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1 Laboratoire "réponses cellulaires et fonctionnelles à l'hypoxie" EA 2363, Association pour la Recherche en Physiologie de l'Environnement, Université Paris XIII, 93017 Bobigny, France; and 2 Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160-7401
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Chronic hypoxic
exposure results in elevated sympathetic activity leading to
downregulation of myocardial 
1- and 
-adrenoceptors (1-AR, -AR). On the other hand, it has been shown
that sympathetic activity is reduced by exercise training. The
objective of this study was to determine whether exercise training
could modify the changes in receptor expression associated with
acclimatization. Four groups of rats were studied: normoxic sedentary
rats (NS), rats living and training in normoxia (NTN), sedentary rats
living in hypoxia (HS, inspired PO2 = 110 Torr), and rats living and training in hypoxia (HTH, inspired
PO2 = 110 Torr). Training consisted of
running in a treadmill at 80% of maximal O2 uptake during
10 wk. Myocardial receptor density was measured by radioactive ligand binding. Right ventricular (RV) hypertrophy occurred in HS but not in
HTH. No effect of exercise was detected in RV weight of normoxic rats.
Acclimatization to hypoxia (HS vs. NS) resulted in a decrease in both
1- and -AR density, whereas muscarinic receptor
(M-Ach) expression increased. Hypoxic exercise training (HS vs. HTH)
moderated -AR downregulation and M-Ach upregulation and prevented
the fall in 1-AR density. Normoxic training (NS vs. NTN) did not change -AR density. On the other hand, densities of
1-AR in both ventricles as well as RV M-Ach increased in
NTN vs. NS. The data show that exercise training in hypoxia
1) prevents RV hypertrophy, 2) suppresses the
downregulation of 1-AR in the left ventricle (LV) and
RV, and 3) attenuates the changes in both -AR and M-Ach
receptor density in LV and RV. Exercise training in normoxia increases
M-Ach receptor expression in the RV.
1-adrenoceptor; -adrenoceptor; M-ACh receptor; right ventricular hypertrophy; moderate hypoxia
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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CHRONIC EXPOSURE TO
SEVERE hypoxia [inspired PO2
(PIO2) = 70 Torr for 3 wk] results
in elevated sympathetic activity leading to downregulation of
myocardial 1- and -adrenoceptors (9, 14,
29) as a consequence of the prolonged agonist stimulation (1, 27). These changes are accompanied by an increase in muscarinic M2 (M-Ach) myocardial receptor expression (9, 15, 33).
Exercise training, on the other hand, results in a decrease in
sympathetic activity (6, 19, 23, 32) and in an increase in
parasympathetic tone at rest and during exercise (6, 23). As a consequence of these effects, heart rate at rest and during submaximal exercise is reduced after exercise training (6, 23). These effects of exercise training on cardiac autonomic control were estimated from the modifications in heart rate after successive blockade of -adrenoceptors by propranolol and cholinergic receptors by atropine (19, 23). Whether these
changes in sympathetic and parasympathetic activity are accompanied by
variations in myocardial adrenergic and muscarinic receptor expression
under normoxic conditions is disputed. Both decreases and no change in
myocardial -adrenoceptor density have been reported after exercise
training (21, 24, 28, 30, 31), whereas a lack of effect on
1-adrenoceptors and muscarinic receptor expression has
been observed (18, 31).
Because acclimatization to hypoxia and exercise training appear to have
opposing effects on autonomic control of cardiac function, we
hypothesized that exercise training could influence the effect of
acclimatization to hypoxia on myocardial adrenergic and cholinergic receptor density. This is a significant problem because one of the
effects of -adrenoceptor downregulation of chronic hypoxia is a
reduced chronotropic response to -adrenergic agonists (1, 7,
9, 12, 27) and a decrease in maximal heart rate (1, 7, 11,
25, 26). The reduced maximal heart rate is one of the factors
responsible for the limitation in maximal exercise capacity observed
after acclimatization (5, 10).
