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Am J Physiol Heart Circ Physiol 290: H1214-H1219, 2006. First published October 28, 2005; doi:10.1152/ajpheart.01051.2005
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P2 antagonist PPADS attenuates responses of thin fiber afferents to static contraction and tendon stretch

Angela E. Kindig, Shawn G. Hayes, Ramy L. Hanna, and Marc P. Kaufman

Division of Cardiovascular Medicine, University of California, Davis, California

Submitted 4 October 2005 ; accepted in final form 24 October 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
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.

purinergic receptors; exercise; neural control of circulation; cats; skeletal muscle; pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid

THE EXERCISE PRESSOR REFLEX is evoked by mechanical and metabolic stimuli arising in contracting skeletal muscles (8, 22). The reflex is believed to contribute toward the maintenance of adequate perfusion of contracting muscles by increasing the cardiac output and by constricting the vasculature (24). Groups III and IV muscle afferents comprise the sensory arm of the exercise pressor reflex arc (18). Historically, these afferents were believed to provide a metabolic error signal to the spinal cord and brain stem that blood flow to the contracting muscles was not adequate to meet the metabolic requirements of the muscles (33). Support for metabolic stimuli evoking the exercise pressor reflex has come from studies (30) showing that groups III and IV afferents were stimulated by substances known to be produced by muscles when they were contracted. Recently, mechanical stimuli were also shown to play a role in evoking the exercise pressor reflex. Support for a mechanical stimulus came from studies in animals showing that blockade of mechanogated channels with gadolinium attenuated both the exercise pressor reflex and the pressor reflex evoked by tendon stretch as well as from studies in humans showing that nonnoxious stretching of muscle evoked increases in heart rate and muscle sympathetic nerve activity (2, 21).

Group III afferents are thinly myelinated and are responsive, for the most part, to nonnoxious mechanical stimuli, such as gentle probing of their receptive fields and tendon stretch (9, 20). Nevertheless, metabolic stimuli are capable of increasing the sensitivity of group III afferents to mechanical stimuli (19, 31, 34). Group III afferents are considered to be responsible for evoking the mechanical component of the exercise pressor reflex (35). Group IV afferents are unmyelinated and, for the most part, are much less sensitive to nonnoxious mechanical stimuli, such as probing and stretch, than are group III afferents (9, 20). Instead, group IV afferents are responsive to chemical stimuli (29, 31); these unmyelinated afferents are considered to be responsible for evoking the metabolic component of the exercise pressor reflex (10, 20).

The specific metabolite(s) that sensitizes group III afferents to mechanical stimuli and stimulates group IV afferents is not known, but the possibility is high that there are more than one (32, 36, 37). Several recent findings about ATP have raised the possibility that this purine plays an important role in evoking the metabolic component of the exercise pressor reflex. For example, ATP concentrations in the interstitium of muscle are known to increase during contraction (14, 23). Moreover, injections of ATP or {alpha},beta-methylene ATP, a P2X receptor agonist, into the arterial supply of hindlimb muscle reflexly increased mean arterial pressure and heart rate (3, 15). Finally, injection of {alpha},beta-methylene ATP into the popliteal artery stimulated slowly conducting group III afferents as well as group IV afferents (5).

We hypothesized that P2 receptors located on the sensory endings of groups III and IV afferents contribute to the metabolic component of the exercise pressor reflex. We also hypothesized that P2 receptors contribute to the mechanical component of this reflex. We tested these hypotheses by recording the responses of groups III and IV afferents to static contraction of the triceps surae muscles and to tendon stretch before and after P2 receptor blockade with pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS).


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
General. The Institutional Care and Use Committee of the University of California, Davis, approved all procedures in this report. Cats (n = 35; weight range 2–6 kg) were anesthetized with halothane (3–4%) and oxygen. The trachea was cannulated, and the lungs were mechanically ventilated (Harvard Apparatus) with 3% halothane in oxygen until after the decerebration and surgery were completed. Catheters were placed in the right common carotid artery and the right jugular vein. Arterial blood pressure was measured by connecting the carotid catheter to a pressure transducer (model P23 XL, Statham). Heart rate was calculated beat-to-beat from the arterial pressure pulse (Gould Biotech).

