| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Division of Cardiology, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, Hershey 17033; and 2 Lebanon Veterans Affairs Medical Center, Lebanon, Pennsylvania 17042
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
We examined
whether ATP stimulation of P2X purinoceptors would raise blood pressure
in decerebrate cats. Femoral arterial injection of the P2X receptor
agonist 
,
-methylene ATP into the blood supply of the triceps
surae muscle induced a dose-dependent increase in arterial blood
pressure. The maximal increase in mean arterial pressure (MAP) evoked
by 0.1, 0.2, and 0.5 mM ,-methylene ATP (0.5 ml/min injection
rate) was 6.2 ± 2.5, 22.5 ± 4.4, and 35.2 ± 3.9 mmHg,
respectively. The P2X receptor antagonist pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (2 mM ia) attenuated the
increase in MAP elicited by intra-arterial ,-methylene ATP (0.5 mM), whereas the P2Y receptor antagonist reactive blue 2 (2 mM ia) did
not affect the MAP response to ,-methylene ATP. In a second group
of experiments, we tested the hypothesis that ATP acting through P2X
receptors would sensitize muscle afferents and, thereby, augment the
blood pressure response to muscle stretch. Two kilograms of muscle
stretch evoked a 26.5 ± 4.3 mmHg increase in MAP. This MAP
response was enhanced when 2 mM ATP or 0.1 mM ,-methylene ATP
(0.5 ml/min) was arterially infused 10 min before muscle stretch.
Furthermore, this effect of ATP on the pressor response to stretch was
attenuated by 2 mM pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (P < 0.05) but not by the P1 purinoceptor
antagonist 8-(p-sulfophenyl)-theophylline (2 mM). These data
indicate that activation of ATP-sensitive P2X receptors evokes a
skeletal muscle afferent-mediated pressor response and that ATP at
relatively low doses enhances the muscle pressor response to stretch
via engagement of P2X receptors.
,-methylene ATP; muscle stretch; skeletal muscle; exercise
pressor reflex; arterial blood pressure
| |
INTRODUCTION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
STATIC EXERCISE REFLEXLY INCREASES renal and cardiac sympathetic nerve activity, arterial blood pressure, heart rate (HR), and myocardial contractility (11, 12, 24, 28, 31, 32, 34, 36, 37). Neural signals from exercising skeletal muscle are generated by activating metabolically and mechanically sensitive nerve endings (receptors) located in the skeletal muscle (24, 25, 36). These neural signals are subsequently carried to the central nervous system by group III and IV afferent fibers (11, 34). Together, activation of these receptors by mechanical and metabolic stimulation of skeletal muscle, along with the reflex cardiovascular responses, is termed the "exercise pressor reflex" (34, 36, 37). In this report, we focus on the potential role that ATP might play in stimulating muscle afferents that contribute to the exercise pressor reflex.
A number of issues related to ATP pharmacology are germane to this
discussion. First, it is known that mechanical stimulation of
epithelial and neuronal cells is a sufficient stimulus for ATP release
(18, 51, 54, 55). Additionally, it has been demonstrated
that touch-induced sensory nerve discharge frequency increases when ATP
is injected subcutaneously in frogs. This effect was blocked by
injection of a P2 purinoceptor antagonist, suramin, or an ATP-degrading
enzyme, apyrase, within the receptive field (38). These
data strongly suggest that ATP may play a role in sensitizing
mechanically sensitive muscle afferents. If such a process were present
in skeletal muscle, then muscle stretch alone could conceivably
increase interstitial ATP concentrations. Second, it is known that ATP
is coreleased from sympathetic nerve terminals with norepinephrine
(50, 53). Therefore, the mechanical stimulation of
skeletal muscle and the increased sympathetic nerve activity could
cause the release of ATP into muscle interstitium, where the free nerve
endings of group III and IV muscle afferents reside. Third, cellular
destruction, as might be seen during extreme exercise, will lead to a
large increase in interstitial ATP. This may be relevant to the study
of muscle reflexes, because arterial or intra-articular injection of
the selective P2X receptor agonist ,-methylene ATP causes a rapid
short-lasting excitation of a subpopulation of C and A
nociceptive
afferent nerves innervating normal knee joints (13). This
makes it logical to postulate that ATP may serve as a chemoreceptor
stimulant in skeletal muscle. Fourth, ATP stimulates P2X and P2Y
receptors, which are found on sensory neurons (7, 8, 10, 21, 22,
26, 38). Such afferent stimulation can evoke nerve impulse
generation, as well as the release of sensory neurotransmitters at
central and peripheral ends of afferent fibers (7, 8, 26).
