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Am J Physiol Heart Circ Physiol 291: H1255-H1261, 2006. First published February 24, 2006; doi:10.1152/ajpheart.01303.2005
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Temperature modulates P2X receptor-mediated cardiovascular responses to muscle afferent activation

Zhaohui Gao, Valerie Kehoe, Jihong Xing, Lawrence Sinoway, and Jianhua Li

Heart and Vascular Institute and Division of Cardiology, Department of Medicine, Penn State College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania

Submitted 12 December 2005 ; accepted in final form 24 February 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Static muscle contraction increases ATP release into the muscle interstitial space. Elevated ATP in muscle stimulates thin fiber muscle afferents and increases blood pressure via engagement of purinergic P2X receptors. In addition, ATP activates P2X receptors and enhances cardiovascular responses induced by stimulation of muscle mechanoreceptors. In this study, we examined whether elevated muscle temperature would attenuate and whether reduced temperature would potentiate P2X effects on reflex muscle responses. {alpha},beta-Methylene ATP ({alpha},beta-MeATP) was injected into the arterial blood supply of hindlimb muscle to stimulate P2X receptors, and muscle stretch was induced to activate mechanically sensitive muscle afferents as {alpha},beta-MeATP was injected in 10 anesthetized cats. Femoral arterial injection of {alpha},beta-MeATP (1.0 mM) increased mean arterial pressure (MAP) by 35 ± 5 (35°C), 26 ± 3 (37°C), and 19 ± 3 mmHg (39°C; P < 0.05 vs. 35°C), respectively. Muscle stretch (2 kg) elevated MAP. The MAP response was significantly enhanced 34% and 36% when {alpha},beta-MeATP (0.2 mM) was arterially infused 5 min before muscle stretch at 35° and 37°C, respectively. However, as muscle temperature reached 39°C, the stretch-evoked response was augmented only 6% by {alpha},beta-MeATP injection, and the response was significantly attenuated compared with the response with muscle temperature of 35° and 37°C. In addition, we also examined effects of muscle temperature on {alpha},beta-MeATP enhancement of the cardiovascular responses to static muscle contraction while the muscles were freely perfused and the circulation to the muscles was occluded. Because muscle temperature was 37°C, arterial injections of {alpha},beta-MeATP significantly augmented contraction-evoked MAP response by 49% (freely perfused) and 53% (ischemic condition), respectively. It is noted that this effect was significantly attenuated at a muscle temperature of 39°C. These data indicate that the effect of P2X receptor on reflex muscle response is sensitive to alternations of muscle temperature and that elevated temperature attenuates the response.

adenosine 5'-triphosphate; muscle stretch; muscle temperature; muscle pressor reflex; blood pressure

THE SYMPATHETIC NERVOUS SYSTEM is activated during exercise. This contributes to increases in arterial blood pressure, heart rate (HR), myocardial contractility, and peripheral vasoconstriction (18, 25, 30). It is thought that afferent input arising from contracting skeletal muscle causes increases in sympathetic nervous activity and cardiovascular responses (2, 19, 21). This system responds to metabolic stimulation (i.e., "metaboreceptor" stimulation) as well as to mechanical deformation of the muscle afferents receptive field (i.e., "mechanoreceptor" stimulation) (10). Populations of group III and IV afferent fibers have been identified to be in close proximity to collagen bundles, appropriately situated to act as mechanically sensitive receptors (1). Furthermore, group III afferents are thought to be predominantly mechanically sensitive, and group IV afferents are thought to be predominantly metabosensitive afferents (12). When these receptors are activated, thin fiber muscle afferent nerves are engaged, cardiovascular nuclei in the brain stem are activated, sympathetic activity increases, and blood pressure rises (20).

It has been reported that {alpha},beta-methylene ATP ({alpha},beta-MeATP) evokes reflex cardiovascular responses when it is injected into the arterial supply of the hindlimb musculature of the cat (5, 16). This cardiovascular reflex is mediated via stimulation of purinergic P2X receptors. An electrophysiological study shows that 3 of 18 group III and 7 of 9 group IV fibers increased their discharge in response to {alpha},beta-MeATP (6). This suggests that {alpha},beta-MeATP injection preferentially stimulates slowly conducting afferent sensory fibers. In addition, it has been observed that ATP accentuates muscle mechanoreceptor response (16). Specifically, when ATP or {alpha},beta-MeATP is infused into the cat hindlimb, the pressor response evoked by muscle stretch is augmented. Muscle stretch is a potent and specific muscle mechanoreceptor stimulant (28). The effect of ATP and its analog is blocked by the P2X receptor antagonist pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) (16). This suggests that ATP sensitizes mechanically sensitive afferents, and this effect requires stimulation of purinergic P2X receptors.

