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.

Activation of thin-fiber muscle afferents by a P2X agonist in cats

2004 ◽  
Vol 96 (3) ◽  
pp. 1166-1169 ◽  
Author(s):  
Ramy L. Hanna ◽  
Marc P. Kaufman
Keyword(s):  
Pyridoxal Phosphate ◽  
Muscle Afferents ◽  
Group Iv ◽  
Triceps Surae ◽  
Disulfonic Acid ◽  
P2 Receptor ◽  
Thin Fiber ◽  
Group Iii ◽  
Decerebrate Cats ◽  
Stimulation Of

The responses of group III and IV triceps surae muscle afferents to intra-arterial injection of α,β-methylene ATP (50 μg/kg) was examined in decerebrate cats. We found that this P2X3 agonist stimulated only three of 18 group III afferents but 7 of 9 group IV afferents ( P < 0.004). The three group III afferents stimulated by α,β-methylene ATP conducted impulses below 4 m/s. Pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid, a P2-receptor antagonist, prevented the stimulation of these afferents by α,β-methylene ATP. We conclude that P2X3 agonists stimulate only the slowest conducting group III muscle afferents as well as group IV afferents.

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.

Comparison between the effect of static contraction and tendon stretch on the discharge of group III and IV muscle afferents

2005 ◽  
Vol 99 (5) ◽  
pp. 1891-1896 ◽  
Author(s):  
Shawn G. Hayes ◽  
Angela E. Kindig ◽  
Marc P. Kaufman
Keyword(s):  
Muscle Metabolism ◽  
Muscle Afferents ◽  
Group Iv ◽  
Triceps Surae ◽  
Tension Development ◽  
Group Iii ◽  
Exercise Pressor Reflex ◽  
Mechanical Component ◽  
Static Contraction ◽  
Pressor Reflex

The exercise pressor reflex is evoked by both mechanical and metabolic stimuli. Tendon stretch does not increase muscle metabolism and therefore is used to investigate the mechanical component of the exercise pressor reflex. An important assumption underlying the use of tendon stretch to study the mechanical component of the exercise pressor reflex is that stretch stimulates the same group III mechanosensitive muscle afferents as does static contraction. We have tested the veracity of this assumption in decerebrated cats by comparing the responses of group III and IV muscle afferents to tendon stretch with those to static contraction. The tension-time indexes as well as the peak tension development for both maneuvers did not significantly differ. We found that static contraction of the triceps surae muscles stimulated 18 of 30 group III afferents and 8 of 11 group IV afferents. Similarly, tendon stretch stimulated 14 of 30 group III afferents and 3 of 11 group IV afferents. However, of the 18 group III afferents that responded to static contraction and the 14 group III afferents that responded to tendon stretch, only 7 responded to both stimuli. On average, the conduction velocities of the 18 group III afferents that responded to static contraction (11.6 ± 1.6 m/s) were significantly slower ( P = 0.03) than those of the 14 group III afferents that responded to tendon stretch (16.7 ± 1.5 m/s). We have concluded that tendon stretch stimulated a different population of group III mechanosensitive muscle afferents than did static contraction. Although there is some overlap between the two populations of group III mechanosensitive afferents, it is not large, comprising less than half of the group III afferents responding to static contraction.

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.

Increasing gracilis muscle interstitial potassium concentrations stimulate group III and IV afferents

1985 ◽  
Vol 58 (3) ◽  
pp. 936-941 ◽  
Author(s):  
K. J. Rybicki ◽  
T. G. Waldrop ◽  
M. P. Kaufman
Keyword(s):  
Pressor Response ◽  
Cardiovascular Responses ◽  
Muscular Contraction ◽  
Muscle Afferents ◽  
Group Iv ◽  
Gracilis Muscle ◽  
Group Iii ◽  
Arterial Blood ◽  
Static Contraction ◽  
Anesthetized Dogs

Static muscular contraction reflexly increases arterial blood pressure and heart rate. One possible mechanism evoking this reflex is that potassium accumulates in the interstitial space of a working muscle to stimulate group III and IV afferents whose activation in turn evokes a pressor response. The responses of group III and IV muscle afferents to increases in interstitial potassium concentrations within the range evoked by static contraction are unknown. Thus we injected potassium chloride into the gracilis artery of anesthetized dogs while we measured both gracilis muscle interstitial potassium concentrations with potassium-selective electrodes and the impulse activity of afferents in the gracilis nerve. We found that increasing interstitial potassium concentrations to levels similar to those seen during static contraction stimulated 14 of 16 group III and 29 of 31 group IV afferents. The responses of the afferents to potassium were concentration dependent. The typical response to potassium consisted of a burst of impulses, an effect that returned to control firing rates within 26 s, even though interstitial potassium concentrations remained elevated for several minutes. Although our results suggest that potassium may play a role in initiating the reflex cardiovascular responses to static muscular contraction, the accumulation of this ion does not appear to be solely responsible for maintaining the pressor response for the duration of the contraction.