On the basis of these data, we postulated that the arterial administration of ATP into the blood supply of the triceps surae muscle would raise blood pressure and that ATP would also sensitize thin-fiber muscle afferents. This, in turn, would lead to a greater pressor response for a given degree of deformation of the muscle afferent receptive field. Our data support these hypotheses.
| |
METHODS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
General Methods
Animal surgical preparation. Fourteen adult cats (4.0-5.0 kg) of either gender were anesthetized initially with ketamine (25 mg/kg im) and then by inhalation of isoflurane-oxygen. An endotracheal tube was inserted and attached to a ventilator (model 683, Harvard, South Natick, MA). Polyethylene (PE-90) catheters were inserted into an external jugular vein and a common carotid artery for drug administration and measurement of arterial blood pressure, respectively.
The femoral arteries and arterial collaterals of both hindlimbs were carefully isolated. The saphenous artery or descending genicular artery, arterial branches of the femoral artery, was cannulated with PE-10 catheters. This allowed for arterial injections of drugs while the arterial blood supply to the hindlimb muscles was maintained. The triceps surae muscle group was isolated, and the Achilles tendons were cut. A tie was placed around the tendon and attached to a tension transducer (model FT10, Grass Instruments). The legs were stabilized with ties around the ankles and at the top of the knees. In these experiments, the skin covering the triceps surae muscle and femoral region was surgically separated from the muscles below. This procedure should eliminate the inputs from skin afferents in the hindlimb. In some of the studies, the sciatic nerves on both legs were carefully isolated so that they could be sectioned at the end of study. 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 mmHg, and HCO
Decerebration. Decerebration was performed because it allowed an examination of autonomic reflex responses without the need to consider the confounding effects of anesthesia (23). Before the decerebration procedure, dexamethasone (4 mg iv) was administered to help prevent procedure-induced brain stem edema. The cat's head was fixed in 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 mammillary 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 (30).
Measurement of arterial blood pressure and peak tension. 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 determined from the arterial pressure pulse. The Achilles tendon was connected to a force transducer (model FT10, Grass Instruments) for measurement of developed tension during muscle stretch. The pelvis was stabilized in a spinal unit (Kopf Instruments), and the knee joints were secured by attaching the patellar tendon to a steel post. All measured variables were continuously recorded on an eight-channel chart recorder. The digital signal was relayed to a Dell (Dimension P75t) computer system that employed PowerLab (AD Instruments, Castle Hill, Australia) systems software for storage and analysis of data.
Experimental Protocols
Arterial injection of ,-methylene ATP to activate
cardiovascular responses.
The purpose of this protocol was to determine whether ,-methylene
ATP activated the muscle pressor reflex via P2X purinoceptors. The
animals were surgically prepared as described in General
Methods. At 40-60 min after decerebration, 0.5 ml of 0.1, 0.2, and 0.5 mM ,-methylene ATP (dissolved in saline; Sigma) was
injected into the blood supplies of the triceps surae muscle. The
duration of injections was 1 min. At least 20 min were allowed between the injections.
Effect of P2X and P2Y receptor blockade on intra-arterial
,-methylene ATP.
To test the role of P2X and P2Y receptors, 0.5 ml of 2 mM pyridoxal
phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS) and 2 mM reactive
blue 2 (RB-2; Sigma), respectively (both dissolved in saline), were
injected. Injections were performed 5 min before injections of 0.5 mM
,-methylene ATP. In addition, 0.5 ml of ,-methylene ATP was
injected by femoral artery after occlusion of the femoral vein and
section of the sciatic nerve to confirm that the pressor response was
due to stimulation of afferents within the hindlimb.
Effect of ATP on the cardiovascular response evoked by muscle
stretch.
The concentrations of ,-methylene ATP and ATP were chosen on the
basis of previous studies (13, 52). It has been reported that intra-arterial and intra-articular injection of 60 nmol of ,-methylene ATP or 2,000 nmol of ATP (both in 0.1 ml volume) increased excitation of C and A afferent fibers
innervating knee joints (13). Additionally, intravesicular
administration of 100 µM ,-methylene ATP and 1 mM ATP
(in 100 µl volume) activated bladder afferents and increased the
discharge response to bladder distension (52).
,-methylene ATP (dissolved in saline; Sigma),
respectively. In separate experiments, we determined whether the
ATP-sensitizing effect was mediated by P1 or P2X receptors. P1
receptors mediate the effects of adenosine, a metabolic breakdown
product of ATP. Accordingly, 8-(p-sulfophenyl)-theophylline (8-PT, a P1 purinoceptor antagonist) and PPADS were administered 5 min
before arterial injection of 2 mM ATP. The muscle was stretched 10 min
later. At the end of the experiments, the sciatic nerve was cut and
muscle stretch was repeated.
