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,
-Methylene ATP elicits a reflex pressor response
arising from muscle in decerebrate cats
Division of Cardiovascular Medicine, Departments of Internal Medicine and Human Physiology, University of California, Davis, California 95616
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In part, the exercise pressor
reflex is believed to be evoked by chemical stimuli signaling that
blood supply to exercising muscles is not adequate to meet its
metabolic demands. There is evidence that either ATP or
adenosine may function as one of these chemical stimuli. For example,
muscle interstitial concentrations of both substances have been found
to increase during exercise. This finding led us to test the hypothesis
that popliteal arterial injection of 
,
-methylene ATP (5, 20, and
50 µg/kg), which stimulates P2X receptors, and 2-chloroadenosine (25 µg/kg), which stimulates P1 receptors, evokes reflex pressor
responses in decerebrate, unanesthetized cats. We found that popliteal
arterial injection of the two highest doses of ,-methylene ATP
evoked pressor responses, whereas popliteal arterial injection of
2-chloroadenosine did not. In addition, the pressor responses evoked by
,-methylene ATP were blocked either by section of the sciatic
nerve or by prior popliteal arterial injection of pyridoxal
phosphate-6-azophenyl-2',4'-disulfonic acid (10 mg/kg), a selective
P2-receptor antagonist. We conclude that the stimulation of P2
receptors, which are accessible through the vascular supply of skeletal
muscle, evokes reflex pressor responses. In addition, our findings are
consistent with the hypothesis that the stimulation of P2 receptors
comprises part of the metabolic error signal evoking the exercise
pressor reflex.
purines; exercise; autonomic nervous system; thin fiber muscle afferents; metabolic error signal
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A REFLEX ARISING FROM CONTRACTING skeletal muscles is believed to evoke some of the cardiovascular and ventilatory responses to exercise (1, 7, 16, 21). This neural mechanism, which appears to be evoked by both metabolic (1) and mechanical (15) stimuli, has been named the exercise pressor reflex (23). Much attention has been paid to the nature of the metabolic stimuli causing the exercise pressor reflex, because these stimuli, which are believed to be produced by muscular contraction, might provide an error signal that blood supply to exercising muscle is not adequate to meet its metabolic demand.
Previously, evidence has been presented that bradykinin and lactic acid provide part of this metabolic error signal. For example, both substances are produced by contraction of limb muscles (28, 30, 32, 35). In addition, injection of either bradykinin (31) or lactic acid (27) into the arterial supply of skeletal muscle evokes reflex increases in mean arterial pressure and heart rate, both of which are components of the exercise pressor reflex (23).
Other candidates that might provide part of this metabolic error signal are the purines, ATP, and adenosine. Muscle interstitial concentrations of both substances have been shown to increase during either exercise or static contraction (9, 14, 24). Moreover, adenosine is a metabolite of ATP, a high-energy compound that is released as a neurotransmitter by sympathetic postganglionic endings (3). These findings prompted us to test the hypothesis that ATP and adenosine, injected into the arterial supply of hindlimb muscle, evoke reflex increases in mean arterial pressure, heart rate, and ventilation.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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General. Cats were anesthetized with a mixture of 5% halothane and oxygen. Catheters were placed into the right common carotid artery, the right jugular vein, and the right femoral vein. The carotid arterial catheter was connected to a Statham pressure transducer (model 23 XL) to measure arterial blood pressure. Heart rate was calculated beat to beat from the arterial pressure pulse by a Gould Biotach amplifier. The trachea was cannulated, and the lungs were ventilated mechanically (Harvard Apparatus). The fifth cervical rootlet of the phrenic nerve was exposed and cut, and its central end was placed on a bipolar recording electrode. The phrenic signals were amplified (Grass P511) and then integrated (Gould) with a sample-and-hold function that reset every 100 ms. The left triceps surae muscles and the left popliteal artery were isolated. In addition, the skin covering the left hindlimb from the hip to the paw was separated from the muscles and was tied to brass bars; its cranial aspect was left intact. The calcaneal bone was severed and then attached to a force transducer (model FT-10C, Grass). The left obturator, common peroneal, and femoral nerves were cut, as were all visible branches of the left sciatic nerve that did not supply the triceps surae muscles. Particular attention was paid to the cutting of all visible nerves supplying the knee.