scholarly journals Peripheral µ-opioid receptors attenuate the responses of group III and IV afferents to contraction in rats with simulated peripheral artery disease

2018 ◽  
Vol 119 (6) ◽  
pp. 2052-2058 ◽  
Author(s):  
Jonathan Harms ◽  
Audrey J. Stone ◽  
Marc P. Kaufman
Keyword(s):  
Peripheral Artery Disease ◽  
Group Iv ◽  
Peripheral Artery ◽  
Opioid Agonist ◽  
Group Iii ◽  
Femoral Arteries ◽  
Exercise Pressor Reflex ◽  
Static Contraction ◽  
Pressor Reflex ◽  
Artery Disease

Patients with peripheral artery disease show an exaggerated pressor response to mild exercise, an effect attributable to the exercise pressor reflex, whose afferent arm comprises the thinly myelinated group III and unmyelinated group IV afferents. Previously, we found that DAMGO, a µ-opioid agonist injected into the femoral artery, attenuated the exaggerated exercise pressor reflex in rats with ligated femoral arteries, a preparation that simulates the blood flow patterns to muscle that is seen in patients with peripheral artery disease. Continuing this line of investigation, we recorded the responses of group III and IV afferents to static contraction before and after injecting DAMGO (1 µg) into the superficial epigastric artery in rats with patent femoral arteries and in rats with ligated femoral arteries. In rats with patent arteries, DAMGO did not change the responses to contraction of either group III ( n = 9; P = 0.83) or group IV ( n = 8; P = 0.34) afferents. In contrast, in rats with ligated femoral arteries, DAMGO injection (1 µg) significantly decreased the responses to contraction of both group III afferents ( n = 9, P < 0.01) and group IV afferents ( n = 9; P < 0.01). DAMGO did not significantly attenuate the responses of either group III or IV afferents to capsaicin in rats with either patent or ligated femoral arteries. These findings are in agreement with our previous studies that showed that peripheral DAMGO injection attenuated the exercise pressor reflex in rats with ligated femoral arteries but had only a modest effect on the exercise pressor reflex in rats with patent femoral arteries. NEW & NOTEWORTHY In an animal model of peripheral artery disease, we show that the µ-opioid agonist, DAMGO reduces the afferent response rate resulting from stimulated static contraction. These results suggest that peripherally active opioid agonists that do not cross the blood-brain barrier may be therapeutic for treatment of peripheral artery disease without the negative and addictive side effects associated with opioids in the central nervous system.

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.

Effects of static muscular contraction on impulse activity of groups III and IV afferents in cats

1983 ◽  
Vol 55 (1) ◽  
pp. 105-112 ◽  
Author(s):  
M. P. Kaufman ◽  
J. C. Longhurst ◽  
K. J. Rybicki ◽  
J. H. Wallach ◽  
J. H. Mitchell
Keyword(s):  
Gastrocnemius Muscle ◽  
Pressor Response ◽  
Muscular Contraction ◽  
Muscle Afferents ◽  
Exercise Group ◽  
Group Iv ◽  
Group Iii ◽  
Arterial Blood ◽  
Static Contraction ◽  
Stimulation Of

Static contraction of the hindlimb muscles, induced by electrical stimulation of the ventral roots, reflexly increases arterial blood pressure and heart rate. Although stimulation of groups III and IV muscle afferents is believed to cause these reflex increases, the responses of these afferents to a level of static contraction that increases arterial pressure have not yet been determined. Therefore, in barbiturate-anesthetized cats, afferent impulses arising from endings in the gastrocnemius muscle were recorded from the L7 or S1 dorsal roots, while the cut peripheral end of the L7 ventral root was stimulated. In addition, the effects of capsaicin (100-200 micrograms) and bradykinin (25 micrograms) on the activity of the groups III and IV afferents stimulated by contraction were examined. Contraction of the gastrocnemius muscle to a level equal to or greater than that needed to cause a pressor response stimulated 12 of 19 (63%) group III afferents and 13 of 19 (68%) group IV afferents. However, the discharge patterns of the group III afferents stimulated by contraction were very different from those of the group IV fibers. No relationship was found between those fibers stimulated by contraction and those stimulated by chemicals. Our results suggest that although both groups III and IV muscle afferents contribute to the reflex cardiovascular increases evoked by static exercise, group III fibers were likely to be stimulated by the mechanical effects of muscular contraction, whereas at least some group IV fibers were likely to be stimulated by the metabolic products of muscular contraction.

