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1Division of Cardiology, Penn State College of Medicine, Milton S. Hershey Medical Center, Hershey 17033; and 2Lebanon Veterans Affairs Medical Center, Lebanon, Pennsylvania 17042
Submitted 24 February 2003 ; accepted in final form 23 April 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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exercise pressor reflex; muscle contraction; muscle afferent; adenosine 5'-diphosphate
It has been shown that ATP and analogs excite sensory afferent nerves. For example, ATP depolarizes isolated vagus nerve trunks (47, 48), and it excites cutaneous, visceral, and knee joint afferent nerves (4, 11, 23) and carotid chemoreceptors (33). Furthermore, it has also been reported that ATP is released in vitro mouse bladder-pelvic nerve preparation by urinary bladder distension and that an ATP agonist activates pelvic afferents and potentiates their response to bladder distention (50).
Our recent study (25) has shown that 1) activation of ATP-sensitive P2X receptors evokes a skeletal afferent-mediated pressor response and 2) ATP enhances the muscle pressor response to muscle stretch via P2X receptors. Additionally, a recent report also supports the concept that ATP mediates the exercise pressor reflex via P2X receptors (17). This recent report demonstrates that the pressor response seen with static hindlimb contraction in cats is attenuated when P2X-receptor blockers are administered. Accordingly, these studies suggest that activation of ATP receptors may play an important role in mediating the autonomic adjustments to exercise.
In the present report, we examined whether the muscle interstitial ATP concentration increases with muscle contraction. We found that muscle dialysate ATP increases with contraction and that the rise in ATP is linked to the tension generated during contraction. Additional studies demonstrated that the sympathetic or motor nerves are not the major source of ATP release in skeletal muscle and that muscle contraction per se is a necessary and sufficient stimulus to raise dialysate ATP.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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General Methods
Animal surgical preparation. The cats were anesthetized initially
with ketamine (25 mg/kg im). An endotracheal tube was inserted into the
trachea and attached to a ventilator (model 683, Harvard, South Natick, MA).
The cats were then anesthetized by inhalation of an isoflurane-oxygen mixture.
Polyethylene catheters (PE-90) were inserted into an external jugular vein and
a common carotid artery for drug administration and measurements of arterial
blood pressure, respectively. The triceps surae muscles of both limbs were
isolated, and the Achilles (calcaneal) tendons were cut. The ventilator was
set with a tidal volume of 20 ml/stroke and a rate of 20–30 strokes/min.
Arterial blood gases and pH were periodically checked (ABL 510 pH blood gas
analyzer, Radiometer, Copenhagen, Demark). pH was maintained at
7.35–7.45, PCO2 at 30–40 Torr, and
at 20–25 mmol/l by
adjusting the ventilator or by intravenous injection of a 1 M sodium
bicarbonate solution. Body temperature was continuously monitored with a
rectal thermometer (series 400, Yellow Springs Instruments) and maintained
between 37.0 and 38.5°C by a water-perfused heating pad and external heat
lamps.
Decerebration was performed because it allowed an examination of autonomic reflex responses without having to consider the confounding effects of anesthesia (20). Before the decerebration procedure, the cats were given a 4-mg intravenous injection of dexamethasone to help prevent decerebration-induced brain stem edema. The head was fixed into a Kopf stereotaxic instrument, and decerebration was performed as anesthesia was continued. The majority of the temporal and parietal plates were removed. The two cortical hemispheres were also removed. A transverse section was made anterior to the superior colliculus and extending ventrally to the mamillary bodies. The brain rostral to the section was removed, and bleeding was controlled with cotton gauze that had been soaked in boiling saline. Gauze filled the vault, and gentle manual pressure was applied. Once the decerebration was completed, anesthesia was removed from the inhaled mixture. The general procedures employed for decerebration were performed as reported previously (25, 30).
A laminectomy was performed to expose the lower lumbar and upper sacral portions of the spinal cord.
The dura was then opened, allowing visual identification of the L7 and S1 spinal roots. The dorsal and ventral roots of L7 and S1 were carefully separated, and the ventral roots were 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. A pool was formed around the exposed neural and muscular tissue by using skin flaps sutured to brass bars, and the exposed spinal cord region was immersed in a pool of warm (37°C) mineral oil.
Insertion of microdialysis probes. The semipermeable fibers with a
molecular weight cutoff of 30,000 (0.20 mm ID, 0.22 mm OD; Spectrum
Laboratories, Laguna, CA) were used to construct the microdialysis probes.