Experimental Data Analysis
All measured variables were continuously recorded on an eight-channel chart recorder (model TA 4000, Gould, Valley View, OH). These variables were also sampled by a personal computer-based Pentium computer that was equipped with analog-to-digital conversion and PowerLab data acquisition (AD Instruments). Computer-acquired data were used in post hoc analyses. Control values were determined by analyzing
30 s of the data immediately before femoral arterial injection or
muscle stretch. The peak response of each variable was determined by
the peak change from the control value.
Measured variables were analyzed by using a one-way repeated-measure analysis of variance. As appropriate, a Tukey post hoc test was utilized. Values are means ± SE. For all analyses, differences were considered significant at P < 0.05. All statistical analyses were performed by using Sigma Stat for Windows version 2.03 (SPSS, Chicago, IL).
| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
Cardiovascular Responses to Arterial Injections of
,-Methylene ATP
,-methylene ATP at 0.1, 0.2, and 0.5 mM (in 0.5 ml of saline)
evoked the pressor response (Fig. 1). The
peak responses to the three dose levels were 6.2 ± 2.5, 22.5 ± 4.4, and 35.2 ± 3.9 mmHg, respectively. The basal MAP before
injection of 0.1, 0.2, and 0.5 mM ,-methylene ATP was 105.7 ± 8.6, 94.2 ± 7.7, and 105.7 ± 4.8 mmHg (P > 0.05), respectively. After occlusion of the femoral vein, 0.5 mM
,-methylene ATP infusions still increased MAP by 34.9 ± 8.78 mmHg (P < 0.05). After section of the sciatic
nerve, arterial injection of 0.5 mM ,-methylene ATP increased MAP
by 8.4 ± 2.7 mmHg (Fig. 1). ,-Methylene ATP at 0.5 mM also
increased the HR response significantly. The HR response to
,-methylene ATP is shown in Table
1.
|
|
Effects P2X and P2Y Receptor Blockade on the Cardiovascular
Response Evoked by Arterial Injections of 0.5 mM ,-Methylene ATP
,-methylene ATP (Fig. 2).
However, arterial administration of 2 mM RB-2, a P2Y receptor
antagonist, did not affect the MAP response elicited by 0.5 mM
,-methylene ATP (Fig. 2). The peak increase in MAP elicited by
,-methylene ATP was 35.6 ± 4.1 mmHg (basal MAP = 118.7 ± 10.2 mmHg). The peak increases in MAP elicited by
,-methylene ATP after administration of PPADS and RB-2 were 24.9 ± 3.8 and 33.7 ± 10.1 mmHg, respectively. Thus P2X
blockade with 2 mM PPADS reduced the pressor response to the ATP analog by ~30%, whereas P2Y receptor blockade with 2 mM RB-2 had no effect on this response.
|
Effects of Arterial Infusions of ATP and ,-Methylene ATP on
the Cardiovascular Response to Muscle Stretch
,-Methylene ATP at 0.1 mM also significantly increased the pressor response to muscle stretch,
with the maximal pressor response being 44.4 ± 4.2 mmHg
(baseline = 122.6 ± 11.8 mmHg). ,-Methylene ATP at 0.1 mM caused a more sustained effect than did 2 mM ATP (Fig.
3A). In a fourth trial,
stretch after saline administration led to a 27.7 ± 5.9 mmHg
increase in MAP from a baseline of 116.7 ± 11.4 mmHg. The effect
of ATP and ,-methylene ATP on the HR response to muscle stretch
is shown in Table 2.
|
|
The sensitizing effect of ATP on the pressor response was reduced by
78% by the preadministration of 2 mM PPADS (maximal MAP response = 29.5 ± 7.8 mmHg; Figs. 4 and
5). Preadministration of 8-PT did not
attenuate the ATP-sensitizing effect (maximal MAP response = 45.7 ± 7.3 mmHg; Fig. 5).
|
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
In the present studies, we have shown that arterial infusions of
,-methylene ATP (an ATP analog) evoked a dose-dependent pressor
response (Fig. 1). This effect of ,-methylene ATP was decreased
from 35.2 ± 3.9 to 8.4 ± 2.7 mmHg (76%) after section of
the sciatic nerve (Fig. 1). Thus the effect of ,-methylene ATP
was due primarily to stimulation of afferents within the hindlimb. The
8.4-mmHg response after sciatic nerve section was not due to skin
afferents, because they were sectioned. Moreover, the pressor response
was not due to a "systemic" effect of the infused ,-methylene
ATP, because local venous occlusion that preceded the arterial infusion
did not attenuate the response. Therefore, the most likely cause of the
8-mmHg response was that the arterial injections stimulated muscle
afferents subserved by the femoral or obturator nerves.