The cat was placed in a Kopf stereotaxic and spinal unit and given dexamethasone (4 mg iv). A midcollicular decerebration was performed, and all neural tissue rostral to the section was removed. Hemostasis was achieved and the cranial vault filled with agar (37°C). A laminectomy was performed to expose the L6-S1 dorsal roots. The left triceps surae muscles were isolated, and the calcaneal bone was severed. The left leg was fixed in place with a clamp and knee brace so that the angle between the upper and lower leg was ~115°. The free end of the left calcaneal tendon was attached to a force transducer (model FT-10C, Grass Instrument) to measure the tension developed by the left triceps surae muscles. All visible branches of the left sciatic nerve except for those innervating the triceps surae muscles were cut. The left femoral nerve was also cut.

Recording impulse activity from groups III and IV afferents. Afferent impulses were recorded from thin filaments dissected from either L7 or S1 dorsal roots. We located the receptive fields of groups III and IV afferents by probing the left triceps surae muscles with both noxious and nonnoxious stimuli. Noxious probing consisted of vigorously pinching the muscles with the fingers; likewise, nonnoxious probing consisted of either gently stroking the triceps surae with a blunt rod or gently squeezing the muscles with the fingers. The afferent signals were passed through a high-impedance probe (HIP 511, Grass Instrument), amplified, and filtered (100–3,000 Hz; P511, Grass Instrument). Action potentials were displayed on a computer monitor (Spike 2; Cambridge Electronics Design, Cambridge, UK) and on a storage oscilloscope (HP 54603B).

The conduction velocity of an afferent was calculated by dividing the conduction distance between the recording electrode on the dorsal root and the stimulating electrode on the tibial nerve by the conduction time, which was measured on the storage oscilloscope. Group III fibers had conduction velocities between 2.5 and 30 m/s. Group IV fibers had conduction velocities of <2.5 m/s (8). Afferents having a conduction velocity of >30 m/s were discarded.

Protocols. The left triceps surae muscles were contracted statically for 60 s by electrically stimulating the tibial nerve (15 Hz; 25 µs; 1.5–2 times motor threshold). This method of contracting the triceps surae muscles does not electrically stimulate the axons of groups III and IV afferents (8). The triceps surae muscles were stretched for 60 s by turning a rack and pinion attached to the calcaneal tendon. We attempted to match the tension developed during tendon stretch to that developed during static contraction. The order of the two manipulations (i.e., static contraction and tendon stretch) was randomly varied.

P2 receptor blockade with PPADS. Static contraction and/or tendon stretch was repeated after injecting PPADS into the left popliteal artery, provided that a particular group III or IV afferent responded to at least one of the two maneuvers. Consequently, not all of the afferents were tested with each maneuver after P2 receptor blockade. PPADS was placed into solution with saline and was injected in a volume of 1 ml. Before injecting PPADS, we tightened snares placed around the left external iliac artery and left common iliac vein. We injected PPADS (10 mg/kg) into the left popliteal artery, trapping it within the circulation of the lower leg. The PPADS solution had an orange color and consequently could be seen entering the vascular bed of the triceps surae muscles. If this was not seen by the experimenters, the data were discarded. We released the snares after 15 min and allowed the leg to be freely perfused for 15 min before initiating either contraction or tendon stretch. We (3, 5) have shown previously that popliteal arterial injections of this dose of PPADS blocked both the reflex pressor responses and the thin fiber muscle afferent responses to popliteal arterial injection of {alpha},beta-methylene ATP. In addition, we (30) have shown previously that arterial injections of 1 ml of saline, the vehicle for PPADS, had no effect on the discharge properties of groups III and IV muscle afferents. Consequently, vehicle control experiments were not needed.

