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Departments of Anesthesiology and Physiology, Medical College of Wisconsin and Veterans Affairs Medical Center, Milwaukee, Wisconsin 53295
Submitted 19 February 2003 ; accepted in final form 19 May 2003
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ABSTRACT |
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 TOP ABSTRACT METHODS AND PROCEDURESRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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,
-methylene ATP would produce vasoconstriction in resting
and exercising skeletal muscle. Six mongrel dogs were instrumented chronically
with flow probes on the external iliac arteries of both hindlimbs and a
catheter in one femoral artery. The selective P2X agonist
,-methylene ATP was infused as a bolus into the femoral artery
catheter at rest and during mild, moderate, and heavy exercise. Intra-arterial
infusions of ,-methylene ATP elicited reductions in vascular
conductance of 54 ± 5, 49 ± 8, 39 ± 8, and 30 ± 6%
at rest, 3 miles/h, 6 miles/h, and 6 miles/h at a 10% grade, respectively. The
agonist infusions did not affect blood flow in the contralateral iliac artery.
To examine whether nitric oxide is responsible for the attenuated
vasoconstrictor response to P2X stimulation, the infusions were repeated in
the presence of NG-nitro-L-arginine methyl
ester. After nitric oxide synthase blockade, intra-arterial infusions of
,-methylene ATP elicited reductions in vascular conductance of 56
± 7, 61 ± 8, 52 ± 9, and 40 ± 7% at rest, 3
miles/h, 6 miles/h, and 6 miles/h at a 10% grade, respectively. P2X-receptor
responsiveness was attenuated during exercise compared with rest. Blockade of
nitric oxide production did not affect the attenuation of P2X-receptor
responsiveness during exercise. These data support the hypothesis that P2X
purinergic receptors can produce vasoconstriction in exercising skeletal
muscle. blood flow; sympatholysis; autonomic nervous system; dogs
In the past, the ability of the sympathetic nervous system to restrain blood flow in active skeletal muscle has been questioned (14, 24, 26). However, there is clear and convincing evidence that there is sympathetic restraint of skeletal muscle hyperemia during exercise (3, 5, 20, 34, 35, 43). Although the existence of sympathetic vasoconstriction in active skeletal muscle is generally accepted, whether the magnitude of this vasoconstriction is attenuated during exercise compared with rest remains an issue of debate. Indeed, it has been argued that, as exercise intensity increases, sympathetic vasoconstriction in active skeletal muscle also increases (34). An attenuation of vasoconstriction in the arterial vasculature of skeletal muscle during muscle contraction has been reported by a number of investigators (8, 22, 23, 36, 37, 42). This diminished vascular responsiveness to sympathetic stimulation during muscular contraction was termed "functional sympatholysis" by Remensnyder et al. (36). Recently, studies by Thomas and colleagues (12, 38, 40, 41) have provided evidence that the mechanism by which sympatholysis occurs is related to the production of nitric oxide.
The purpose of this study was to examine the effect of P2X-receptor stimulation on the skeletal muscle vasculature of conscious dogs at rest and during exercise. We hypothesized that P2X-receptor stimulation would elicit vasoconstriction in resting and exercising skeletal muscle. Furthermore, we hypothesized that P2X-receptor responsiveness would be attenuated from rest to exercise in an exercise intensity-dependent manner by the production of nitric oxide.
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METHODS AND PROCEDURES |
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TOPABSTRACTMETHODS AND PROCEDURESRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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All experiments were performed in a laboratory in which the temperature was maintained below 20°C. On the day of the experiment, the dog was brought to the laboratory, and a 20-gauge intravascular catheter (Insyte, Becton Dickinson, Deseret, Sandy, UT) was inserted retrogradely into the lumen of the carotid artery. The carotid catheter was attached to a solid-state pressure transducer (Ohmeda, Madison, WI), and the flow probes were connected to a transit-time flowmeter (Transonic Systems).