The increase in blood pressure due to an arterial infusion of
,-methylene ATP was attenuated by 30% by the P2X receptor antagonist PPADS. However, the same concentration of the P2Y receptor antagonist RB-2 had no effect on the reflex (Fig. 2). On the basis of
previous reports, we believe that the dose of RB-2 was sufficient to
block P2Y receptors (29, 33, 49). We believe that these findings suggest that P2X (but not P2Y) receptor activation contributed to the pressor response seen with ATP administration. Recent
preliminary reports also support the idea that ATP mediates the muscle
pressor reflex via P2X receptors (19, 20).
We have also shown that ATP and ,-methylene ATP, a P2X-specific
analog, sensitized the pressor response evoked by mechanically sensitive skeletal muscle stretch (Figs. 3 and 5). Furthermore, PPADS
reduced the ATP-sensitizing effect on the reflex by 78%, whereas the
P1 receptor antagonist 8-PT produced no effect on the reflex (Figs. 4
and 5). When these results are viewed together, we believe that they
suggest that ATP is a direct chemical stimulant as well as a reversible
mechanoreceptor sensitizer.
It is intriguing to note that the same dose of PPADS that reduced the sensitizing effect by 78% reduced the chemical effect by only 30%. These findings may suggest that the mechanoreceptor-sensitizing effect of ATP is more specific for the P2X receptor than is its direct metaboreceptor-stimulating effect.
In the present study, we considered the possibility that ATP infused into the arterial circulation of the triceps surae muscle could have been broken down to adenosine (27). Adenosine is a P1 receptor agonist. Accordingly, the P1 receptor antagonist 8-PT was injected by femoral artery before ATP injections. The P1 receptor agonist did not alter the pressor response to the infused ATP. Thus adenosine played no role in mediating the observed ATP effect.
General Issues Regarding ATP
Electrical stimulation of the L7/S1 ventral roots in cats evokes pressor and HR responses, and the magnitude of these responses is proportional to the generated muscle tension (11). It has also been reported that significant reflex cardiovascular responses occur when the triceps surae muscle is stretched mechanically to produce a pattern and amount of tension similar to that seen during static contraction (45). Studies by McCloskey and Mitchell (34) provided the first evidence that group III and IV afferents represent the afferent limb of the reflex pressor response to muscle contraction. The free nerve endings of 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 (3).Adreani et al. (1) used a "walking cat preparation" to investigate the discharge properties of group III and IV afferents, the receptor fields of which were in the triceps surae muscle. In these extremely demanding studies, normal gait was induced by electrical stimulation of the mesencephalic locomotor region. Group III and IV fibers discharged synchronously with muscle contraction (1). In a separate study with the same model, Adreani and Kaufman (2) showed that ischemia increased the discharge of equal percentages of group III and IV afferent fibers.
A number of substances, including diprotonated phosphate, prostaglandin, bradykinin, and lactic acid, have been suggested as potential chemical stimulants and mechanoreceptor sensitizers of muscle afferents (40-44, 46, 47). It must be emphasized that the precise role of each of these substances in evoking the muscle reflex remains to be determined. It is with this background and for the reasons previously cited that we performed studies to examine the role of ATP in stimulating muscle afferents.
In addition to intracellular functions (5, 6), purine nucleotides play a role as extracellular neurotransmitters or modulators by engaging P1 and P2 purinoceptors. P1 receptors are important in mediating the modulatory effects of adenosine. P2 receptors mediate the actions of ATP and related substances. Two main types of P2 purinoceptors have been recognized: P2X and P2Y (5, 16). P2X receptors are ligand-gated ion channels, and P2Y receptors are linked to G proteins. Stimulation of P2X receptors appears to be the primary way in which ATP evokes its effect on sensory nerves (4, 35, 48, 52). For example, in the urinary bladder, ATP is released by smooth muscle cells during stretch. This released ATP stimulates P2X receptors on afferent nerves, evoking pain and bladder distension (9, 14).
ATP can be released from exercising muscle cells (15, 39). This effect need not involve muscle cell destruction, because it has been demonstrated that mechanical stimulation from excitable and nonexcitable cells, including epithelial, neuronal, and muscle cells, can cause the release of ATP (18, 38, 51, 54). Thus mechanical stimulation of muscle, as well as muscle cell destruction, can lead to the release of ATP by muscle. It has also been reported that ATP and norepinephrine are coreleased from sympathetically innervated smooth muscle (50, 53). Thus sympathoexcitation during exercise may release ATP, which in turn may sensitize sensory afferents in muscle. Despite the ability of muscle cells and sympathetic nerves to release ATP, it must be emphasized that muscle cells are not permeable to the relatively large ATP molecule and that ATP in the extracellular milieu is normally kept extremely low by extracellular ectonucleotidases (17).