Data analysis. Baseline impulse activity was counted for 60 s before a maneuver (i.e., static contraction or tendon stretch), during the maneuver, and for 60 s after the maneuver ended. Activity is expressed as impulses (imp) per second. The tension time index (25) was calculated by integrating the area between the tension trace and the baseline level (Spike 2). Peak developed tension was calculated by subtracting the resting tension from the maximum tension. All values are expressed as means ± SE. Two-by-two repeated-measures ANOVA followed by Tukey post hoc tests was used to determine statistical significance. The criterion for statistical significance was set at P < 0.05.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
We recorded the impulse activity of 29 group III afferents (conduction velocity = 10.0 ± 1.3 m/s) and 19 group IV afferents (conduction velocity = 1.4 ± 0.1 m/s), each of which had its receptive field in the triceps surae muscles. For the most part, group III afferents responded to light mechanical probing of their receptive fields, whereas group IV afferents responded to noxious pinching of their receptive fields. Group IV afferents did not respond to gentle stroking or nonnoxious pinching of the muscles.

Static Contraction

Group III afferents. Static contraction of the triceps surae muscles increased the discharge rate of 16 (conduction velocity = 10.6 ± 1.7 m/s) of the 29 group III afferents tested. Static contraction before PPADS injection increased activity from 0.1 ± 0.05 to 1.6 ± 0.5 imp/s (P < 0.05; n = 16), whereas static contraction after PPADS injection increased activity from 0.2 ± 0.1 to 1.0 ± 0.5 imp/s (Figs. 1–3; P < 0.05; n = 16). For the 16 group III afferents responsive to static contraction, PPADS significantly attenuated their responses by 47% (Fig. 2A; P < 0.05). PPADS did not change the baseline activity of the 16 group III afferents (Figs. 2A and 3). The tension time indexes (Table 1) and peak tensions (Table 2) developed by contraction before and after PPADS injection were not significantly different from each other (P > 0.05; n = 16).


Figure 1
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  		Fig. 1. Responses of a group III muscle afferent (conduction velocity = 16.4 m/s) to static contraction of triceps surae muscles before (A) and after (B) popliteal arterial injection of pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS; 10 mg/kg). Static contraction started at time 0 and lasted for 60 s. Insets: recordings of action potentials and tension developed by triceps surae muscles at start of static contraction (arrows). TTI, tension time index; Imp, impulse. Stars identify action potentials discharged by group III afferent. Large vertical lines are stimulus artifact. Each horizontal mark on vertical axis represents 1 kg of developed tension.

 

Figure 3
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  		Fig. 3. Cumulative histograms of group III and IV muscle afferent responses to static contraction or to tendon stretch before and after PPADS (10 mg/kg) injection into popliteal artery. Horizontal bar represents period of time during which triceps surae muscles were either statically contracted or stretched.

 

Figure 2
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  		Fig. 2. Summary of responses to static contraction and to tendon stretch for group III and IV muscle afferents. Discharge rates of group III and IV muscle afferents responding to static contraction (A and B) and tendon stretch (C and D) before and after popliteal arterial injection of PPADS (10 mg/kg). Solid bars represent baseline (B) means and open bars represent means for either contraction (CX) or tendon stretch (TS). Vertical brackets represent standard errors. *Significant difference (P < 0.05) between baseline and either CX or TS. Horizontal brackets represent significant difference (P < 0.05) between increase in discharge (i.e., CX or TS minus B) before and after PPADS; n, no. of cats.

 

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  		Table 1. Tension time indexes for static contraction and tendon stretch

 

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  		Table 2. Peak developed tensions evoked by static contraction and by tendon stretch

 
Group IV afferents. Static contraction increased the discharge rate of 13 (conduction velocity = 1.5 ± 0.1 m/s) of the 14 group IV afferents tested. Static contraction before PPADS injection increased activity from 0.3 ± 0.1 to 1.0 ± 0.3 imp/s, whereas after injection, it increased activity from 0.2 ± 0.1 to only 0.3 ± 0.1 imp/s (Figs. 2–4; P < 0.05). For the 13 group IV afferents responsive to static contraction, PPADS significantly attenuated their responses by 86% (Figs. 2B and 3; P < 0.05). PPADS did not change baseline activity of the 13 group IV afferents (Figs. 2B and 3). The tension time indexes and peak tensions developed by contraction before and after PPADS injection were not significantly different from each other (Tables 1 and 2; P > 0.05).