Each end of a single fiber was inserted 1 cm into a hollow polyamide tube
(0.25 mm ID, 0.36 mm OD) and glued. The length of the probe semipermeable
fiber was 4 cm (between 2 polyamide tubes). The skin directly over the triceps
surae muscle on both hindlimbs was dissected away, and four microdialysis
probes were inserted into the gastrocnemius muscle of each hindlimb. The
probes were inserted into the muscle parallel to fiber orientation via a
cannula. The microdialysis probes were then attached to a perfusion pump
(model 102, CMA) and perfused at a rate of 5 µl/min with Ringer solution.
The dialysate was collected in 250-µl microcentrifuge tubes and immediately
sealed (to prevent evaporation) and stored at -80°C freezer until
analyzed.
In all experiments, "control dialysate" was also collected from the probes in the leg contralateral to the contracting hindlimb. We reasoned that if the ATP concentrations seen during contraction rose to the same degree in the contracting and control limbs, then we could conclude that muscle reflex engagement and the resultant engagement of sympathetic efferent nerves were responsible for the increase in dialysate ATP.
Microdialysis probe recovery. The percent recovery rate of microdialysis probes for ATP was examined in vitro. Briefly, four probes were inserted into a dish containing varying concentrations of ATP (2.5, 5, 7.5, and 10 µM, dissolved in artificial extracellular fluid). Each of the probes was then connected to a perfusion pump (model 102, CMA) and perfused with a Ringer solution at the same perfusion rate that was used for the animal experiment (5 µl/min). A minimum of three timed collections were taken from each dish to ensure that stabilization of the concentration gradient occurred. Dual 50-µl samples were collected over 20 min. The dialysate ATP concentrations were divided by the ATP concentration within the collection dish to obtain percent recovery values at the different concentrations. The probe recovery rates for 2.5, 5, 7.5, and 10 µM were 33.1 ± 1.9, 30.8 ± 2.9, 26.8 ± 2.3, and 26.5 ± 1.2%, respectively. The relationship between dish and dialysate concentration was linear (r = 0.957, P < 0.001; Fig. 1), indicating that the dialysate concentration was directly proportional to the dish ATP concentration. From these results, we concluded that dialysate ATP would be linearly related to the interstitial ATP obtained from the cat hindlimb.
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Determination of Adenine Nucleotides Concentrations
In this study, we measured dialysate ATP as well as the concentrations of ADP, AMP, and adenosine by using HPLC methods (49). This approach allowed the determination of purine nucleotides in the picomolar range on very small sample volumes (40–50 µl). Because the dialysate samples were ultraclean, purification was not required before analysis. All metabolites were determined in each of the dialysis probes. In this report, we present dialysate concentrations without considering the recovery rate of the probes.
Experimental Protocols
After the microdialysis probes were inserted, a 2-h equilibration period was observed. This allowed resting ATP concentrations to reach a stabilized state (5). Contractions induced by electrical stimulation of the L7 and S1 ventral roots were then performed. In eight cats, two bouts of rhythmic contraction were conducted at frequencies of 3 and 5 Hz (3 times motor threshold and 0.1-ms duration). Each of the two frequencies was sustained for 10 min. There was a 60-min rest period between each bout of contraction. The previous work has shown that this time period is sufficient to allow high-energy phosphate stores to replete (24, 41). Additionally, prior work has also shown that interstitial ATP falls to values that are not different from the baseline within the first 10 min of recovery after muscle contraction (36). The samples for baseline, contraction, and recovery data were collected for 10 min before, during, and after each workload.
In separate experiments (n = 6), the dorsal roots of L7 and S1 were cut and a bout of contraction at 5 Hz was performed. If interstitial ATP failed to rise under these circumstances, it would suggest that engagement of the muscle reflex was necessary to evoke the response.
In a final group of studies (n = 4), the cats were paralyzed by intravenous injection of pancuronium bromide (200 µg/kg wt). The ventral roots were then stimulated at 5 Hz. This experiment was performed to determine whether muscle contraction per se was a necessary contributor to the ATP response.
Experimental Data Analysis
Experimental data acquisition. Arterial blood pressure was measured by connecting the carotid arterial catheter to a pressure transducer (model P23ID, Statham). 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. Ties were placed around the tendons, and they were attached to a tension transducer (model F10, Grass Instruments) for measurement of developed tension. All measured variables were continuously recorded on an eight-channel chart recorder (model TA 4000, Gould, Valley View, OH) and a computer (Dell, Dimension P75t) that used PowerlLab system software (ADInstruments, Castle Hill, Australia). Computer-acquired data were used in the post hoc analyses. Control values were determined by analyzing at least 30 s of the data immediately before electrical stimulation. The peak response of each variable was determined by the peak change from the control value.
