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 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.

Sensing vascular distension in skeletal muscle by slow conducting afferent fibers: neurophysiological basis and implication for respiratory control

2004 ◽  
Vol 96 (2) ◽  
pp. 407-418 ◽  
Author(s):  
Philippe Haouzi ◽  
Bruno Chenuel ◽  
Andrew Huszczuk
Keyword(s):  
Arterial Occlusion ◽  
Respiratory Control ◽  
Vascular Network ◽  
Mechanical Stimuli ◽  
Peripheral Vascular ◽  
Group Iii ◽  
Arterial Blood ◽  
Afferent Fibers ◽  
Muscle Afferent ◽  
Neurophysiological Basis

This review examines the evidence that skeletal muscles can sense the status of the peripheral vascular network through group III and IV muscle afferent fibers. The anatomic and neurophysiological basis for such a mechanism is the following: 1) a significant portion of group III and IV afferent fibers have been found in the vicinity and the adventitia of the arterioles and the venules; 2) both of these groups of afferent fibers can respond to mechanical stimuli; 3) a population of group III and IV fibers stimulated during muscle contraction has been found to be inhibited to various degrees by arterial occlusion; and 4) more recently, direct evidence has been obtained showing that a part of the group IV muscle afferent fibers is stimulated by venous occlusion and by injection of vasodilatory agents. The physiological relevance of sensing local distension of the vascular network at venular level in the muscles is clearly different from that of the large veins, since the former can directly monitor the degree of tissue perfusion. The possible involvement of this sensing mechanism in respiratory control is discussed mainly in the light of the ventilatory effects of peripheral vascular occlusions during and after muscular exercise. It is proposed that this regulatory system anticipates the chemical changes that would occur in the arterial blood during increased metabolic load and attempts to minimize them by adjusting the level of ventilation to the level of muscle perfusion, thus matching the magnitudes of the peripheral and pulmonary gas exchange.

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.

Estrogen attenuates the cardiovascular and ventilatory responses to central command in cats

2002 ◽  
Vol 92 (4) ◽  
pp. 1635-1641 ◽  
Author(s):  
Shawn G. Hayes ◽  
Nicolas B. Moya Del Pino ◽  
Marc P. Kaufman
Keyword(s):  
Triceps Surae ◽  
Central Command ◽  
Neuronal Function ◽  
Ventilatory Responses ◽  
Exercise Pressor Reflex ◽  
Arterial Blood ◽  
Static Contraction ◽  
17Β Estradiol ◽  
Pressor Reflex ◽  
Triceps Surae Muscles

Static exercise is well known to increase heart rate, arterial blood pressure, and ventilation. These increases appear to be less in women than in men, a difference that has been attributed to an effect of estrogen on neuronal function. In decerebrate male cats, we examined the effect of estrogen (17β-estradiol; 0.001, 0.01, 0.1, and 1.0 μg/kg iv) on the cardiovascular and ventilatory responses to central command and the exercise pressor reflex, the two neural mechanisms responsible for evoking the autonomic and ventilatory responses to exercise. We found that 17β-estradiol, in each of the three doses tested, attenuated the pressor, cardioaccelerator, and phrenic nerve responses to electrical stimulation of the mesencephalic locomotor region (i.e., central command). In contrast, none of the doses of 17β-estradiol had any effect on the pressor, cardioaccelerator, and ventilatory responses to static contraction or stretch of the triceps surae muscles. We conclude that, in decerebrate male cats, estrogen injected intravenously attenuates cardiovascular and ventilatory responses to central command but has no effect on responses to the exercise pressor reflex.

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.

Vasopressin acts in the area postrema to attenuate the exercise pressor reflex in anesthetized cats

1998 ◽  
Vol 274 (6) ◽  
pp. H2116-H2122 ◽  
Author(s):  
Charles L. Stebbins ◽  
Stefani Bonigut ◽  
Lea R. Liviakis ◽  
Paul A. Munch
Keyword(s):  
Blood Pressure ◽  
Area Postrema ◽  
Cardiovascular Response ◽  
Exercise Pressor Reflex ◽  
Arterial Blood ◽  
Baroreflex Function ◽  
Static Contraction ◽  
Before And After ◽  
Pressor Reflex ◽  
Anesthetized Cat

Circulating arginine vasopressin (AVP) can enhance baroreflex function via its action in the area postrema (AP). We tested the hypothesis that AVP acts in the AP to enhance baroreflex function during static contraction and, in turn, attenuates the exercise pressor reflex. Thus mean arterial blood pressure ( n = 9) and heart rate (HR) ( n = 9) during 30 s of electrically stimulated hindlimb contraction were compared before and after bilateral microinjections of 200 nl of the AVP V1-receptor antagonist d(CH2)5Tyr(Me)-AVP (V1x) (1 ng/nl) into the AP of the anesthetized cat. This protocol was repeated in three other cats in which sinoaortic denervation (SAD) was performed before any intervention. Injection of V1xinto the AP had no effect on baseline blood pressure or HR. However, pressor and HR responses to static contraction were augmented by 44 ± 10 and 29 ± 9%, respectively. Static contraction also increased plasma AVP from 15.9 ± 2.0 to 25.5 ± 3.4 pg/ml. In the SAD cats, microinjection of V1x had no effect on contraction-induced increases in blood pressure or HR. These results suggest that baroreflex opposition of the reflex cardiovascular response to static contraction is enhanced by the action of AVP in the AP.