Study Limitations
A few issues need to be addressed before it can be definitively concluded that ATP is an important stimulant of the muscle reflex during physiological circumstances. First, it must be determined that muscle contraction and/or muscle stretch increases interstitial ATP concentrations to a level necessary to stimulate and/or sensitize muscle afferents. Second, it must be demonstrated that the effects seen with injections of ATP are not due to the release of other substances from muscle or nerve into the interstitium. Third, the effects of P2X receptor blockade on the pressor response to muscle contraction must be determined. A recent preliminary report (20) has shown that the P2X receptor antagonist PPADS, injected into the femoral artery, attenuates the pressor response seen with static muscle contraction.Conclusion
The findings of this report suggest that ATP stimulates P2X receptors located on the free nerve endings of muscle afferents in a manner similar to that whereby ATP and its analogs excite sensory afferent nerves in other organs. Arterial injection of the P2X receptor agonist,-methylene ATP in the blood supply of the triceps surae
muscle evoked a pressor response that was a reflex localized to the cat
hindlimb. The reflex response to arterial infusions of ATP was reduced
by 30% by P2X receptor blockade. Furthermore, the findings of this
report suggest that ,-methylene ATP and ATP enhance the muscle
pressor response evoked by mechanically sensitive muscle stretch. The
P2X receptor antagonist PPADS reduces the effect of ATP by 78%. This
activation of ATP-sensitive P2X purinoceptors in skeletal muscle may
play a role in mediating the autonomic adjustments to exercise.
| |
ACKNOWLEDGEMENTS |
|---|
The authors are grateful to V. Kehoe, K. Rice, and G. Hartman for excellent technical assistance and J. Stoner for outstanding secretarial skills.
| |
FOOTNOTES |
|---|
This study was supported by National Heart, Lung, and Blood Institute Grants R01 HL-60800 (L. I. Sinoway) and R01 HL-70222 (L. I. Sinoway) and American Heart Association Grant-in-Aid 0265375U (J. Li).
Address for reprint requests and other correspondence: J. Li, Div. of Cardiology, MC H047, The Pennsylvania State University College of Medicine, The Milton S. Hershey Medical Center, PO Box 850, 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.
10.1152/ajpheart.00395.2002
Received 13 May 2002; accepted in final form 2 August 2002.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Adreani, CM,
Hill JM,
and
Kaufman MP.
Responses of group III and IV muscle afferents to dynamic exercise.
J Appl Physiol
82:
1811-1817,
1997
2.
Adreani, CM,
and
Kaufman MP.
Effect of arterial occlusion on responses of group III and IV afferents to dynamic exercise.
J Appl Physiol
84:
1827-1833,
1998
3.
Andres, KH,
von During M,
and
Schmidt RF.
Sensory innervation of the Achilles tendon by group III and IV afferent fibers.
Anat Embryol (Berl)
172:
145-156,
1985[Medline].
4.
Bleehen, T.
The effects of adenine nucleotides on cutaneous afferent nerve activity.
Br J Pharmacol
62:
573-577,
1978[ISI][Medline].
5.
Burnstock, G.
Purinergic nerves.
Pharmacol Rev
24:
509-581,
1972
6.
Burnstock, G.
Purinergic mechanisms.
Ann NY Acad Sci
603:
1-17,
1990[ISI][Medline].
7.
Burnstock, G.
A unifying purinergic hypothesis for the initiation of pain.
Lancet
347:
1604-1605,
1996[ISI][Medline].
8.
Burnstock, G,
and
Wood JN.
Purinergic receptors: their role in nociception and primary afferent neurotransmission.
Curr Opin Neurobiol
6:
526-532,
1996[ISI][Medline].
9.
Chizh, BA,
and
Illes P.
P2X receptors and nociception.
Pharmacol Rev
53:
553-568,
2001
10.
Cook, SP,
Vulchanova L,
Hargreaves KM,
Elde R,
and
McCleskey EW.
Distinct ATP receptors on pain-sensing and stretch-sensing neurons.
Nature
387:
505-508,
1997[Medline].
11.
Coote, JH,
Hilton SM,
and
Pérez-González JF.
The reflex nature of the pressor response to muscular exercise.
J Physiol
215:
789-804,
1971
12.
Diepstra, G,
Gonyea W,
and
Mitchell JH.