The objective of these experiments was to determine whether exercise training modifies the effect of hypoxia on myocardial adrenergic and muscarinic receptor expression. Myocardial receptor characteristics were determined in rats in which the effect of living and training in hypoxia on exercise performance and systemic O2 transport was studied. The exercise data have been published separately (12).1
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal Model and Training Protocol
All procedures were carried out following the regulations for laboratory animal care and use of the French Ministère de l'agriculture and the Guide for the Care and Use of Laboratory Animals. Seven-week-old male Sprague-Dawley rats were randomly assigned to live in normoxia (PIO2 = 147 Torr) or in moderate hypoxia (PIO2 = 110 Torr; 2,300 m). Each group was then subdivided into sedentary and trained subgroups. This resulted in four experimental groups of seven to eight rats each: normoxic sedentary (NS), normoxic trained in normoxia (NTN), hypoxic sedentary (HS), and hypoxic trained in hypoxia (HTH). All four groups were housed in the same room with the hypoxic groups placed in hypobaric chambers set to PIO2 = 110 Torr. Training lasted 10 wk and was performed in an eight-lane treadmill through which the appropriate O2-N2 gas mixtures could be circulated; NTN trained at PIO2 = 147 Torr and HTH at PIO2 = 110 Torr. Absolute training intensity was the same for NTN and HTH, starting at ~80% of the maximal O2 uptake of normoxic sedentary animals. Equal training intensity for hypoxic and normoxic groups was selected because at work rates O2 needs are the same, independent of the PO2 and of O2 fluxes. This approach eliminates work intensity as a confounding variable. Work rate was increased gradually over 6 wk until it reached 30 m/min on a 10° incline, 1 h/day, 5 days/wk. This work rate was maintained for the last 4 wk of the training protocol.Studies of Myocardial Autonomic Receptors
At the end of training, the animals exercised maximally. These data on exercise capacity and O2 transport have been published elsewhere (12). After the exercise bout, the animals were killed with an overdose of pentobarbital sodium (60 mg/kg iv), and the heart was rapidly removed. The left ventricle with septum was separated from the right ventricular free wall, and both ventricles were immediately frozen in liquid nitrogen.Myocardial cell membrane isolation.
The procedure used was a slightly modified version of the method of
Kacimi et al. (14). The ventricles were weighed and immediately homogenized in 6 ml of buffer (30 mM Tris
HCl, 100 mM
NaCl, 5 mM MgCl2, 1 mM EGTA, 1 mM trypsin inhibitor, 1 mg/ml leupeptin; pH 7.5) with a polytron tissue homogenizer. The
suspension was centrifuged at 1,000 g for 10 min at 4°C.
The supernatant was transferred to another tube and centrifuged at
50,000 g for 30 min at 4°C. The supernatant was discarded,
and the pellet was resuspended with 6 ml of buffer and centrifuged at
50,000 g for 30 min at 4°C.
HCl, 5 mM MgCl2; pH 7.5) and stored at 
80°C.
Protein content was measured with a dye-binding assay using a
commercial kit (Bio-Rad; Ref. 4) and using bovine serum
albumin as standard.
1-Adrenoceptor-binding assay.
[3H]prazosin, an 1-adrenoceptor
antagonist, was used to label the receptors. Eight different
concentrations of [3H]prazosin (Amersham Pharmacia
Biotech; specific activity of 75 Ci/mmol) ranging from 0.02 to 1.5 nM
were used in each assay. Unlabeled prazosin (1 µM) was added to
determine nonspecific binding. Protein concentration of each sample was
adjusted to 40-80 µg/100 µl on the day of the assay.
-Adrenoceptor-binding assay.
The procedure used was the same as that described for the
1-adrenoceptor binding assay, except for the following
modification: 3H-labeled CGP-12177
[()-4-(3-t-butyl amino-2-hydroxy-propoxy) benzimidazole-2-one, Amersham Pharmacia Biotech; specific activity of
45 Ci/mmol], a -adrenoceptor antagonist, was used to label the
receptors. Eight different concentrations of 3H-labeled
CGP-12177 ranging from 0.06 to 4 nM were used in each assay. Unlabeled
propranolol (10 µM) was added to determine nonspecific binding. The
protein concentration was adjusted to 30-60 µg/100 µl on the
day of the assay. Duplicate samples of the membrane preparations were
incubated for 1 h at 37°C. Average nonspecific binding was 9%
of the total binding.
M-Ach receptor-binding assay. The procedure used was the same as the ones described above, except for the following: [3H]quinuclidinyl benzilate (Amersham Pharmacia Biotech; specific activity of 45 Ci/mmol), a M-ACh antagonist, was used to label the receptors. Eight different concentrations of [3H]quinuclidinyl benzilate, ranging from 0.01 to 0.8 nM, were used in each assay. Unlabeled atropine (10 µM) was added to determine nonspecific binding. The protein concentration was adjusted to 25-60 µg/100 µl on the day of the assay. Duplicate samples of the membrane preparations were incubated for 1 h at 25°C. Average nonspecific binding was 7.5% of the total binding.