Because P2X receptor activity increases as temperature falls and decreases as temperature rises (31), we postulated in this report that P2X-mediated cardiovascular responses to muscle afferent stimulation would be modulated as muscle temperature is altered. The data from this report support the hypothesis that the effect of the P2X receptor on the muscle pressor reflex is attenuated as temperature is elevated.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
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 REFERENCES
 
All experimental procedures were approved by the Animal Care Committee of this institution and complied with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

Surgical preparation. Fourteen adult male cats (4.5–5.6 kg) were anesthetized initially with ketamine (25 mg/kg im) and then by inhalation of isoflurane oxygen mixture. An endotracheal tube was inserted into the trachea and attached to a ventilator (model 683, Harvard, South Natick, MA). Polyethylene catheters (PE-90) were inserted into an external jugular vein and into a common carotid artery for drug administration and measurement of arterial blood pressure (ABP), respectively. The gaseous anesthetic was discontinued after {alpha}-chloralose (80 mg/kg) and urethane (200 mg/kg) were injected intravenously. Throughout the experiment, supplemental injections of {alpha}-chloralose (15 mg/kg) and urethane (40 mg/kg) were given if the cats exhibited a corneal reflex or withdrew a limb in response to a noxious stimulus. The femoral arteries and arterial collaterals of both hindlimbs were carefully isolated. An arterial branch of the femoral artery was cannulated with PE-10 catheter. This allowed arterial injection of drugs while the arterial blood supply to hindlimb muscles was maintained. In four cats, an arterial occluder was positioned around the femoral artery of each leg to occlude circulation of the hindlimb muscles. The triceps surae muscle was isolated, and the Achilles tendons were cut. A tie was placed around the tendon and attached to a tension transducer. The legs were stabilized with ties around the ankles at the top of the knees. The pelvis was stabilized in a spinal unit, and the knee joints secured by attaching the patellar tendon to a steel post. The skin covering the triceps surae muscle and femoral region was surgically separated from the muscles below. It is a procedure that should eliminate inputs from skin afferents in the hindlimb. Thus we believe that {alpha},beta-MeATP injected into the blood supply of the hindlimb muscles did not stimulate skin afferents.

The lower lumbar and upper sacral portions of the spinal cord were exposed. The dura was then opened. The L7 and S1 spinal ventral roots were carefully separated and cut close to the spinal cord. The peripheral ends of the transected L7 and S1 ventral roots were then placed on platinum bipolar-stimulating electrodes, and the exposed spinal cord region was immersed in a pool of warm mineral oil (37°C).

The respiratory activities were monitored by a respiratory gas monitor (Datex-Ohmeda, Madison, WI). Arterial blood gases and pH were periodically checked (RapidLab 865 Blood Gas Analyzer, Bayer) and maintained within normal limits (pH, 7.35–7.45; PCO2, 32–36 mmHg; PO2 >80 mmHg; and HCO3–, 20–25 mmol/l) by adjusting the ventilator or by intravenously injecting a 1 M sodium bicarbonate solution. Body temperature was continuously monitored with a rectal thermometer (YSI series 400) and maintained at 37°C by a water-perfused heating pad and external heat lamps.

Experimental protocol. The cats were allowed to stabilize for at least 40 min after surgical preparation was completed. A temperature probe was inserted in the triceps surae muscle and connected to a monitor to obtain muscle temperature. Twenty minutes were allowed for the probe stabilization in the muscle. Muscle temperature was continuously monitored and controlled at 35°, 37°, and 39°C, respectively. A water-perfused heating pad or ice was used around the hindlimb muscle to adjust muscle temperature. ABP and HR responses to a femoral injection and muscle stretch/contraction were recorded. The injected volume was 0.5 ml. The same volume of saline was then injected to flush the arterial catheter. The duration of injection was 1 min. The triceps surae muscle was stretched, and tension of 2 kg was produced over 5–10 s by means of a rack and pinion. Muscle stretch was maintained for 1 min after tension of 2 kg was achieved. Static contraction of the triceps surae muscle was induced by electrical stimulation (three times motor threshold; 0.1-ms duration; 40 Hz) of the peripheral ends of the L7 and S1 ventral roots for 1 min. There was a 20-min rest period between injections and 40 min between bouts of muscle stretch/contraction.