A midcollicular decerebration was performed under the halothane anesthesia. All neural tissue rostral to the plane of section was removed. Bleeding was controlled, and the cranial vault was filled with agar (37°C). Once the decerebration was completed, the cat was paralyzed with vecuronium bromide (0.01 mg/kg iv), and its lungs were ventilated with room air. PCO2 was maintained between 35 and 40 Torr by either adjusting ventilation or injecting sodium bicarbonate intravenously (8.5%).Protocols.
We examined the arterial pressure, heart rate, and ventilatory
responses to injecting ,-methylene ATP (5, 20, and 50 µg/kg) and 2-chloroadenosine (25 µg/kg) into the left popliteal artery of
decerebrate, unanesthetized cats. The molecular weight of
,-methylene ATP is 505.2 and that of 2-chloroadenosine is
301.7. The injection volumes ranged from 0.3 to 1.0 ml and
required 5-10 s to complete. The doses of ,-methylene ATP
were injected in ascending order, and the interval between injections
was 20 min. Not every dose of ,-methylene was given to every cat.
The doses of ,-methylene ATP were selected because they have been
shown previously to stimulate mesenteric sympathetic afferents in rats
(17). To minimize circulation of the injectate to other
vascular beds, such as those in the lungs and the carotid and the
aortic bodies, we clamped the left medial saphenous and popliteal
veins. This procedure proved to be less than satisfactory to
demonstrate a reflex mechanism (see below), and, therefore, we
performed another series of experiments in which we also placed a
ligature around the left thigh. At the end of each of these
experiments, we injected 0.5-1.0 ml of 2% Evans blue dye into the
popliteal artery and noted the structures stained by this agent.
,-methylene ATP (5, 20, 50 µg/kg) into the right jugular vein. In some experiments, if ,-methylene ATP, injected into the left popliteal artery, evoked an increase in arterial pressure, we repeated the injection after cutting the left sciatic nerve. In others, we repeated the injection with the sciatic nerve intact; instead we examined these responses after injecting into the
left popliteal artery the P2 antagonist pyridoxal
phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS; 10 mg/kg)
(18). We used ,-methylene ATP because it is a
selective P2X1- and P2X3-receptor agonist
(5). Moreover, thin fiber afferents have receptors to the
latter (6). Similarly, we used 2-chloroadenosine because
it is a P1-receptor agonist and is not taken up by red blood cells, as
is adenosine (4, 10).
Data analysis.
We compared baseline values with peak responses to either
intra-arterial or intravenous injection of ,-methylene ATP and 2-chloroadenosine. Baseline values for mean arterial pressure and heart
rate were taken as the steady-state values immediately preceding
injection of either agent. Mean arterial pressure was calculated as
diastolic pressure plus one-third the pulse pressure. The integral of
phrenic nerve activity was used as an index of ventilation
(12). Baseline values for phrenic nerve activity were
composed of the sum of the neural tidal volumes for the 1-min period
immediately preceding injection, and, for the peak value, it was
composed of the sum of the neural tidal volumes for the 1-min period
immediately after injection. Each neural tidal volume was expressed as
a proportion of a maximal value, which was obtained by stopping the ventilator.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In our first series of experiments, we injected three doses of
,-methylene ATP into the left popliteal artery of decerebrate, unanesthetized cats. The left medial saphenous and popliteal veins were
occluded. We found that each of the three doses [i.e., 5 (n = 10), 20 (n = 15), and 50 (n = 14) µg/kg] significantly increased (P < 0.05) mean arterial pressure but had no effect on
either heart rate or phrenic nerve activity (Fig.
1). The onset latencies of the pressor
responses to the three doses (in ascending order) were 10 ± 1, 8 ± 1, and 4 ± 1 s, respectively. Section of the left
sciatic nerve significantly reduced (P < 0.05) the
pressor responses to each of the three doses of ,-methylene ATP.
After nerve section, the onset latencies of the pressor responses were (in ascending order of dose) 12 ± 3, 14 ± 3, and 10 ± 1 s, respectively. In addition, section of the sciatic nerve
abolished the previously modest and nonsignificant (P > 0.05) increases in phrenic nerve activity and converted them to
decreases (Fig. 1).