To examine the effect of P2X-receptor stimulation on skeletal muscle
vascular tone, ,-methyleneadenosine 5'-triphosphate lithium
salt (,-methylene ATP, Sigma, St. Louis, MO), a selective P2X
agonist (11), was infused into
one hindlimb at rest and during exercise. This agonist was chosen for its
ability to be dissolved easily in aqueous solution and infused in a conscious,
chronically instrumented dog without detrimental effects. We reasoned that,
because hindlimb blood flow increases in an exercise intensity-dependent
manner, administration of an identical amount of agonist at rest and exercise
would result in a lower effective concentration of the drug during exercise.
Therefore, as in previous investigations
(6,
7), the dose of the agonist
administered during exercise was increased from rest. The bolus infusion of
,-methylene ATP given throughout this study was equal to 1 µg
of ,-methylene ATP per milliliter of external iliac blood flow.
Infusions were performed at rest and during steady-state exercise while the
dogs ran on the treadmill at three different intensities: a mild exercise
intensity of 3 miles/h (4.8 km/h) at a 0% grade, a moderate exercise intensity
of 6 miles/h (9.7 km/h) at 0% grade, and a heavy exercise intensity of 6
miles/h (9.7 km/h) at a 10% grade. Each exercise intensity was performed on a
separate day. For each exercise intensity, there were two infusions of
,-methylene ATP. The dog performed one bout of exercise at a
given intensity during which ,-methylene ATP was infused. After
10 min of rest, the bout of exercise was repeated. The data from the two
infusions were averaged for determination of P2X-receptor responsiveness under
each condition. During preliminary studies to examine the reproducibility of
repeated infusions of ,-methylene ATP, it was determined that 10
min between the infusions of ,-methylene ATP was sufficient time
to avoid any tachyphylaxis.
To determine whether the production of nitric oxide was responsible for the
attenuation of P2X-receptor responsiveness from rest to exercise, additional
experiments were performed in all the animals. Nitric oxide production was
inhibited with an intravenous infusion of
NG-nitro-L-arginine methyl ester
(L-NAME, Sigma Chemical) at a dose of 15 mg/kg. Effective nitric
oxide synthase blockade was inferred from a rise in resting mean arterial
pressure of >15 mmHg. At least 10 min after administration of
L-NAME, P2X-receptor responsiveness was determined with
intra-arterial infusions of ,-methylene ATP at rest and during
exercise at 3 miles/h (4.8 km/h), 0% grade, 6 miles/h (9.7 km/h), 0% grade,
and 6 miles/h (9.7 km/h), 10% grade. These data were collected in the same
manner as the data without nitric oxide synthase inhibition (described
above).
To demonstrate that ,-methylene ATP selectively activated P2X
receptors and not -receptors, both norepinephrine and
,-methylene ATP were given before and after
-adrenergic-receptor blockade. In two dogs, a bolus infusion of
norepinephrine and ,-methylene ATP was given while the dogs ran
at 6 miles/h. After 10 min of rest, the dog ran again at 6 miles/h. During
steady-state exercise, -adrenergic-receptor blockade was accomplished
with an infusion of prazosin (100 µg) and rauwolscine (1 mg). The doses of
norepinephrine and ,-methylene ATP were then repeated.
A computer (Apple G3 Power PC) using a Powerlab system (ADInstruments, Castle Hill, Australia) was used to record (at 100 Hz) arterial blood pressure and right and left external iliac blood flow during all experiments. Data were analyzed off-line by using the MacLab software to calculate mean arterial pressure, heart rate, iliac blood flow, and iliac vascular conductance (blood flow/mean arterial pressure). Vascular conductance was calculated rather than vascular resistance because conductance better reflects vascular tone when the experimental manipulation causes a change primarily in flow and not pressure (25). Control measurements were averaged over 30 s before agonist infusion. After the agonist infusion, all variables were averaged over 1-s intervals (100 consecutive data points), and the nadir 1-s average for vascular conductance was chosen as the peak response.