Cardiovascular response to static exercise during selective autonomic blockade in the conscious cat.
Circ Res
47:
530-535,
1980
13.
Dowd, E,
McQueen DS,
Chessell IP,
and
Humphrey PP.
P2X receptor-mediated excitation of nociceptive afferents in the normal and arthritic rat knee joint.
Br J Pharmacol
125:
341-346,
1998[ISI][Medline].
14.
Ferguson, DR,
Kennedy I,
and
Burton TJ.
ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes
a possible sensory mechanism?
J Physiol
505:
503-511,
1997
15.
Forrester, T.
An estimate of adenosine triphosphate release into the venous effluent from exercising human forearm muscle.
J Physiol
224:
611-628,
1972
16.
Fredholm, BB,
Abbracchio MP,
Burnstock G,
Daly JW,
Harden TK,
Jacobson KA,
Leff P,
and
Williams M.
Nomenclature and classification of purinoceptors.
Pharmacol Rev
46:
143-156,
1994[ISI][Medline].
17.
Gordon, JL.
Extracellular ATP: effects, sources and fate.
Biochem J
233:
309-319,
1986[ISI][Medline].
18.
Grygorczyk, R,
and
Hanrahan JW.
CFTR-independent ATP release from epithelial cells triggered by mechanical stimuli.
Am J Physiol Cell Physiol
272:
C1058-C1066,
1997
19.
Hanna, RL,
Hayes SG,
and
Kaufman MP.
,-Methylene ATP elicits the muscle chemoreflex in decerebrate cats.
Soc Neurosci Abstr
572:
14,
2001.
20.
Hanna, RL,
Hayes SG,
and
Kaufman MP.
Role played by P2X receptors in the exercise reflex (Abstract).
FASEB J
16:
A1141,
2002.
21.
Harden, TK,
Barnard EA,
Boeynaems HM,
Burnstock G,
Dubyak G,
Hourani SMO,
and
Insel PA.
P2Y receptors.
In: The IUPHAR Compendium of Receptor Characterization and Classification, edited by Girdlestone D.. Cambridge, UK: Burlington, 1998, p. 209-217.
22.
Humphrey, PPA,
Khakh BS,
Kennedy C,
King BF,
and
Burnstock G.
P2X receptors.
In: The IUPHAR Compendium of Receptor Characterization and Classification, edited by Girdlestone D.. Cambridge, UK: Burlington, 1998, p. 195-208.
23.
Iwamoto, GA,
and
Botterman BR.
Peripheral factors influencing expression of pressor reflex evoked by muscular contraction.
J Appl Physiol
58:
1676-1682,
1985
24.
Kaufman, MP,
and
Forster HV.
Reflexes controlling circulatory, ventilatory, and airway responses to exercise.
In: Handbook of Physiology. Exercise: Regulation and Integration of Multiple Systems. Bethesda, MD: Am. Physiol. Soc, 1996, sect. 12, chapt. 10, p. 381-447.
25.
Kaufman, MP,
Waldrop TG,
Rybicki KJ,
Ordway GA,
and
Mitchell JH.
Effects of static and rhythmic twitch contractions on the discharge of group III and IV muscle afferents.
Cardiovasc Res
18:
663-668,
1984[ISI][Medline].
26.
Kennedy, C,
and
Leff P.
Painful connection for ATP.
Nature
377:
385-386,
1995[Medline].
27.
Kuzmin, AI,
Lakomkin VL,
Kapelko VI,
and
Vassort G.
Interstitial ATP level and degradation in control and postmyocardial infarcted rats.
Am J Physiol Cell Physiol
275:
C766-C771,
1998
28.
Lind, AR.
Cardiovascular adjustments to isometric contractions: static effort.
In: Handbook of Physiology. The Cardiovascular System. Peripheral Circulation and Organ Blood Flow. Bethesda, MD: Am. Physiol. Soc, 1983, sect. 2, vol. III, pt. 2, chapt. 26, p. 947-966.
29.
Liu, M,
King BF,
Dunn PM,
Rong W,
Townsend-Nicholson A,
and
Burnstock G.
Coexpression of P2X3 and P2X2 receptor subunits in varying amounts generates heterogeneous populations of P2X receptors that evoke a spectrum of agonist responses comparable to that seen in sensory neurons.
J Pharmacol Exp Ther
296:
1043-1050,
2001
30.
MacLean, DA,
Vickery LM,
and
Sinoway LI.
Elevated interstitial adenosine concentrations do not activate the muscle reflex.
Am J Physiol Heart Circ Physiol
280:
H546-H553,
2001
31.