Figure 4
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  		Fig. 4. Responses of a group IV muscle afferent (conduction velocity = 1.7 m/s) to static contraction of triceps surae muscles before (A) and after (B) popliteal arterial injection of PPADS (10 mg/kg). Static contraction started at time 0 and lasted for 60 s. Insets: recordings of action potentials at start of static contraction (arrows). Horizontal bar represents 500 ms. Stars identify action potentials discharged by group IV afferent.

 
Tendon Stretch

Group III afferents. Stretching the calcaneal tendon for 60 s increased the activity of 13 (conduction velocity = 12.9 ± 1.7 m/s) of the 25 group III afferents tested. Tendon stretch before PPADS increased activity of the 13 group III afferents from 0.2 ± 0.1 to 1.2 ± 0.2 imp/s (P < 0.001), whereas stretch after PPADS injection increased the activity of these afferents from 0.1 ± 0.1 to 0.6 ± 0.1 imp/s (P < 0.05; Figs. 2C and 3). For the 13 group III afferents responsive to tendon stretch, PPADS significantly attenuated their responses to this maneuver by 50% (Figs. 2C and 3; P < 0.01). Moreover, PPADS did not change baseline activity of the 13 group III afferents (Figs. 2C and 3). The tension time indexes and peak tensions developed by stretch before and after PPADS injection were not significantly different from each other (Tables 1 and 2; P > 0.05; n = 13).

Group IV afferents. Stretching the calcaneal tendon for 60 s increased the activity of 7 (conduction velocity = 1.6 ± 0.2 m/s) of the 14 group IV afferents tested. Tendon stretch before PPADS increased activity of the seven group IV afferents from 0.6 ± 0.1 to 1.1 ± 0.3 imp/s (P < 0.05); stretch after PPADS injection increased the activity of these afferents from 0.6 ± 0.2 to 1.0 ± 0.3 imp/s (Figs. 2 and 3; P > 0.05). Tendon stretch significantly increased the discharge rate of the group IV afferents over their baseline levels before PPADS injection (P < 0.05) but had no significant effect on this discharge rate after PPADS (P > 0.05; Fig. 2D). Nevertheless, the attenuation by PPADS was very small (Fig. 2D) and was found not to be significant (P > 0.05) when tested as an interaction in a two-way repeated-measures ANOVA. PPADS injection did not change the baseline discharge rates of the seven group IV afferents responding to tendon stretch (Fig. 2D; P > 0.05). The tension time indexes and peak tensions developed by tendon stretch before PPADS injection were not significantly different from each other (Tables 1 and 2; P > 0.05; n = 7).


   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Purinergic receptors are of two types, P1 and P2. The first type, P1, is stimulated by adenosine, whereas the second type is stimulated by ATP. There is substantial evidence that the P2 receptor on thin fiber (i.e., group III and IV) muscle afferents plays an important role in evoking both mechanical and metabolic components of the exercise pressor reflex. For example, PPADS has been shown to attenuate the reflex pressor response to tendon stretch in cats (4); likewise, it has also been shown to prevent the ATP-induced sensitization of the reflex pressor response to tendon stretch in rats (15). Tendon stretch does not cause an increase in muscle metabolism and is considered to be a pure mechanical stimulus (35); nevertheless, stretch recently has been shown to increase the concentration of ATP in the interstitial space of muscle (13). In addition, PPADS has been shown to attenuate the exercise pressor reflex, which is evoked by a combination of mechanical and metabolic stimuli (4), and to abolish the pressor reflex evoked by postcontraction circulatory occlusion, which is evoked solely by metabolic stimuli (4). Finally, the P2 receptor agonists ATP or {alpha},beta-methylene ATP have been shown to stimulate group III afferents with conduction velocities of <4 m/s as well as group IV afferents (5, 27).

In contrast to P2 receptors, P1 receptors on thin fiber muscle afferents do not appear to play a role in generating the exercise pressor reflex. For example, blockade of P1 receptors in cats had no effect on the exercise pressor reflex (4); likewise, blockade of P1 receptors had no effect on the reflex pressor response to tendon stretch in either cats (4) or rats (15). Furthermore, injecting or infusing adenosine into the arterial supply of either animals (3, 17, 38) or humans (16) did not evoke a muscle metaboreflex. In addition, preventing the reuptake of adenosine with brachial arterial injections of dipyridamole in humans increased interstitial concentrations of adenosine but did not increase the exercise pressor reflex (28). Finally, blockade of P1 receptors with aminophylline in humans had no effect on the increase in muscle sympathetic nerve activity evoked by mild rhythmic forearm exercise (21).

