
Pressor Responses ◽  
Static Contraction ◽  
Muscle Mechanoreflex

Injection into the arterial supply of skeletal muscle of pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), a P2 receptor antagonist, has been shown previously to attenuate the reflex pressor responses to both static contraction and to tendon stretch. In decerebrated cats, we tested the hypothesis that PPADS attenuated the responses of groups III and IV muscle afferents to static contraction as well as to tendon stretch. We found that injection of PPADS (10 mg/kg) into the popliteal artery attenuated the responses of both group III ( n = 16 cats) and group IV afferents ( n = 14 cats) to static contraction. Specifically, static contraction before PPADS injection increased the discharge rate of the group III afferents from 0.1 ± 0.05 to 1.6 ± 0.5 impulses/s, whereas contraction after PPADS injection increased the discharge of the group III afferents from 0.2 ± 0.1 to only 1.0 ± 0.5 impulses/s ( P < 0.05). Likewise, static contraction before PPADS injection increased the discharge rate of the group IV afferents from 0.3 ± 0.1 to 1.0 ± 0.3 impulses/s, whereas contraction after PPADS injection increased the discharge of the group IV afferents from 0.2 ± 0.1 to only 0.3 ± 0.1 impulses/s ( P < 0.05). In addition, PPADS significantly attenuated the responses of group III afferents to tendon stretch but had no effect on the responses of group IV afferents. Our findings suggest that both groups III and IV afferents are responsible for evoking the purinergic component of the exercise pressor reflex, whereas only group III afferents are responsible for evoking the purinergic component of the muscle mechanoreflex that is evoked by tendon stretch.

scholarly journals Aging alters muscle reflex control of autonomic cardiovascular responses to rhythmic contractions in humans

2015 ◽  
Vol 309 (9) ◽  
pp. H1479-H1489 ◽  
Author(s):  
Simranjit K. Sidhu ◽  
Joshua C. Weavil ◽  
Massimo Venturelli ◽  
Matthew J. Rossman ◽  
Benjamin S. Gmelch ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Cardiovascular Response ◽  
Knee Extensor ◽  
Cardiovascular Responses ◽  
Muscle Afferents ◽  
Group Iii ◽  
Exercise Pressor Reflex ◽  
Pressor Reflex ◽  
Exercise Induced ◽  
The Impact

We investigated the influence of aging on the group III/IV muscle afferents in the exercise pressor reflex-mediated cardiovascular response to rhythmic exercise. Nine old (OLD; 68 ± 2 yr) and nine young (YNG; 24 ± 2 yr) males performed single-leg knee extensor exercise (15 W, 30 W, 80% max) under control conditions and with lumbar intrathecal fentanyl impairing feedback from group III/IV leg muscle afferents. Mean arterial pressure (MAP), cardiac output, leg blood flow (QL), systemic (SVC) and leg vascular conductance (LVC) were continuously determined. With no hemodynamic effect at rest, fentanyl blockade during exercise attenuated both cardiac output and QL ∼17% in YNG, while the decrease in cardiac output in OLD (∼5%) was significantly smaller with no impact on QL ( P = 0.8). Therefore, in the face of similar significant ∼7% reduction in MAP during exercise with fentanyl blockade in both groups, LVC significantly increased ∼11% in OLD, but decreased ∼8% in YNG. The opposing direction of change was reflected in SVC with a significant ∼5% increase in OLD and a ∼12% decrease in YNG. Thus while cardiac output seems to account for the majority of group III/IV-mediated MAP responses in YNG, the impact of neural feedback on the heart may decrease with age and alterations in SVC become more prominent in mediating the similar exercise pressor reflex in OLD. Interestingly, in terms of peripheral hemodynamics, while group III/IV-mediated feedback plays a clear role in increasing LVC during exercise in the YNG, these afferents seem to actually reduce LVC in OLD. These peripheral findings may help explain the limited exercise-induced peripheral vasodilation often associated with aging.