Study 1: arterial injection of {alpha},beta-MeATP. {alpha},beta-MeATP (0.1, 0.5, and 1.0 mM, dissolved in saline; Sigma) was injected into the arterial blood supply of the triceps surae muscle as muscle temperature was adjusted to 35°, 37°, and 39°C, respectively (n = 10 animals). In this study the temperatures were chosen in a random fashion. It has been reported that this range of dosage of {alpha},beta-MeATP stimulates thin fiber muscle afferent nerves and increases blood pressure (5, 6, 16) via the engagement of P2X receptors.

Study 2: muscle stretch after {alpha},beta-MeATP injection. Muscle stretch was performed 5 min after femoral arterial injections of 0.5 ml saline and 0.2 mM {alpha},beta-MeATP, respectively (n = 10 animals). It has been reported that {alpha},beta-MeATP infused into the arterial blood supply of the cat hindlimb muscle sensitizes the pressor response evoked by muscle stretch, and this effect was blocked by the P2X receptor antagonist PPADS (16). In this study, we examined whether P2X sensitization of the muscle mechanoreflex was influenced by muscle temperature. Thus muscle stretch was performed as muscle temperature was adjusted to 35, 37 and 39°C, respectively. The sequence of changes in muscle temperature was selected in a random fashion.

Study 3: muscle contraction with muscles freely perfused and circulatory occlusion after {alpha},beta-MeATP injection. The effects of heating muscles on the P2X-mediated pressor response to static muscle contraction under freely perfused and ischemic conditions were also examined (n = 6 animals). First, the muscle contraction was induced by electrical stimulation of the L7 and S1 ventral roots for 1 min. An arterial occluder was then used to occlude the femoral artery for 3 min, and static contraction was then induced. After arterial injection of 0.2 mM of {alpha},beta-MeATP, those protocols were also repeated. The protocols were performed as muscle temperature was randomly adjusted to 37° and 39°C, respectively. Because in the previous protocol it was found that there was a significant difference for P2X-mediated reflex response at muscle temperature of 37° and 39°C, we examined the effect of {alpha},beta-MeATP as temperature was adjusted to 37° and 39°C in this group of experiments.

Data acquisition and analysis. ABP was measured with a pressure transducer (model P23ID, Statham, Oxnard, CA) connected to an arterial catheter. Mean arterial pressure (MAP) was obtained by integrating the arterial signal with a time constant of 4 s. HR was derived from the arterial pressure pulse. The Achilles tendon was connected to a force transducer for measurement of developed tension during muscle stretch/contraction. All measured variables were continuously recorded on an eight-channel chart recorder (Gould Instruments, model TA 4000, Valley View, OH). These variables were also sampled by an iMac computer that was equipped with the PowerLab data acquisition system (ADInstruments, Castle Hill, Australia).

Control values were determined by analyzing at least 30 s of the data immediately before femoral injection, a given level of muscle stretch or muscle contraction. The peak response of each variable was determined by the peak change from the control value. Experimental data (MAP, HR, and tension) were analyzed by one-way ANOVA with repeated measures. A Tukey post hoc test was utilized as appropriate. All values were expressed as means ± SE. For all analyses, differences were considered significant if P < 0.05. All statistical analyses were performed with SPSS for Windows, Version 11.5 (SPSS).


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
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Effect of temperature on reflex cardiovascular responses by arterial injection of {alpha},beta-MeATP. Baseline values for MAP and HR before arterial injections of {alpha},beta-MeATP are presented in Table 1. There were no significant differences in baseline MAP and HR before drug injections at muscle temperatures of 35°, 37°, and 39°C, respectively. Figure 1 shows that {alpha},beta-MeATP increased MAP and HR. Furthermore, among three levels of muscle temperature, there was no significant difference in the MAP responses to arterial injection of 0.1 and 0.5 mM {alpha},beta-MeATP. However, an effect of temperature was noted that the ABP response at 35°C was different than that seen at 39°C when 1.0 mM {alpha},beta-MeATP was injected. The HR response was not significantly altered by muscle temperature. It has been reported that {alpha},beta-MeATP stimulates thin fiber muscle afferent nerves and increases BP via P2X receptors (5, 6, 16). Thus the result from present study suggests that temperature affects reflex cardiovascular responses evoked when {alpha},beta-MeATP stimulates P2X receptors on thin fiber nerves.