Mark, AL,
Victor RG,
Nerhed C,
and
Wallin BG.
Microneurographic studies of the mechanisms of sympathetic nerve responses to static exercise in humans.
Circ Res
57:
461-469,
1985
32.
Matsukawa, K,
Wall PT,
Wilson LB,
and
Mitchell JH.
Reflex responses of renal nerve activity during isometric muscle contraction in cats.
Am J Physiol Heart Circ Physiol
259:
H1380-H1388,
1990
33.
Matsuo, K,
Katsuragi T,
Fujiki S,
Sato C,
and
Furukawa T.
ATP release and contraction mediated by different P2-receptor subtypes in guinea-pig ileal smooth muscle.
Br J Pharmacol
121:
1744-1748,
1997[ISI][Medline].
34.
McCloskey, DI,
and
Mitchell JH.
Reflex cardiovascular and respiratory responses originating in exercising muscle.
J Physiol
224:
173-186,
1972
35.
McQueen, DS,
Bond SM,
Moores C,
Chessell I,
Humphrey PP,
and
Dowd E.
Activation of P2X receptors for adenosine triphosphate evokes cardiorespiratory reflexes in anaesthetized rats.
J Physiol
507:
843-855,
1998
36.
Mitchell, JH,
Kaufman MP,
and
Iwamoto GA.
The exercise pressor reflex: its cardiovascular effects, afferent mechanism, and central pathways.
Annu Rev Physiol
45:
229-242,
1983[ISI][Medline].
37.
Mitchell, JH,
Reardon WC,
and
McCloskey DI.
Reflex effects on circulation and respiration from contracting skeletal muscle.
Am J Physiol Heart Circ Physiol
233:
H374-H378,
1977
38.
Nakamura, F,
and
Strittmatter SM.
P2Y1 purinergic receptors in sensory neurons: contribution to touch-induced impulse generation.
Proc Natl Acad Sci USA
93:
10465-10470,
1996
39.
Parkinson, PI.
The effect of graduated exercise on the concentration of adenine nucleotides in plasma.
J Physiol
234:
72P-74P,
1973[Medline].
40.
Rotto, DM,
Hill JM,
Schultz HD,
and
Kaufman MP.
Cyclooxygenase blockade attenuates responses of group IV muscle afferents to static contraction.
Am J Physiol Heart Circ Physiol
259:
H745-H750,
1990
41.
Rotto, DM,
and
Kaufman MP.
Effect of metabolic products of muscular contraction on discharge of group III and IV afferents.
J Appl Physiol
64:
2306-2313,
1988
42.
Rotto, DM,
Schultz HD,
Longhurst JC,
and
Kaufman MP.
Sensitization of group III muscle afferents to static contraction by arachidonic acid.
J Appl Physiol
68:
861-867,
1990
43.
Sinoway, LI,
Hill JM,
Pickar JG,
and
Kaufman MP.
Effects of contraction and lactic acid on the discharge of group III muscle afferents in cats.
J Neurophysiol
69:
1053-1059,
1993
44.
Sinoway, LI,
Smith MB,
Enders B,
Leuenberger U,
Dzwonczyk T,
Gray K,
Whisler S,
and
Moore RL.
Role of diprotonated phosphate in evoking muscle reflex responses in cats and humans.
Am J Physiol Heart Circ Physiol
267:
H770-H778,
1994
45.
Stebbins, CL,
Brown B,
Levin D,
and
Longhurst JC.
Reflex effect of skeletal muscle mechanoreceptor stimulation on the cardiovascular system.
J Appl Physiol
65:
1539-1547,
1988
46.
Stebbins, CL,
Carretero OA,
Mindroiu T,
and
Longhurst JC.
Bradykinin release from contracting skeletal muscle of the cat.
J Appl Physiol
69:
1225-1230,
1990
47.
Stebbins, CL,
Maruoka Y,
and
Longhurst JC.
Prostaglandins contribute to cardiovascular reflexes evoked by static muscular contraction.
Circ Res
59:
645-654,
1986
48.
Trezise, DJ,
Kennedy I,
and
Humphrey PP.
The use of antagonists to characterize the receptors mediating depolarization of the rat isolated vagus nerve by ,-methylene adenosine 5'-triphosphate.
Br J Pharmacol
112:
282-288,
1994[ISI][Medline].
49.
Tuluc, F,
Bültmann R,
Glänzel M,
Frahm AW,
and
Starke K.
P2-receptor antagonists. IV. Blockade of P2-receptor subtypes and ecto-nucleotidases by compounds related to reactive blue 2.
Naunyn Schmiedebergs Arch Pharmacol
357:
111-120,
1998[ISI][Medline].