Experimental data (MAP, HR, muscle peak tension, and adenine nucleotides concentrations) were analyzed by using one-way repeated-measures ANOVA. As appropriate, Tukey's post hoc analyses were utilized. All values are expressed as means ± SE. For all analyses, differences were considered significant if P < 0.05. All statistical analyses were performed by using Sigma Stat for Windows version 2.03 (SPSS, Chicago, IL).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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Muscle tensions and cardiovascular responses. Electrical stimulation of the ventral roots at 3 and 5 Hz was performed to evoke twitch muscle contractions (n = 8). The evoked maximal tensions were 3.9 ± 0.4 and 4.3 ± 0.3 kg (P < 0.05), respectively. The 3-Hz stimulation increased MAP from 146 ± 10 to 159 ± 10 mmHg, and the 5-Hz stimulation increased MAP from 141 ± 8 to 157 ± 8 mmHg (P < 0.05 for both stimulation paradigms). The maximal HR response was from 181 ± 13 to 186 ± 7 beats/min with 3-Hz stimulation, and it was from 187 ± 7 to 189 ± 15 beats/min with 5-Hz stimulation (P > 0.05 for both paradigms). The changes in tension and MAP during 10-min stimulation are shown in Fig. 2.
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Changes in dialysate ATP concentration. Figure 3 shows that electrical stimulation of the ventral roots at 3 and 5 Hz significantly increased the dialysate ATP concentration in contracting muscle (n = 8). ATP increased from 0.317 ± 0.11 µM at rest to 0.793 ± 0.15 µM (150% increase; P < 0.05) during 3-Hz stimulation. At 5 Hz, ATP increased from 0.325 ± 0.08 to 0.985 ± 0.13 µM (200%; P < 0.05). ATP concentrations at 3- and 5-Hz frequency of stimulation are not different. Changes in ADP, AMP, and adenosine during twitch muscle contractions evoked by 3- and 5-Hz stimulations are shown in Table 1.
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To examine whether tension developed during the two paradigms were linked to the dialysate ATP concentration, a linear regression analysis was performed and a significant relationship was demonstrated (r = 0.909, P < 0.001; Fig. 4).
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Stimulation of the ventral roots did not significantly increase the dialysate ATP concentration in the triceps surae of the opposite noncontracting hindlimb (3 Hz: rest 0.347 ± 0.08; stimulation: 0.330 ± 0.08 µM; 5 Hz: rest 0.328 ± 0.08; stimulation 0.329 ± 0.09 µM).
5-Hz Stimulation After Section of the Dorsal Roots
Section of the L7 and S1 dorsal roots eliminated the pressor response to ventral roots stimulation of 5 Hz (Fig. 2). Ventral roots stimulation of 5 Hz evoked a peak tension response of 4.4 ± 0.5 kg (P < 0.05), and the dialysate ATP rose (0.311 ± 0.09 to 0.919 ± 0.13 µM, 195%; P < 0.05; Fig. 5). ATP concentrations with and without dorsal roots sectioned were not different (Table 1). The changes in ADP, AMP, and adenosine during this paradigm are shown in Table 1.
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5-Hz Stimulation After Paralysis of Muscle
After muscle paralysis, electrical stimulation of the L7 and S1 ventral roots evoked no change in muscle tension or in the cardiovascular responses (Fig. 2). Additionally, the increase in dialysate ATP evoked by the electrical stimulation was eliminated (0.394 ± 0.04 to 0.393 ± 0.04 µM, n = 4; Fig. 5). ADP, AMP, and adenosine values are shown in Table 1.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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In the present study, we have shown that contraction of skeletal muscle induced by electrical stimulation of the ventral roots caused significant increases in blood pressure (Fig. 2) and dialysate ATP concentrations (Fig. 3). The increases in ATP were 150 and 200%, respectively, for 3- and 5-Hz stimulations. Moreover, the increase in dialysate ATP was linked to muscle tension (Fig. 4). The rise in ATP was not eliminated by sectioning the dorsal roots, and no change was seen in ATP in the control limb (Figs. 3 and 5). Finally, the ATP response was eliminated by paralysis (Fig. 5). Thus muscle cell contraction is the necessary and sufficient stimulus for the rise in ATP concentrations. If the ATP response were part of the muscle reflex, we would have expected an effect of dorsal root sectioning. If interstitial ATP were released from sympathetic nerves, then we should have seen an increase in interstitial ATP in the opposite limb. Finally, the fact that tension was linked to interstitial ATP and the rise in interstitial ATP was eliminated during paralysis supports that the ATPi came from skeletal muscle cells and not from motor nerves.
ATP released from the muscle cells during contraction can act as a stimulus
for transduction of the muscle pressor reflex. The free nerve endings of
groups III and IV muscle afferents residing in the muscle interstitium respond
to chemical and/or mechanical stimulation to evoke a muscle pressor reflex.