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  		Table 1. Baseline MAP and HR before arterial injection of 0.1, 0.5, and 1.0 mM of {alpha},beta-MeATP at muscle temperatures of 35°, 37°, and 39°C

 

Figure 1
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  		Fig. 1. Effect of muscle temperature on reflex cardiovascular responses by arterial injection of {alpha},beta-methylene ATP ({alpha},beta-MeATP) in different concentrations (0.1, 0.5, and 1.0 mM) into blood supply of hindlimb muscle. Femoral arterial injection of P2X receptor agonist {alpha},beta-MeATP evoked the dose-dependent cardiovascular responses. There is significant difference for peak pressor response evoked by 1.0 mM of {alpha},beta-MeATP as muscle temperature is different. MAP, mean arterial pressure (top); HR, heart rate (bottom). Data are means ± SE. *P < 0.05, significance between 35° and 39°C (n = 10 animals).

 
Effect of temperature on {alpha},beta-MeATP sensitizing cardiovascular responses by muscle stretch. Baseline MAP and HR values obtained before passive muscle stretch are shown in Table 2. There were no significant differences in baseline values of MAP and HR at muscle temperatures of 35°, 37°, and 39°C. Muscle stretch significantly increased MAP and HR in all groups (Fig. 2). Furthermore, arterial injections of {alpha},beta-MeATP significantly augmented stretch-evoked MAP and HR responses at 35° and 37°C of muscle temperature. Of note, cardiovascular enhancing effects of {alpha},beta-MeATP were significantly attenuated when muscle temperature was 39°C (Fig. 2). As muscle temperature was 35°, 37°, and 39°C, {alpha},beta-MeATP increased MAP response by 34 ± 9%, 36 ± 8%, and 6 ± 7% (P < 0.05 vs. 35° and 37°C), respectively. Representative traces showing this result are presented in Fig. 3. We have previously demonstrated that {alpha},beta-MeATP sensitizes the pressor response evoked by muscle stretch via P2X receptors (16). Thus our current result suggests that higher temperature attenuates a sensitizing effect of P2X receptor on muscle mechanoreceptor reflex.


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  		Table 2. Baseline MAP and HR before muscle stretch with prior saline (control) and 0.2 mM of {alpha},beta-MeATP injection at muscle temperatures of 35°, 37°, and 39°C

 

Figure 2
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  		Fig. 2. Effect of muscle temperature on {alpha},beta-MeATP-sensitizing cardiovascular responses by muscle stretch. Muscle stretch (2 kg tension) significantly increases MAP (top) and HR (bottom). {alpha},beta-MeATP (0.2 mM) injected into the arterial blood supply of hindlimb muscle significantly elevated reflex MAP and HR responses evoked by activation of skeletal muscle afferents during muscle stretch as muscle temperature was 35° and 37°C. The effect was blunted as temperature was 39°C. Data are means ± SE. *P < 0.05, significance saline vs. {alpha},beta-MeATP injection (n = 10 animals).

 

Figure 3
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  		Fig. 3. Original traces from one cat show that {alpha},beta-MeATP-sensitizing effect on pressor response by muscle stretch is attenuated as muscle temperature is 39°C. ABP, arterial blood pressure.

 
Effect of temperature on {alpha},beta-MeATP enhancing cardiovascular responses by muscle contraction under freely perfused and circulatory occlusion. Table 3 shows baseline MAP and HR values obtained before static muscle contraction. There were no significant differences in baseline values of MAP and HR at muscle temperatures of 37° and 39°C. Muscle contraction under freely perfused and circulatory occlusion significantly increased MAP and HR in all groups (Fig. 4). Furthermore, as muscle temperature was 37°C, arterial injections of {alpha},beta-MeATP significantly augmented contraction-evoked MAP response by 49 ± 11% (freely perfused) and 53 ± 16% (ischemic condition), respectively. However, enhancing effects of {alpha},beta-MeATP on reflex cardiovascular responses were significantly attenuated when muscle temperature was 39°C (Fig. 4). {alpha},beta-MeATP increased MAP response by 10 ± 3% (freely perfused, P < 0.05 vs. 37°C) and 14 ± 7% (ischemic condition, P < 0.05 vs. 37°C), respectively. Finally, Fig. 4 also shows that there is indifference in developed muscle tension among those groups.