50.
Vizi, ES,
and
Burnstock G.
Origin of ATP release in the rat vas deferens: concomitant measurement of [3H]noradrenaline and [14C]ATP.
Eur J Pharmacol
158:
69-77,
1988[ISI][Medline].
51.
Vizi, ES,
Sperlagh B,
and
Baranyi M.
Evidence that ATP released from the postsynaptic site by noradrenaline is involved in mechanical responses of guinea-pig vas deferens: cascade transmission.
Neuroscience
50:
455-465,
1992[ISI][Medline].
52.
Vlaskovska, M,
Kasakov L,
Rong W,
Bodin P,
Bardini M,
Cockayne DA,
Ford AP,
and
Burnstock G.
P2X3 knock-out mice reveal a major sensory role for urothelially released ATP.
J Neurosci
21:
5670-5677,
2001
53.
Von Kügelgen, I,
and
Starke K.
Noradrenaline-ATP co-transmission in the sympathetic nervous system.
Trends Pharmacol Sci
12:
319-324,
1991[Medline].
54.
Wang, Y,
Roman R,
Lidofsky SD,
and
Fitz JG.
Autocrine signaling through ATP release represents a novel mechanism for cell volume regulation.
Proc Natl Acad Sci USA
93:
12020-12025,
1996
55.
Watt, WC,
Lazarowski ER,
and
Boucher RC.
Cystic fibrosis transmembrane regulator-independent release of ATP. Its implications for the regulation of P2Y2 receptors in airway epithelia.
J Biol Chem
273:
14053-14058,
1998
This article has been cited by other articles:
|
|
 |
|
  R. C. Drew, D. B. McIntyre, C. Ring, and M. J. White Local metabolite accumulation augments passive muscle stretch-induced modulation of carotid-cardiac but not carotid-vasomotor baroreflex sensitivity in man Exp Physiol, September 1, 2008; 93(9): 1044 - 1057. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Xing, L. Sinoway, and J. Li Differential responses of sensory neurones innervating glycolytic and oxidative muscle to protons and capsaicin J. Physiol., July 1, 2008; 586(13): 3245 - 3252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Cui, R. Moradkhan, V. Mascarenhas, A. Momen, and L. I. Sinoway Cyclooxygenase inhibition attenuates sympathetic responses to muscle stretch in humans Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2693 - H2700. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Gao, S. Koba, L. Sinoway, and J. Li 20-HETE increases renal sympathetic nerve activity via activation of chemically and mechanically sensitive muscle afferents J. Physiol., May 15, 2008; 586(10): 2581 - 2591. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Momen, J. Cui, P. McQuillan, and L. I. Sinoway Local prostaglandin blockade attenuates muscle mechanoreflex-mediated renal vasoconstriction during muscle stretch in humans Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2184 - H2190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. C. Drew, M. P. D. Bell, and M. J. White Modulation of spontaneous baroreflex control of heart rate and indexes of vagal tone by passive calf muscle stretch during graded metaboreflex activation in humans J Appl Physiol, March 1, 2008; 104(3): 716 - 723. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Taylor and S. C. Gandevia A comparison of central aspects of fatigue in submaximal and maximal voluntary contractions J Appl Physiol, February 1, 2008; 104(2): 542 - 550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Hayes, J. L. McCord, and M. P. Kaufman Role played by P2X and P2Y receptors in evoking the muscle chemoreflex J Appl Physiol, February 1, 2008; 104(2): 538 - 541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Cui, V. Mascarenhas, R. Moradkhan, C. Blaha, and L. I. Sinoway Effects of muscle metabolites on responses of muscle sympathetic nerve activity to mechanoreceptor(s) stimulation in healthy humans Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2008; 294(2): R458 - R466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Kindig, S. G. Hayes, and M. P. Kaufman Blockade of purinergic 2 receptors attenuates the mechanoreceptor component of the exercise pressor reflex Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H2995 - H3000. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Koba, J. Xing, L. I. Sinoway, and J. Li Differential sympathetic outflow elicited by active muscle in rats Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2335 - H2343. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Nakamoto and K. Matsukawa Muscle mechanosensitive receptors close to the myotendinous junction of the Achilles tendon elicit a pressor reflex J Appl Physiol, June 1, 2007; 102(6): 2112 - 2120. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Gao, J. D. Li, L. I. Sinoway, and J. Li Effect of muscle interstitial pH on P2X and TRPV1 receptor-mediated pressor response J Appl Physiol, June 1, 2007; 102(6): 2288 - 2293. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Burnstock Physiology and Pathophysiology of Purinergic Neurotransmission Physiol Rev, April 1, 2007; 87(2): |