KV7 Channels are Potential Regulators of the Exercise Pressor Reflex

2021 ◽  
Author(s):  
Andrew B Wright ◽  
Khrystyna Yu Sukhanova ◽  
Keith S Elmslie
Keyword(s):  
Neuronal Excitability ◽  
Specific Inhibitor ◽  
Group Iii ◽  
Kv7 Channels ◽  
Exercise Pressor Reflex ◽  
Arterial Blood ◽  
Afferent Fibers ◽  
Muscle Afferent ◽  
Pressor Reflex ◽  
Exercise Induced

The exercise pressor reflex (EPR) originates in skeletal muscle and is activated by exercise-induced signals to increase arterial blood pressure and cardiac output. Muscle ischemia can elicit the EPR, which can be inappropriately activated in patients with peripheral vascular disease or heart failure to increase the incidence of myocardial infarction. We seek to better understand the receptor/channels that control excitability of group III and group IV muscle afferent fibers that give rise to the EPR. Bradykinin (BK) is released within contracting muscle and can evoke the EPR. However, the mechanism is incompletely understood. KV7 channels strongly regulate neuronal excitability and are inhibited by BK. We have identified KV7 currents in muscle afferent neurons by their characteristic activation/deactivation kinetics, enhancement by the KV7 activator retigabine, and block by KV7 specific inhibitor XE991. The block of KV7 current by different XE991 concentrations suggests that the KV7 current is comprised of both KV7.2/7.3 (high affinity) and KV7.5 (low affinity) channels. The KV7 current was inhibited by 300 nM BK in neurons with diameters consistent with both group III and IV afferents. The inhibition of KV7 by BK could be a mechanism by which this metabolic mediator generates the EPR. Furthermore, our results suggest that KV7 channel activators such as retigabine, could be used to reduce cardiac stress resulting from the exacerbated EPR in patients with cardiovascular disease.

scholarly journals Femoral artery ligation increases the responses of thin-fiber muscle afferents to contraction

2015 ◽  
Vol 113 (10) ◽  
pp. 3961-3966 ◽  
Author(s):  
Audrey J. Stone ◽  
Steven W. Copp ◽  
Jennifer L. McCord ◽  
Marc P. Kaufman
Keyword(s):  
Femoral Artery ◽  
Muscle Afferents ◽  
Group Iv ◽  
Artery Ligation ◽  
Thin Fiber ◽  
Group Iii ◽  
Exercise Pressor Reflex ◽  
Hindlimb Muscles ◽  
Static Contraction ◽  
Pressor Reflex

Previous evidence has shown that ligating the femoral artery for 72 h resulted in an exaggerated exercise pressor reflex. To provide electrophysiological evidence for this finding, we examined in decerebrated rats whose femoral arteries were either freely perfused or ligated for 72 h the responses of thin-fiber (i.e., groups III and IV) afferents to static contraction of the hindlimb muscles. We found that contraction increased the combined activity of group III and IV afferents in both freely perfused ( n = 29; baseline: 0.3 ± 0.1 imp/s, contraction: 0.8 ± 0.2 imp/s; P < 0.05) and ligated rats ( n = 28; baseline: 0.4 ± 0.1 imp/s, contraction: 1.4 ± 0.1 imp/s; P < 0.05). Most importantly, the contraction-induced increase in afferent activity was greater in ligated rats than it was in freely perfused rats ( P = 0.005). In addition, the responses of group III afferents to contraction in ligated rats ( n = 15; baseline 0.3 ± 0.1 imp/s, contraction 1.5 ± 0.2 imp/s) were greater ( P = 0.024) than the responses to contraction in freely perfused rats ( n = 18; baseline 0.3 ± 0.1 imp/s, contraction 0.9 ± 0.2 imp/s). Likewise, the responses of group IV afferents to contraction in ligated rats ( n = 13; baseline 0.5 ± 0.1 imp/s, contraction 1.3 ± 0.2 imp/s) were greater ( P = 0.048) than the responses of group IV afferents in freely perfused rats ( n = 11; baseline 0.3 ± 0.1 imp/s, contraction 0.6 ± 0.2 imp/s). We conclude that both group III and IV afferents contribute to the exaggeration of the exercise pressor reflex induced by femoral artery ligation.