An -level of P < 0.05 was used to establish statistical
significance during all analysis. Statistical analyses of the data were
performed with a three-way (drug x nitric oxide blockade x
exercise intensity) repeated-measures analysis of variance. The percent
changes in vascular conductance from baseline after the infusion of the
agonists were calculated for each individual dog and analyzed with a two-way
(nitric oxide blockade x exercise intensity) repeated-measures analysis
of variance. Where significant F-ratios were found, a Tukey's post
hoc test was performed. All data are expressed as means ± SE.
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RESULTS |
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TOPABSTRACTMETHODS AND PROCEDURESRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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,-methylene ATP produced a
localized vasoconstriction in the experimental limb without corresponding
changes in blood flow or conductance in the contralateral limb.
Figure 1 is an original tracing
from one experiment in which the adrenergic-receptor agonist norepinephrine
and the selective P2X agonist ,-methylene ATP were infused during
steady-state exercise at 6 miles/h. In response to the agonist infusions,
there were substantial decreases in blood flow in the experimental limb
without a corresponding alteration in blood flow to the contralateral limb. In
two dogs, the infusion of norepinephrine resulted in an average reduction in
conductance of 21%. The infusion of ,-methylene ATP caused an
average reduction in conductance of 25%. To demonstrate that vasoconstriction
to ,-methylene ATP was independent of -adrenergic
receptors, the intra-arterial infusions of both norepinephrine and
,-methylene ATP were repeated after -adrenergic-receptor
blockade. It can be seen in Fig.
2 that -adrenergic blockade abolished the vasoconstrictor
effects of norepinephrine, but not the vasoconstrictor response to
,-methylene ATP. In two dogs, the infusion of norepinephrine
resulted in an average reduction in conductance of 2%, whereas the infusion of
,-methylene ATP reduced conductance by 37%. These data support
the premise that the vasoconstrictor effects of ,-methylene ATP
are independent of -adrenergic receptors.
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Table 1 gives the baseline
hemodynamic measurements before intra-arterial infusion of
,-methylene ATP. As expected, there were significant (P
< 0.05) exercise intensity-dependent increases in hindlimb blood flow, mean
arterial pressure, and heart rate from rest to exercise. The
,-methylene ATP infusions significantly (P < 0.05)
reduced experimental limb blood flow and conductance (Figs.
3 and
4, respectively). However, at
the time of maximal vasoconstriction in the experimental limb, there were no
significant (P > 0.05) changes from baseline in heart rate, mean
arterial pressure, or blood flow in the contralateral limb.
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The absolute changes in experimental limb blood flow with intra-arterial
infusion of ,-methylene ATP at rest and during exercise are shown
in Fig. 3. However, vascular
responsiveness is best described in vivo by using the percent change in
vascular conductance from baseline
(4).
Figure 4 depicts the percent
changes in iliac conductance with intra-arterial infusion of
,-methylene ATP at rest and during exercise. There was a
significant effect of exercise intensity on the percent changes in iliac
conductance (P = 0.003). The attenuation of vascular responsiveness
from rest to exercise was more pronounced as exercise intensity increased.
To examine whether nitric oxide production during exercise was responsible
for the reduced vascular responsiveness, ,-methylene ATP
infusions were repeated after nitric oxide synthase inhibition with
L-NAME. L-NAME administration reduced baseline
experimental limb blood flow and elevated baseline mean arterial pressure
(P < 0.05; Table
1). However, the ,-methylene ATP infusions still
produced significant (P < 0.05) reductions in experimental limb
blood flow and conductance (Figs.
3 and
4, respectively). As in the
previous series, at the time of maximal vasoconstriction in the experimental
limb, there were no significant (P > 0.05) changes from baseline
in heart rate, mean arterial pressure, or blood flow in the contralateral
limb. The absolute changes in experimental limb blood flow with intra-arterial
infusion of ,-methylene ATP at rest and during exercise with
L-NAME are presented in Fig.