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.

Augmentation of the exercise pressor reflex in prehypertension: roles of the muscle metaboreflex and mechanoreflex

2013 ◽  
Vol 38 (2) ◽  
pp. 209-215 ◽  
Author(s):  
Hyun-Min Choi ◽  
Charles L. Stebbins ◽  
Og-Taeg Lee ◽  
Hosung Nho ◽  
Joon-Hee Lee ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Pressure Response ◽  
Pressor Response ◽  
Peripheral Resistance ◽  
Percentage Increase ◽  
Muscle Metaboreflex ◽  
Exercise Pressor Reflex ◽  
Arterial Blood ◽  
Static Contraction ◽  
Pressor Reflex

This study investigated the hemodynamic mechanisms underlying the exaggerated blood pressure response to muscle contraction in prehypertensive humans and the potential role of skeletal muscle metabo- and mechanoreceptors in this response. To accomplish this, changes in peak mean arterial blood pressure (ΔMAP), cardiac output, and total peripheral resistance (ΔTPR) were compared between prehypertensive (n = 23) and normotensive (n = 19) male subjects during 2 min of static contraction (at 50% of maximal tension), 2 min of postexercise muscle ischemia (metaboreflex), and 1 min of passive dorsiflexion of the foot (tendon stretch, mechanoreceptor reflex). These variables were assessed before and during the interventions. Percentage increases from baseline in MAP and TPR in response to the exercise pressor reflex were augmented in the prehypertensives, compared with the normotensives (44% ± 5% vs. 33% ± 4% and 34% ± 15% vs. 2% ± 8%, respectively) (p < 0.05). Metaboreflex-induced increases in MAP and TPR were also augmented in the prehypertensives (28% ± 5% vs. 14% ± 4% and 36% ± 12% vs. 14% ± 9%, respectively) (p < 0.05). In response to the mechanoreflex, no differences in the percentage increase in MAP or TPR were seen between groups. The results indicate that the reflex pressor response to static contraction is augmented in prehypertension and suggest that this phenomenon is due, at least in part, to enhanced activation of metaboreceptors.

c-Fos expression in the midbrain periaqueductal gray during static muscle contraction

2000 ◽  
Vol 279 (6) ◽  
pp. H2986-H2993 ◽  
Author(s):  
Jianhua Li ◽  
Jere H. Mitchell
Keyword(s):  
Skeletal Muscle ◽  
Muscle Contraction ◽  
Neuronal Cells ◽  
Cardiovascular Responses ◽  
Periaqueductal Gray ◽  
Exercise Pressor Reflex ◽  
Arterial Blood ◽  
Static Contraction ◽  
Afferent Inputs ◽  
Pressor Reflex

The periaqueductal gray (PAG) of the midbrain is involved in the autonomic regulation of the cardiovascular system. The purpose of this study was to determine if static contraction of the skeletal muscle, which increases arterial blood pressure and heart rate, activates neuronal cells in the PAG by examining Fos-like immunoreactivity (FLI). Muscle contraction was induced by electrical stimulation of the L7 and S1 ventral roots of the spinal cord in anesthetized cats. An intravenous infusion of phenylephrine (PE) was used to selectively activate arterial baroreceptors. Extensive FLI was observed within the ventromedial region (VM) of the rostral PAG, the dorsolateral (DL), lateral (L), and ventrolateral (VL) regions of the middle and caudal PAG in barointact animals with muscle contractions, and in barointact animals with PE infusion. However, muscle contraction caused a lesser number of FLI in the VM region of the rostral PAG, the DL, L, and VL regions of the middle PAG and the L and VL regions of the caudal PAG after barodenervation compared with barointact animals. Additionally, the number of FLI in the DL and L regions of the middle PAG was greater in barodenervated animals with muscle contraction than in barodenervated control animals. Thus these results indicated that both muscle receptor and baroreceptor afferent inputs activate neuronal cells in regions of the PAG during muscle contraction. Furthermore, afferents from skeletal muscle activate neurons in specific regions of the PAG independent of arterial baroreceptor input. Therefore, neuronal cells in the PAG may play a role in determining the cardiovascular responses during the exercise pressor reflex.

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.

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