An important limitation of our study is that we selected thin fiber muscle afferents on the basis of the fact that they displayed at least some mechanical sensitivity to probing their receptive fields in the triceps surae muscles. Thus we may have excluded afferents that innervated the triceps surae muscles but had no mechanical sensitivity. The presence of mechanically insensitive afferents can be revealed by electrical stimulation of their axons as they exit the muscles. However, the strong currents required to activate group IV afferents when measuring conduction times from stimulating to recording electrodes leave open the possibility that one is activating the axons of afferents that innervate nearby structures, such as joints, bone, and other muscles (10). This possibility caused us to test only groups III and IV afferents that we were sure had their receptive fields in the triceps surae muscles.

PPADS blocks P2 receptors but does not block P1 receptors (12). Moreover, PPADS has only a weak inhibitory effect on ecto-nucleotidases, the enzyme that converts ATP to adenosine in the interstitial space (11). High ecto-nucleotidase blocking activity can be characteristic for purinergic antagonists and when present would serve to increase levels of ATP in the interstitial space. Despite these strengths, PPADS is a nonselective and nonuniversal antagonist of P2 receptors (11). In vitro, PPADS has been shown to block homomeric P2X1, P2X2, P2X3, P2X5, and P2Y1 receptors as well as heteromeric P2X2/3 and P2X1/5 receptors. PPADS, however, does not block homomeric P2X4, P2X6, P2X7, P2Y2, P2Y4, P2Y6, and P2Y11 receptors (26). These in vitro findings combined with our previous finding that popliteal arterial injection of the P2X3 receptor agonist {alpha},beta-methylene ATP evoked a pressor reflex (3) as well as stimulated mostly group IV afferents (5) led us to speculate that PPADS attenuated the responses of these unmyelinated muscle afferents to static contraction by blocking homomeric P2X3 or heteromeric PX2/3 receptors.

We also found that PPADS attenuated the responses of group III afferents to tendon stretch but had no effect on the responses of the group IV afferents. Tendon stretch is a useful technique to mechanically stimulate group III afferents in skeletal muscle and is used in an attempt to avoid the confounding effects of metabolic stimulation that occur when muscle is contracted. Recently, however, we found that tendon stretch and static contraction often stimulated different group III afferents (7). In other words, the finding that tendon stretch stimulated a group III afferent did not offer any certainty that static contraction would stimulate this afferent. The specific P2X receptor on the group III afferents responding to stretch that was blocked by PPADS in our experiments is unknown. However, Cook et al. (1) have suggested that the P2X5 receptor plays a role in activating muscle stretch receptors. We note with interest that PPADS is an effective antagonist to this receptor, and we wonder whether the P2X5 receptor also was responsible for the ATP-induced sensitization of the pressor response to tendon stretch reported by Li and Sinoway (15).

In conclusion, we found that P2 receptor blockade with PPADS significantly attenuated the responses of group III afferents to static contraction as well as to tendon stretch. We also found that PPADS significantly attenuated the responses of group IV afferents to static contraction but did not attenuate the responses of these unmyelinated afferents to tendon stretch. These findings are consistent with our working hypothesis that many group III afferents are mechanoreceptors that can be sensitized by the presence of ATP in the muscle interstitial space, whereas many group IV muscle afferents are metaboreceptors that are stimulated by the presence of ATP in the muscle interstitial space.


   GRANTS
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by National Heart, Lung, and Blood Institute Grant RO1 HL-30710.


   ACKNOWLEDGMENTS
 
We thank Yao Dong for surgical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: A. Kindig, Division of Cardiovascular Medicine, TB 172, One Shields Dr., Univ. of California, Davis, CA 95616 (e-mail: aekindig{at}ucdavis.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
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 DISCUSSION
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