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  		Table 3. Baseline MAP and HR before muscle contraction under freely perfused and circulatory occlusion in control and with prior injection of 0.2 mM of {alpha},beta-MeATP at muscle temperatures of 37° and 39°C

 

Figure 4
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  		Fig. 4. Effect of heating muscles on {alpha},beta-MeATP-enhancing cardiovascular responses by muscle contraction under freely perfused and circulatory occlusion. Static contraction of triceps surae muscle was induced by electrical stimulation of L7 and S1 ventral roots for 1 min. Contraction significantly increases MAP (left) and HR (middle). {alpha},beta-MeATP (0.2 mM) injected into the arterial blood supply of hindlimb muscle significantly augmented reflex cardiovascular responses evoked by activation of skeletal muscle afferents during muscle contraction as muscle temperature was 37°C. This occurred while muscles were freely perfused or while circulation to muscles was occluded during contraction. The effect was significantly attenuated when temperature was 39°C. Of note, there is indifference in developed muscle tension (right) among groups. Data are means ± SE. *P < 0.05, significant differences between control and group with prior injection of {alpha},beta-MeATP (n = 6 animals).

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Previous studies have suggested that {alpha},beta-MeATP injected into the arterial blood supply of the hindlimb muscle stimulates thin fiber muscle afferent nerves and increases blood pressure (5, 6, 16). The effect is mediated via engagement of purinergic P2X receptors. The results from the present study are consistent with these findings. Based on prior work demonstrating that P2X-mediated effects are augmented at lower temperature and attenuated at elevated temperature (31), we examined whether P2X-mediated muscle reflex responses would be modulated as muscle temperature was altered. Our results demonstrated that muscle temperature affected the reflex cardiovascular responses by {alpha},beta-MeATP chemical stimulation of P2X receptors on thin fiber nerves. {alpha},beta-MeATP also sensitizes the pressor response evoked by muscle stretch via P2X receptors (16). Muscle stretch specifically stimulates muscle mechanoreceptors (28). Because the P2X receptor was activated, enhanced muscle mechanoreceptor reflex was significantly attenuated at 39°C compared with 35° and 37°C. This result suggests that higher muscle temperature blunts the P2X-sensitizing effect on mechanically sensitive thin fiber afferent nerves.

In addition, we further examined effects of muscle temperature on {alpha},beta-MeATP enhancement of the cardiovascular responses to static muscle contraction while the muscles were freely perfused and the circulation to the muscles was occluded. Because muscle temperature was raised from 37° to 39°C, augmented contraction-induced pressor response by arterial injections of {alpha},beta-MeATP was significantly attenuated in the muscles freely perfused (49% vs. 10%) and in the muscles under ischemic condition (53% vs. 14%). Thus muscle temperature plays a similar role in P2X-mediated reflex responses while the muscles are freely perfused or while the muscles are under ischemia.

As mentioned above, recent studies suggest that P2X receptor activity is temperature dependent. For example, P2 receptor-mediated vasoconstriction was more prominent at lower temperature than that under "normal" temperature conditions (4). Also, P2 receptor-mediated guinea pig urinary bladder and vas deferens responses were augmented at lower temperatures and attenuated at higher temperatures (31). Of note, in these reports (4, 31), the cooling temperature was ≤30°C. Moderate cooling (35°C) on the other hand did not potentiate P2X-mediated vasoconstriction (13). The results from this report have shown that a muscle temperature of 35°C tended to enhance reflex responses compared with responses seen at 37°C, although the effect was not significant. However, P2X effects were different at 35° and 39°C, respectively. This suggests that muscle temperature does modulate reflex cardiovascular responses evoked as P2X receptors on thin fiber muscle afferent nerves are stimulated.

The free nerve endings of both group III and IV afferent fibers have been identified in the interstitial spaces to be in close proximity to lymphatics and blood vessels of muscle and tendon tissue. These loci seem ideal for chemotransduction. Separate populations of group III and IV fibers have been identified to be in close proximity to collagen bundles. These receptors presumably are appropriately situated to act as mechanically sensitive receptors (1). The reflex cardiovascular responses to static muscle contraction are mediated via both group III and group IV fibers (2, 10). A number of metabolites (such as K+, diprotonated phosphate, and H+) have also been reported to stimulate group III and IV muscle afferents in humans and animals in contribution to the activation of the muscle pressor reflex (3, 15, 17, 23, 25–27).