Data Analysis
Radio ligand binding data were analyzed with Ligand, a weighed, nonlinear, least-square curve-fitting computer program (22). For saturation experiments, equilibrium dissociation constants (receptor apparent affinity) and maximum numbers of binding sites were determined by nonlinear regression fitting.Statistical Analysis
The data are expressed as means ± SE. Statistical analysis was carried out by using a one-way analysis of variance. The effect of acclimatization was evaluated by comparing NS vs. HS. The effect of training in normoxia and in hypoxia was assessed by comparing NS vs. NTN and HS vs. HTH, respectively. Finally, comparison of NTN vs. HTH provided an estimate of the effects of living and training in normoxia vs. living and training in hypoxia. Significance was established with the t-test using the Bonferroni correction for multiple comparisons. A P value <0.05 was considered to indicate a significant difference.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Body and Ventricular Weights
There were no significant differences in body weight (g) among the four groups (NS: 379.2 ± 5.8, NTN: 336.5 ± 5.4, HS: 380.7 ± 7.5, HTH: 334.0 ± 10.2). Acclimatization to hypoxia resulted in the expected increase in right ventricular weight (HS vs. NS, P < 0.05, Fig. 1A). Exercise training, on the other hand, significantly moderated the right ventricular hypertrophy, with right ventricular weight of HTH being significantly lower than that of HS (Fig. 1A, P < 0.05). Normoxic exercise training did not influence right ventricular weight (NS vs. NTN, P > 0.05, Fig. 1A). No significant effects of acclimatization or of exercise training were detected on left ventricular weight (Fig. 1B).
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Density and Affinity of Myocardial Receptors
Acclimatization to moderate hypoxia induced a decrease in-adrenoceptor density in the left (Fig.
2A) and the right (Fig. 3A) ventricles in untrained
rats (NS vs. HS, P < 0.05). This reduction was
attenuated in both ventricles by exercise training during acclimatization: -adrenoceptor density was lowest in HS,
intermediate in HTH, and highest in NTN and NS (Figs. 2A and
3A). No difference was observed between NS and NTN,
indicating that normoxic exercise training does not influence
-adrenergic receptor density in either ventricle.
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1-Adrenoceptor density decreased significantly in both
ventricles during the course of acclimatization to hypoxia (NS vs. HS;
P < 0.05, Figs. 2B and 3B).
Hypoxic exercise training partially moderated this fall in both left
and right ventricles (HS vs. HTH, Figs. 2B and
3B). On the other hand, normoxic exercise led to an increase
in 1-adrenoceptor in both ventricles (NTN vs. NS).
M-Ach receptor density was significantly increased during acclimatization in both ventricles (NS vs. HS, Figs. 2C and 3C). This elevation was attenuated by exercise training in hypoxia, with M-Ach receptor density being significantly lower in HTH than in HS (Fig. 2C and 3C). In addition, exercise training in normoxia also resulted in a significant increase in M-Ach receptor density; however, this occurred only in the right ventricle (Fig. 3C, NS vs. NTN).
No significant effect of hypoxia or training was observed in the affinity of adrenergic or cholinergic receptors for the respective ligand.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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This study represents the first characterization of the effect of exercise training on the response of myocardial autonomic receptors to prolonged hypoxia. The major findings are 1) the protocol of moderate hypoxia used in these studies produced changes in myocardial autonomic receptors that are similar in direction and magnitude to those produced by more severe hypoxia; 2) exercise training profoundly influenced the effects of moderate hypoxia on myocardial autonomic receptors; and 3) exercise training prevented the hypoxia-induced right ventricular hypertrophy.
Effects of Moderate Hypoxia on Myocardial Autonomic Receptors
The present study shows that the effect of moderate hypoxia (PIO2 ~110 Torr) on myocardial adrenergic and cholinergic receptors is similar to that produced by severe hypoxia (PIO2 ~70 Torr). Density of both1- and -adrenoceptors of the sedentary rats living in hypoxia decreased to values that were not different from
those observed in sedentary rats acclimatized to severe hypoxia (9). Key features of the response to prolonged severe
hypoxia are elevated sympathetic activity (1, 27),
decreased myocardial response to -adrenergic agonists
(27), and downregulation of myocardial 1-
and -adrenoceptors (9, 14). The downregulation of
myocardial adrenergic receptors in severe hypoxia may be the result of
the prolonged increased agonist stimulation secondary to the elevated
sympathetic activity (1). The fact that moderate hypoxia
also results in a decrease in myocardial adrenergic receptor density of
an extent similar to that of severe hypoxia suggests that sympathetic
activity is also increased in moderate hypoxia. However, because the
duration of the acclimatization period was longer in the present study
than in those investigating the effects of severe hypoxia (9,
14), it is not possible to determine whether sympathetic
activity increases to similar levels in both conditions. Nevertheless,
the fact remains that this hypoxic exposure protocol does result in
substantial modification of myocardial adrenergic receptor density.
Upregulation of myocardial M-Ach receptors was also of similar magnitude to that observed in severe hypoxia (9). The mechanisms responsible for the increased density of myocardial M-Ach receptors either in moderate or severe hypoxia are not clear. M-Ach receptor stimulation mediates the negative chronotropic and inotropic effects of acetylcholine. It is not known whether acclimatization to hypoxia is associated with changes in vagal output to the heart that could explain the increase in receptor density.