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In the above experiments, section of the sciatic nerve attenuated but
did not abolish the pressor responses to popliteal arterial injection
of ,-methylene ATP. This finding caused us to inject the three
doses (n = 14 for each) of this agent intravenously to
determine whether recirculation contributed to the pressor effect. We
found that injection of the two lowest doses of ,-methylene ATP
into the jugular vein evoked pressor responses (P < 0.05; Fig. 2). The onset latencies of the
pressor responses to the two lowest doses of ,-methylene ATP both
averaged 5 ± 1 s. In addition, intravenous injection evoked
decreases in heart rate that increased in magnitude as the dose
increased (Fig. 2). Finally, intravenous injection had no significant
(P > 0.05) effect on phrenic nerve activity (Fig. 2).
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In our second series of experiments, which were done in different cats
than those used above, we placed and tightened a ligature around the
left thigh and then injected ,-methylene ATP into the left
popliteal artery. The saphenous and popliteal veins were occluded as
they were in the first series of experiments. We found that the two
higher doses (n = 9) of the purine significantly increased mean arterial pressure (onset latencies of 9 ± 2 s
for both doses). On average, the pressor response to the middle (i.e., 20 µg/kg) dose lasted 42 ± 4 s, and that to the high dose
(i.e., 50 µg/kg) lasted 35 ± 6 s. Section of the left
sciatic nerve reduced the pressor responses to ,-methylene ATP to
almost nothing (P < 0.05; Figs.
3 and 4).
The lowest dose (i.e., 5 µg/kg) of this purine increased
mean arterial pressure in only three of the nine cats in which it was
injected, and overall the effect was not significant (P < 0.05). Consequently, we did not examine the effect of sciatic nerve
section on the cardiovascular and phrenic responses to popliteal
arterial injection of the lowest dose of ,-methylene ATP. None of
the three doses of ,-methylene ATP significantly increased
(P < 0.05) phrenic nerve activity over baseline values (P > 0.05). Nevertheless, the interaction between the
phrenic nerve response to the highest dose of ,-methylene ATP
before and after sciatic nerve section was significant
(P < 0.05; Fig. 3). The heart rate responses to
intra-arterial injection of ,-methylene ATP with the sciatic
nerve intact were trivial (P > 0.05; Fig. 3).
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We examined the effect of PPADS, a P2X-receptor antagonist, on the
cardiovascular and phrenic responses to left popliteal arterial
injection of ,-methylene ATP (20 and 50 µg/kg;
n = 12 for the two doses). We did not examine the
effect of PPADS on the responses to the smallest dose of
,-methylene ATP because these responses were trivial. PPADS (10 mg/kg) was injected into the left popliteal artery in cats that both
had a ligature tightened around the thigh and had their left medial
saphenous and popliteal veins clamped. The interval between the
injection of PPADS and the first injection of ,-methylene ATP was
30 min. We found that the pressor and phrenic nerve responses to
,-methylene ATP were abolished by PPADS (Figs.
5 and 6).
In this subset of cats, intra-arterial injection of the
purine did not increase heart rate (Figs. 5 and 6).
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We examined the cardiovascular and phrenic responses to popliteal arterial injection of 2-chloroadenosine (25-30 µg/kg) in nine of the cats in which a ligature was placed around the thigh and in which the saphenous and popliteal veins were clamped. In eight of the nine cats, mean arterial pressure decreased; in the remaining one it did not change. The onset latency for the decrease in mean arterial pressure (from 116 ± 10 to 98 ± 10 mmHg; n = 9; P < 0.01) averaged 6 ± 2 s (n = 8). In six of the nine cats, heart rate increased, and in three it did not change. The onset latency for the heart rate increase (from 137 ± 12 to 144 ± 12 beats/min; n = 9; P < 0.02) averaged 16 ± 4 s. Similarly, in seven of the nine cats, phrenic nerve activity increased. The onset latency averaged 13 ± 3 s (n = 7). Overall, for the nine cats, phrenic nerve activity increased from 153 ± 33 to 214 ± 70 U/min, but the effect was not significant (P > 0.05). We did not examine the effects of popliteal arterial injections of 2-chloroadenosine after cutting the sciatic nerve.