In prior studies it has been shown that ATP injected into the triceps surae muscles of rats stimulated 67% of the group IV afferents tested (9). Intra-arterial injection of {alpha},beta-MeATP into the triceps surae muscles of cats stimulated a large portion of the group IV (~78%) but only a small portion of the group III (~17%) thin fiber nerves (6). Thus, in the present study, we suspect that {alpha},beta-MeATP largely stimulated group IV metabolite sensitive afferents and that muscle temperature thus affected P2X stimulation of chemically sensitive afferents. However, we cannot exclude that {alpha},beta-MeATP stimulated muscle nociceptors that are not involved in the exercise pressor reflex.

Furthermore, in the present study, the sensitizing effect of P2X receptor stimulation seen when muscle was stretched was significantly blunted when muscle temperature was elevated. Because muscle stretch is a potent and specific muscle mechanoreceptor stimulant (28) and group III afferents are mechanically sensitive (12), the findings presented herein suggest that the mechanoreceptor-sensitizing effect of ATP is also sensitive to muscle temperature. Specifically, elevated muscle temperature attenuates the sensitizing effect of P2X receptor stimulation on muscle mechanoreceptors.

Static muscle contraction increases discharges of both group III and group IV muscle afferent fibers (2, 10). Occlusion of the circulation to the contracting muscles increases the responses to static contraction of a significantly higher percentage of group IV afferents than group III afferents (46.7% vs. 12.5%) (11). Thus, based on our present results that muscle temperature plays a similar role in P2X-mediated reflex responses in the muscles freely perfused and muscles with ischemia, it is likely that muscle temperature has the same effect on P2X activation of metabosensitive group IV afferents and mechanically sensitive group III afferents.

ATP concentration in the muscle interstitial space rises with exercise in humans and with static muscle contraction in animals (8, 14, 22), and elevated ATP in muscle then stimulates thin fiber muscle afferents and increases blood pressure (5–7, 16). It is found that ecto-ATPase is temperature dependent: the lower the temperature, the less the ATP level. The release of ATP was significantly blunted at a temperature of 27°C (29). Thus it is unlikely that higher temperature blocks ATP release from active muscle cell, which may blunt ATP from sensitizing the muscle reflex. In addition, because {alpha},beta-MeATP, a stable P2X receptor agonist, injected into the hindlimb muscle was resistive to hydrolyzation of ecto-ATPase (32), we believe that the effect of higher temperature on muscle mechanoreceptor reflex is mediated via P2X receptor but not via interstitial ATP level or its metabolic activity.

In the present study, animal core body temperature was kept at 37°C. Raising muscle temperature from 37° to 39°C did not elevate core temperature. This suggests that the effect of temperature was localized to muscle and was not due to a systemic effect. Finally, baseline MAP and HR were similar before interventions at muscle temperature of 35°, 37°, and 39°C. This suggests that the observed effects are not likely due to an effect of temperature on baroreflex.

In conclusion, this study provides data that suggest that 1) P2X receptor-mediated effects on the muscle pressor reflex are sensitive to alternations in muscle temperature and 2) elevated muscle temperature attenuates the P2X-sensitizing activation of muscle mechanosensitive and metabosensitive afferents. Abnormal temperature responses in skeletal muscle have been noted in patients with cardiovascular diseases such as heart failure (24). Although the cellular and molecular mechanism requires additional studies, the current results may have important implications for understanding responses to exercise where muscle temperature rises. The diminished P2X-mediated responsiveness of higher temperatures may influence the processing of muscle afferent signals.


   GRANTS
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 ABSTRACT
 METHODS
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 GRANTS
REFERENCES
 
This work was supported by National Heart, Lung, and Blood Institute Grants R01-HL-075533 (to J. Li), R01-HL-078866 (to J. Li), and R01-HL-60800 (to L. Sinoway).


   ACKNOWLEDGMENTS
 
The authors thank Jennie Stoner for outstanding secretarial skills.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. Li, Heart and Vascular Institute, Div. of Cardiology, H047, Penn State College of Medicine, Milton S. Hershey Medical Center, 500 Univ. Dr., Hershey, PA 17033 (e-mail: jzl10{at}psu.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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Z. Gao, J. D. Li, L. I. Sinoway, and J. Li
Effect of muscle interstitial pH on P2X and TRPV1 receptor-mediated pressor response
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