Estrogen attenuates the exercise pressor reflex in female cats

2003 ◽  
Vol 95 (4) ◽  
pp. 1418-1424 ◽  
Author(s):  
Petra M. Schmitt ◽  
M. P. Kaufman
Keyword(s):  
Spinal Cord ◽  
Pressor Response ◽  
Muscle Afferents ◽  
Threshold Concentration ◽  
Group Iii ◽  
Exercise Pressor Reflex ◽  
Reflex Arc ◽  
17Β Estradiol ◽  
Pressor Reflex ◽  
The Difference

In humans, the pressor and muscle sympathetic nerve responses to static exercise are less in women than in men. The difference has been attributed to the effect of estrogen on the exercise pressor reflex. Estrogen receptors are abundant in areas of the dorsal horn receiving input from group III and IV muscle afferents, which comprise the sensory limb of the exercise pressor reflex arc. These findings prompted us to investigate the effect of estrogen on the spinal pathway of the exercise pressor reflex arc. Previously, we found that the threshold concentration of 17β-estradiol needed to attenuate the exercise pressor reflex in male decerebrate cats was 10 μg/ml (Schmitt PM and Kaufman MP. J Appl Physiol 94: 1431-1436, 2003). The threshold concentration for female cats, however, is not known. Consequently, we applied 17β-estradiol to a well covering the L6-S1 spinal cord in decerebrate female cats. The exercise pressor reflex was evoked by electrical stimulation of the L7 or S1 ventral root, a maneuver that caused the hindlimb muscles to contract statically. We found that the pressor response to contraction averaged 38 ± 7 mmHg before the application of 17β-estradiol (0.01 μg/ml) to the spinal cord, whereas it averaged only 23 ± 4 mmHg 30 min after application ( P < 0.05). Recovery of the pressor response to contraction was not obtained for 2 h after application of 17β-estradiol. Application of 17β-estradiol in a dose of 0.001 μg/ml had no effect on the exercise pressor reflex ( n = 5). We conclude that the concentration of 17β-estradiol required to attenuate the exercise pressor reflex is 1,000 times more dilute in female cats than that needed to attenuate this reflex in male cats.

scholarly journals Effect of knockout of the ASIC3 on cardiovascular reflexes arising from hindlimb muscle in decerebrated rats

2019 ◽  
Vol 317 (5) ◽  
pp. R641-R648 ◽  
Author(s):  
Joyce S. Kim ◽  
Jonathan E. Harms ◽  
Victor Ruiz-Velasco ◽  
Marc P. Kaufman
Keyword(s):  
Lactic Acid ◽  
Muscle Afferents ◽  
Cardiovascular Reflexes ◽  
Calcaneal Tendon ◽  
Group Iii ◽  
Exercise Pressor Reflex ◽  
Arterial Blood ◽  
Pressor Responses ◽  
Alternative Approach ◽  
Pressor Reflex

The exercise pressor reflex is initiated by the contraction-induced activation of group III and IV muscle afferents. The reflex is manifested by increases in arterial blood pressure and cardiac output, which, in turn, are generated by increases in the sympathetic outflow to the heart and vasculature and decreases in the vagal outflow to the heart. In previous experiments, we used a pharmacological approach to assess the role played by the acid-sensing ion channel 3 (ASIC3) on group III and IV afferents in evoking the exercise pressor reflex. In the present experiments, we used an alternative approach, namely functional knockout (KO) of the ASIC3 gene, to confirm and extend our previous finding that pharmacological blockade of the ASIC3 had only a small impact on the expression of the exercise pressor reflex when the arterial supply to the contracting hindlimb muscles of rats was patent. Using this alternative approach, we compared the magnitude of the exercise pressor reflex evoked in ASIC3 KO rats with that evoked in their wild-type (WT) counterparts. We found both WT and ASIC3 KO rats displayed similar pressor responses to static contraction (WT, n = 10, +12 ± 2 mmHg; KO, n = 9, +11 ± 2 mmHg) and calcaneal tendon stretch (WT, n = 9, +13 ± 2 mmHg; KO, n = 7, +11 ± 2 mmHg). Likewise, both WT and ASIC3 KO displayed similar pressor responses to intra-arterial injection of 12 mM lactic acid (WT, n = 9, +14 ± 3 mmHg; KO, n = 8, +18 ± 5 mmHg), 24 mM lactic acid (WT, n = 9,+24 ± 2 mmHg; KO, n = 8, +20 ± 5 mmHg), capsaicin (WT, n = 9,+27 ± 5 mmHg; KO, n = 10, +29 ± 5 mmHg), and diprotonated phosphate ([Formula: see text]; WT, n = 6,+22 ± 3 mmHg; KO, n = 6, +32 ± 6 mmHg). We conclude that redundant receptors are responsible for evoking the pressor reflexes arising from group III and IV afferents.

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