scholarly journals Purinergic 2X receptors play a role in evoking the exercise pressor reflex in rats with peripheral artery insufficiency

2014 ◽  
Vol 306 (3) ◽  
pp. H396-H404 ◽  
Author(s):  
Audrey J. Stone ◽  
Katsuya Yamauchi ◽  
Marc P. Kaufman
Keyword(s):  
Pyridoxal Phosphate ◽  
Pressor Response ◽  
P2x Receptors ◽  
P2x Receptor ◽  
Disulfonic Acid ◽  
Femoral Arteries ◽  
Exercise Pressor Reflex ◽  
Pressor Responses ◽  
Before And After ◽  
Pressor Reflex

Purinergic 2X (P2X) receptors on the endings of thin fiber afferents have been shown to play a role in evoking the exercise pressor reflex in cats. In this study, we attempted to extend this finding to decerebrated, unanesthetized rats whose femoral arteries were either freely perfused or were ligated 72 h before the start of the experiment. We first established that our dose of pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS; 10 mg/kg), a P2X receptor antagonist, attenuated the pressor response to α,β-methylene ATP (10 μg/kg), a P2X receptor agonist. We then compared the exercise pressor reflex before and after infusing PPADS into the arterial supply of the hindlimb muscles that were statically contracted. In rats with freely perfused femoral arteries, the peak pressor responses to contraction were not significantly attenuated by PPADS (before PPADS: 19 ± 2 mmHg, 13 min after PPADS: 17 ± 2 mmHg, and 25 min after PPADS: 17 ± 3 mmHg). Likewise, the cardioaccelerator and renal sympathetic nerve responses were not significantly attenuated. In contrast, we found that in rats whose femoral arteries were ligated PPADS significantly attenuated the peak pressor responses to contraction (before PPADS: 37 ± 5 mmHg, 13 min after PPADS: 27 ± 6 mmHg, and 25 min after PPADS: 25 ± 5 mmHg; P < 0.05). Heart rate was not significantly attenuated, but renal SNA was at certain time points over the 30-s contraction period. We conclude that P2X receptors play a substantial role in evoking the exercise pressor reflex in rats whose femoral arteries were ligated but play only a minimal role in evoking the reflex in rats whose femoral arteries were freely perfused.

α,β-Methylene ATP elicits a reflex pressor response arising from muscle in decerebrate cats

2002 ◽  
Vol 93 (3) ◽  
pp. 834-841 ◽  
Author(s):  
Ramy L. Hanna ◽  
Shawn G. Hayes ◽  
Marc P. Kaufman
Keyword(s):  
Pyridoxal Phosphate ◽  
Pressor Response ◽  
P2 Receptors ◽  
Vascular Supply ◽  
Disulfonic Acid ◽  
Exercise Pressor Reflex ◽  
Pressor Responses ◽  
Chemical Stimuli ◽  
Pressor Reflex ◽  
Stimulation Of

In part, the exercise pressor reflex is believed to be evoked by chemical stimuli signaling that blood supply to exercising muscles is not adequate to meet its metabolic demands. There is evidence that either ATP or adenosine may function as one of these chemical stimuli. For example, muscle interstitial concentrations of both substances have been found to increase during exercise. This finding led us to test the hypothesis that popliteal arterial injection of α,β-methylene ATP (5, 20, and 50 μg/kg), which stimulates P2X receptors, and 2-chloroadenosine (25 μg/kg), which stimulates P1 receptors, evokes reflex pressor responses in decerebrate, unanesthetized cats. We found that popliteal arterial injection of the two highest doses of α,β-methylene ATP evoked pressor responses, whereas popliteal arterial injection of 2-chloroadenosine did not. In addition, the pressor responses evoked by α,β-methylene ATP were blocked either by section of the sciatic nerve or by prior popliteal arterial injection of pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (10 mg/kg), a selective P2-receptor antagonist. We conclude that the stimulation of P2 receptors, which are accessible through the vascular supply of skeletal muscle, evokes reflex pressor responses. In addition, our findings are consistent with the hypothesis that the stimulation of P2 receptors comprises part of the metabolic error signal evoking the exercise pressor reflex.

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