Finally, we observed the amount of tissue stained by popliteal arterial injections of Evans blue dye. In each of the 11 cats in which no ligature was placed around the thigh, we saw that the lateral gastrocnemius muscle was stained blue. Similarly, in 9 of these 11 cats, the medial gastrocnemius muscle was stained blue; in 6 of the 11, the soleus muscle was stained blue. In addition, in 7 of the 11 cats, the anterior muscles (including the anterior tibialis) of the hindlimb below the knee were stained blue. The skin of the lower hindlimb was not stained.
A similar, but not identical, pattern of staining was observed in the nine cats in which a ligature was placed around the thigh. In each of the cats, the lateral gastrocnemius and the soleus muscles were stained blue. Similarly, in seven, the medial gastrocnemius muscle and the anterior muscles of the hindlimb below the knee were stained blue. The skin of the lower hindlimb was not stained.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Purinergic receptors are believed to be composed of two
types, namely P1 and P2. Adenosine is a potent agonist to the P1
receptor, whereas ATP is a potent agonist to the P2 receptor, which in
turn has two subtypes, X and Y (4). We found that close
arterial injection of ,-methylene ATP, a selective P2X-receptor
agonist, evoked a reflex pressor response. Moreover, the effect was
blocked by PPADS, a compound that antagonizes both P2X and P2Y
receptors. Our findings strongly suggest that the reflex pressor
response evoked by ,-methylene ATP was caused by stimulation of
P2X receptors that were accessible from the vascular bed of hindlimb
skeletal muscle. In our experiments, close arterial injection of
2-chloroadenosine did not evoke a reflex pressor response.
Consequently, the reflex evoked by ,-methylene ATP in our
experiments was not caused by its breakdown to adenosine, which in turn
stimulated P1 receptors.
In our first series of experiments, we attempted to prevent
recirculation of ATP by clamping the popliteal and medial saphenous veins. This maneuver was only partly successful because sciatic nerve
section attenuated, but did not abolish, the cardiovascular and phrenic
responses to popliteal arterial injection of ,-methylene ATP.
Recirculation due to an intact lateral saphenous vein might have been
responsible for the remaining responses and probably was caused by the
ATP-induced stimulation of nerve endings in the lungs, the heart, the
carotid and aortic bodies, as well as in the abdominal viscera.
Specifically, ,-methylene ATP has been shown to evoke both a
pulmonary (13, 25) and coronary chemoreflex
(34), the afferent arm of which is carried in the vagus
nerves. In addition, ,-methylene ATP has been shown to stimulate
carotid body chemoreceptors (22), as well as sympathetic afferents with endings in the intestine (17).
Group III and IV afferents are well known to comprise the afferent arm
of the exercise pressor reflex (16, 21). Stimulation of
these thin fiber muscle afferents by ,-methylene ATP probably caused the pressor reflex evoked in our experiments. Although there is
no information about the effects of this purine on the discharge of
group III (A
-fiber) and IV (C-fiber) muscle afferents, it has been
shown to stimulate equal percentages (i.e., 55-65%) of A- and
C-fiber afferents innervating the knee joint of rats (11).
In vitro, ,-methylene ATP stimulated P2X1 and
P2X3 receptors (5) but did not stimulate P2Y
receptors (36). The P2X3, but not the
P2X1 receptor, has been shown immunocytochemically to be
present on the tooth pulp sensory endings of A and C fibers, all of
which were considered to be nociceptors. In vitro application of
,-methylene ATP to these thin fiber afferents vigorously stimulated them. In contrast, the P2X3 receptor is not
present on the endings of muscle stretch receptors, which respond to
innocuous mechanical stimuli and, therefore, are not considered to be
nociceptors. In vitro application of ,-methylene ATP to these
thick fiber afferents only weakly stimulated them (6).
These findings led to the conclusion that the P2X3 receptor
signals ATP-induced nociceptive input in the presence of tissue damage
(6).
In rats, the P2X3 receptor has been located immunocytochemically on ~40% of dorsal root ganglia (DRG) cells, projecting to either hindlimb skin or abdominal viscera, but only on 2% of those projecting to the gastrocnemius muscles (2). Moreover, P2X3-receptor immunoreactivity has been found on small-diameter DRG cells that display markers indicating that they are responsive to the algogen capsaicin (29). P2X3 immunoreactivity has not been found on large-diameter DRG cells that possess myelinated axons and that respond to innocuous mechanical stimuli (2).