ATP-sensitive P2X receptors have been identified from a subpopulation of
small-diameter afferent sensory neurons in dorsal root ganglia and are
expressed on their central and peripheral nerves
(7,
27,
51,
52). Activation of
ATP-sensitive P2X receptors by injection of 
,
-methylene ATP into
the blood supply of the hindlimb evokes a skeletal afferent-mediated pressor
response (16,
25). ATP also sensitizes the
muscle pressor response to muscle stretch via P2X receptors
(25). The pressor response to
static hindlimb contraction in cats is attenuated when P2X-receptor blockers
are administered (17). These
observations viewed together with the present report suggest that contracting
muscle cells release ATP into the interstitial space where the free nerve
endings of group III and IV muscle afferents reside. Elevated ATP then
stimulates as well as sensitizes the afferent nerve to mediate the exercise
pressor reflex via P2X receptor.
In skeletal muscle, adenosine and adenine nucleotides (ATP, ADP, and AMP) have been reported to be present in the interstitial space (8, 10, 28, 45). Previous studies have shown that interstitial adenosine concentration was increased in the extracellular medium of contracting primary rat skeletal muscle cells (18, 28). It has been suggested that the breakdown of ATP to adenosine is the main source of extracellular adenosine because adenosine concentrations fall if ectonucleotidases are inhibited (38, 46). This suggests that adenosine levels may be reflective of interstitial ATP. Interstitial adenosine and adenine nucleotide have also been shown to rise with knee extension in humans and during obturator nerve stimulation-induced muscle contraction in the dog (19, 36). The source of interstitial nucleotidase is unclear.
In the present study, we employed electrical stimulation of the L7 and S1 ventral roots to induce muscle contraction in decerebrate cats, and we showed that contracting muscle cells are the major source of elevated interstitial ATP. We believe that the failure of ATP to rise in the "control" limb was not due to enhanced nucleotidase activity (42) that can be seen with sympathoexcitation. If this were the case, we would have expected a rise in the concentrations of one or more of the ATP breakdown products.
Elevated adenosine and ATP have been shown to be released from nerves (10, 45). In these reports, adenosine and ATP samples were collected from the bath in which the isolated skeletal muscle preparations were electrically stimulated (10, 45). The concentration of adenosine and ATP were much lower than those reported in this paper. Thus it is possible that in this report a relatively small amount of ATP was released from sympathetic and/or motor nerves.
The membrane permeability to ATP is very low, in agreement with the
molecular size of ATP, and its extracellular concentration remains low because
of ectonucleotidase activity
(15). However, arterial
occlusion and exercise may increase extracellular ATP by 50-fold from
basal levels in human venous plasma
(14). The potential mechanisms
by which ATP can be released from skeletal muscle cells are not entirely
clear. ATP can be released by exocytosis from platelets, epithelium and nerves
like other neurotransmitters
(12,
15). The cystic fibrosis
transmembrane conductance regulator (CFTR) has recently been suggested to act
as an ATP channel and enable intracellular ATP to cross the cell membrane
(1–3,
53). Other studies have shown
that mechanical stimulation of the epithelial cell surface, rather than CFTR
activation, is sufficient to release ATP
(54). It is known that
mechanical stimulation of epithelial and neuronal cells is a sufficient
stimulus for ATP release (37,
53). Evidence also suggests
that gadolinium, an inhibitor of stretch-activated channels, suppresses ATP
efflux from eukaryotic cells
(6). Moreover, the rise is seen
with increased extracellular ATP rat hepatocytes and epithelial cells volume
is inhibited by gadolinium
(39). The precise mechanism by
which ATP exits muscle cells cannot be determined from data in the present
report, and further studies are needed to evaluate this issue.
Conclusions
The results of this report demonstrate that contracting muscle elevates interstitial ATP concentrations. Muscle afferent nerve endings reside in the muscle interstitium. When these findings are viewed in conjunction with prior work showing that arterial injections of ATP evokes and sensitizes the muscle pressor response, they suggest that ATP is released from contracting muscle cells and stimulate P2X receptors on muscle afferent nerves as an endogenous muscle afferent stimulant. This in turn leads to stimulation and sensitization of the exercise pressor reflex.
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DISCLOSURES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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FOOTNOTES |
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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.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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,-Methylene ATP elicits a reflex pressor
response arising from muscle in decerebrate cats. J Appl
Physiol 93:
834-841, 2002.,-methylene adenosine 5'-triphosphate. Br J
Pharmacol 112:
282-288, 1994.[Web of Science][Medline]
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