3. Figure 4 depicts
the percent changes in iliac conductance with intra-arterial infusion of
,-methylene ATP at rest and during exercise. In the presence of
L-NAME, intra-arterial infusion of ,-methylene ATP
produced more vasoconstriction compared with the control condition (P
< 0.05). Although L-NAME enhanced the vasoconstrictor effects of
,-methylene ATP, vascular responsiveness was still attenuated
during exercise (P < 0.05). However, there was not a statistically
significant interaction (P = 0.18) between exercise intensity and the
L-NAME condition for the percent change in conductance. Thus the
administration of L-NAME did not alter the degree to which exercise
attenuated the responsiveness of P2X purinergic receptors to stimulation by
,-methylene ATP.
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DISCUSSION |
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TOPABSTRACTMETHODS AND PROCEDURESRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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,-methylene ATP
produced less vasoconstriction during heavy exercise compared with rest.
Finally, the production of nitric oxide does not appear to be responsible for
the reduction in P2X-receptor responsiveness during exercise. To our
knowledge, this is the first demonstration in conscious animals that
stimulation of P2X receptors produces vasoconstriction in resting and
exercising skeletal muscle.
There is compelling evidence that ATP acts as a neurotransmitter in
vascular smooth muscle and is coreleased with norepinephrine from sympathetic
nerves (9,
18,
21,
29). Burnstock and Kennedy
(11) proposed the subdivision
of P2 purinergic receptors into P2X, which mediate vasoconstriction, and P2Y,
which mediate vasodilation. P2X receptors on vascular smooth muscle cells are
preferentially stimulated by ATP from sympathetic nerve endings
(17). P2Y receptors are found
predominantly on endothelial cells, but there is limited evidence for this
receptor subtype on vascular smooth muscle
(12). It should be stated that
ADP is a weak agonist for the P2X receptor (100-fold less potent than ATP) and
that UTP is inactive (2).
Several studies have shown stimulation of neurotransmitter release caused
vascular smooth muscle contractions in the presence of adrenergic blockade
(10,
21,
32,
44). These nonadrenergic
contractions can be abolished with desensitization of P2X purinoceptors
(10), suggesting that the
vasoconstriction is mediated by ATP or a related purine nucleotide. Two recent
studies have shown that P2X-receptor stimulation will produce vasoconstriction
in the hindlimb of anesthetized animals. Bivalacqua et al.
(1) produced vasoconstriction
in the isolated hindlimb of anesthetized cats with localized infusions of
,-methylene ATP. In anesthetized rats, Johnson et al.
(19) provided evidence that
P2X receptors contribute to sympathetic vasoconstriction in skeletal muscle.
Electrical stimulation of the sympathetic nerves innervating the hindlimb of
the rat produced vasoconstriction that was attenuated with P2X-receptor
blockade. Although our laboratory
(3,
5,
15) and others
(34) have previously
demonstrated sympathetic restraint of blood flow to exercising skeletal muscle
mediated by -adrenergic receptors, it is unknown whether P2X receptors
mediate vasoconstriction in exercising skeletal muscle. Data from the present
study, coupled with those provided by Johnson et al.
(19), might lead one to
speculate that tonic sympathetic restraint of blood flow to exercising
skeletal muscle is mediated by P2X receptors in addition to -adrenergic
receptors. Future investigation is needed to determine whether P2X receptors
mediate tonic vascular tone in exercising skeletal muscle.
A previous study from our laboratory showed exogenous activation of both
1- and 2-adrenergic receptors produced
vasoconstriction during exercise
(7). However, compared with
rest, exercise intensity differentially attenuated the responsiveness of
1- and 2-adrenergic receptors in the
arterial vasculature of exercising skeletal muscle. The vasoconstriction to a
selective 1-adrenergic-receptor agonist was only attenuated
during heavy exercise, whereas the vasoconstriction to a selective
2-adrenergic-receptor agonist was attenuated during mild
exercise and further attenuated by subsequent increases in exercise intensity.
The results of the present study suggest that P2X receptors are more similar
to 1-adrenergic receptors in their pattern of attenuation in
that, compared with rest, a mild bout of exercise did not alter the
responsiveness of P2X receptors. The present study is the first to demonstrate
functional sympatholysis involving a postsynaptic vascular receptor other than
an -adrenergic receptor.