The above findings provide further evidence that the P2X3
receptor, which is stimulated by ,-methylene ATP, is found on nociceptors. If this is the case, then one might speculate that the
muscle afferents stimulated by this substance in our experiments were
unmyelinated and were responsive to algesic stimuli, such as those that
might be generated by muscular contraction when blood/oxygen supply is
inadequate to meet metabolic demands. This speculation does not of
course account for the small number of muscle afferents possessing the
P2X3 receptor in rats (2). Perhaps there might
be a species difference between the cat and the rat. On this note, one
should recognize that the specificity of ,-methylene ATP for
P2X3 receptors is based on in vitro evidence obtained from
rodents. The specificity of this purine for P2X3 receptors
in vivo in cats is not known.
The ability of adenosine to evoke a pressor reflex when injected into the arterial supply of skeletal muscle is controversial. For example, Costa and Biaggioni (8) and Costa et al. (9) reported that brachial arterial injections of adenosine in humans increased mean arterial pressure and muscle sympathetic nerve activity. In contrast, MacLean et al. (19) found that femoral arterial injections of adenosine in humans increased mean arterial pressure and muscle sympathetic nerve activity only if it was allowed to recirculate to the systemic circulation; no effect was found if the injectate was restricted by ligature to the femoral arterial circulation. In both rabbits (33) and cats (20), injections of adenosine into the arterial supply of hindlimb skeletal muscle failed to increase mean arterial pressure. In the latter study (20), muscular interstitial concentrations of adenosine were measured and were found to be similar to those produced by contraction (14). In cats, arterial injections of 2-chloroadenosine stimulated only 15% of the group III and IV muscle afferents tested (26), a finding that does not lead one to expect that this substance would cause much of a reflex pressor response. Our present findings are consistent with the view that adenosine does not evoke a pressor reflex arising from skeletal muscle because its injection into the popliteal artery did not increase mean arterial pressure. In fact, on average, its injection decreased arterial pressure, an effect that was probably caused by the well-known vasodilator property of adenosine. In our experiments, the onset of the cardioaccelerator and phrenic neural responses to 2-chloroadenosine occurred well after the depressor responses, effects that strongly suggested that these increases were caused by the arterial baroreflex.
Two limitations of our work come to mind. First, we did not measure the
concentration of ATP in the interstitial space of the muscle when we
injected this substance into the popliteal artery. As a consequence, we
cannot compare the interstitial concentration of ATP found in skeletal
muscle when it is exercised with the interstitial concentration of ATP
when it was injected into the popliteal artery. Second, the magnitude
of the reflex pressor response evoked by ,-methylene ATP, while
substantial, was not large. Moreover, a reflex phrenic nerve response
was found only with the highest dose. In addition, we could find no
evidence that this purine evoked a reflex increase in heart rate that
arose from hindlimb muscles. We speculate that the small number of
muscle afferents having P2X3 receptors (2)
might explain these moderate effects. Alternatively, this substance
might stimulate many group III and IV muscle afferents, but only
weakly. For either possibility, the level of stimulation might reach
the threshold for vasoconstriction but still be below threshold to
evoke any cardiac or phrenic neural effect.
Our interest in ATP and adenosine was prompted by the possibility that one or both of these purines could contribute to the metabolic error signal indicating that blood/oxygen supply to exercising muscle was not adequate to meet its demand. Part of the usual approach to determine whether or not a substance can provide this error signal is to inject it into the arterial supply of skeletal muscle to see if it can increase mean arterial pressure by a reflex mechanism (16). In the decerebrate, unanesthetized cat, we have found this to be the case for ATP but not for adenosine.
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ACKNOWLEDGEMENTS |
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We thank Angela DiStefano for technical assistance.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute grant HL-30710.
Address for reprint requests and other correspondence: R. L. Hanna, TB 172, Division of Cardiovascular Medicine, Univ. of California, Davis, CA 95616 (E-mail: rlhanna{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.
May 17, 2002;10.1152/japplphysiol.00237.2002
Received 19 March 2002; accepted in final form 13 May 2002.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Effect with the sciatic nerve intact was significantly greater
(P < 0.05) than its corresponding effect with the
sciatic nerve cut. 
, Change.