Although the exact mechanism responsible for exercise sympatholysis remains
to be definitively determined, alterations in the chemical environment of the
vascular smooth muscle have been shown to change -adrenergic-receptor
responsiveness. Postsynaptic 2-adrenergic-receptor-mediated
vasoconstriction appears to be readily attenuated by modest reductions in pH
(27,
30,
39), hypoxia
(27,
39), elevated temperature
(13), and ischemia
(28), whereas the
responsiveness of 1-adrenergic receptors is relatively
unaltered by these factors. The production of nitric oxide in exercising
skeletal muscle is another localized factor that has been hypothesized to
alter the chemical environment of vascular smooth muscle and mediate
functional sympatholysis (12,
38,
40,
41). Thomas and Victor
(41) first demonstrated that
acute inhibition of nitric oxide synthase partially restores sympathetic
vasoconstriction in contracting rat limbs. In addition, mice with genetic
deficiencies in neuronal nitric oxide synthase do not exhibit sympatholysis
(40). Recent work in humans
has found similar results. Children with Duchenne muscular dystrophy, which
results in a loss of neuronal nitric oxide synthase, do not show blunting of
sympathetic vasoconstriction in exercising skeletal muscle
(38). Furthermore, in healthy
subjects, acute inhibition of nitric oxide synthase abolishes the attenuation
of sympathetic vasoconstriction in the microcirculation of contracting human
skeletal muscle (12). In the
present study, we expected that nitric oxide production was at least partially
responsible for the attenuation in P2X-receptor responsiveness during
exercise. Surprisingly, the data do not support this hypothesis. Although
nitric oxide production does modulate P2X-receptor-mediated constriction, as
evident by an enhanced vasoconstriction with P2X-receptor stimulation after
L-NAME, there was no change in the attenuation of
P2X-receptor-mediated vasoconstriction from rest to exercise after acute
nitric oxide synthase blockade with L-NAME. These results suggest
that the attenuation of -adrenergic receptors and P2X receptors is
accomplished by different mechanisms.
The results of this study demonstrate that P2X receptors can produce
vasoconstriction in resting and exercising skeletal muscle. There are several
strengths to the experimental protocol used in this study to draw this
conclusion. The use of a conscious animal avoids the confounding effects of
anesthesia. Conscious, dynamically exercising dogs allowed natural patterns of
muscle recruitment and permitted a higher intensity of exercise than is
achievable in anesthetized animal preparations. This is particularly
advantageous because it appears that more intense exercise is necessary for
attenuation of P2X-receptor-mediated vasoconstriction in the arterial
vasculature of skeletal muscle. Finally, continuous blood flow measurements
are essential given the transient nature of the vasoconstrictor response to
the intra-arterial infusion of ,-methylene ATP.
The results from the present study reveal that stimulation of P2X receptors
in the arterial vasculature of skeletal muscle elicits vasoconstriction in
both resting and active skeletal muscle. In addition, the responsiveness of
P2X receptors is attenuated from rest to exercise such that stimulation with
the selective P2X agonist ,-methylene ATP produces less
vasoconstriction during heavy exercise compared with rest. Surprisingly, the
production of nitric oxide does not appear to be responsible for the reduction
in P2X-receptor responsiveness during exercise compared with rest.
Nonetheless, the present study is the first to demonstrate that stimulation of
P2X purinergic receptors in the arterial vasculature of exercising skeletal
muscle produces vasoconstriction. These results raise the possibility that the
P2X purinergic receptor may regulate skeletal muscle vascular tone during
exercise.
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DISCLOSURES |
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TOPABSTRACTMETHODS AND PROCEDURESRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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ACKNOWLEDGMENTS |
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TOPABSTRACTMETHODS AND PROCEDURESRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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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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TOPABSTRACTMETHODS AND PROCEDURESRESULTSDISCUSSIONDISCLOSURESACKNOWLEDGMENTSREFERENCES |
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1998.This article has been cited by other articles:
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