Effect of Exercise Training on Myocardial Autonomic Function
The animals that lived and trained in hypoxia showed a smaller reduction in density of1- and -adrenoceptors in both
ventricles than that observed in the sedentary hypoxic rats. Because
exercise training is known to decrease sympathetic activity (19,
23, 32), a possible explanation for the attenuation of
hypoxia-induced adrenoceptor downregulation is that exercise training
results in a lower level of sympathetic activity during hypoxia. This would lead to a lower degree of adrenoceptor stimulation and
attenuation of receptor downregulation.
The functional significance of the changes in myocardial adrenoceptor
density associated with training and hypoxia cannot be surmised from
the present data. One characteristic feature of acclimatization to more
severe hypoxia (PIO2 ~70 Torr) is the decrease in maximal exercise heart rate (5, 11), which
contributes to limit maximal cardiac output and exercise capacity
(2, 25). Maximal heart rate correlates tightly with
ventricular -adrenoceptor and M-Ach receptor density during
acclimatization to severe hypoxia (9). The decrease in
chronotropic response to -adrenergic agonists observed in humans
(27) and rats (7) acclimatized to severe
hypoxia is consistent with the downregulation of ventricular -adrenoceptors seen in this condition. In the present study, however, acclimatization to moderate hypoxia did not result in the
decrease in maximal heart rate characteristic of more severe hypoxia:
maximal heart rate values observed during exercise were 536 ± 5, 530 ± 2, 535 ± 9, and 534 ± 9 beats/min in NS, HS,
NTN, and HTH, respectively (12). A lack of effect of
acclimatization to moderate hypoxia on maximal heart rate has also been
observed in humans (26). One possible explanation for the
lack of correlation between maximal heart rate values and ventricular
-adrenoceptor density is that ventricular receptor density in
moderate hypoxia does not reflect atrial receptor density. Atrial
-adrenoceptor density, particularly in or near the sinoatrial node,
is likely to have a larger influence in heart rate responses to
adrenergic agonists than ventricular -adrenoceptor density. In
severe hypoxia, the strong correlation between ventricular
-adrenoceptor density, maximal heart rate, and chronotropic
responses to isoproterenol observed across several studies (7, 9,
14, 15, 26, 27) suggests that ventricular receptor density
changes parallel changes in atrial receptors. However, several
interventions (3, 20), including moderate hypoxia
(8), have been shown to influence atrial and ventricular
adrenoceptors to different extents. Doshi et al. (8)
showed in the newborn lamb that moderate hypoxia resulted in
downregulation of ventricular -adrenoceptors without changes in
atrial -adrenoceptor density. A similar effect of moderate hypoxia
in the present experiments could explain the lack of effect of
acclimatization to hypoxia on maximal heart rate of sedentary rats in
the presence of ventricular -adrenoceptor downregulation, and, by
extension, the lack of effect of exercise training on heart rate of
hypoxic rats. Thus whether hypoxia influences atrial or ventricular
receptors may depend on its severity; this could explain the lack of
correlation between changes in -adrenoceptor density and maximal
heart rate observed in moderate hypoxia and the good correlation
between these variables seen in more severe hypoxia.
M-Ach receptor density increased in moderate hypoxia, and exercise training attenuated this increase. Maximal exercise in trained as well as untrained subjects is accompanied by decreased vagal output; accordingly, a change in M-Ach receptor density should have only limited inotropic and chronotropic effects during maximal exercise.
Effect of Exercise Training on Right Ventricular Hypertrophy
Prolonged hypoxia results in right ventricular hypertrophy as a result of pulmonary hypertension due, in part, to hypoxic pulmonary vasoconstriction. In the present study, the rats living and training in hypoxia showed no significant increase in right ventricular weight, in contrast with the hypoxic sedentary rats. The lack of increase in right ventricular weight in the exercise-trained rats observed in the present study was accompanied by a substantial moderation of hypoxic pulmonary hypertension determined by direct measurement of pulmonary arterial pressure at rest and during maximal exercise (12). The mechanism responsible for the lower pulmonary arterial pressure in the exercise-trained rats living in hypoxia has not been determined; however, it has been shown previously that exercise training prevents hypoxic pulmonary vasoconstriction (16) and attenuates the response to pulmonary vasoconstrictors (17). The effect of exercise training on hypoxic pulmonary vasoconstriction, in turn, could be related to the increase in endothelium-dependent pulmonary vasodilation observed after exercise training (13).In summary, the results of this study show that moderate hypoxia maintained for 10 wk leads to changes in myocardial autonomic receptors similar to those observed in more severe hypoxia and that these changes are substantially attenuated by exercise training in hypoxic conditions. The effect of exercise training extends to the pulmonary circulation by preventing the hypertension-induced right ventricular hypertrophy. The mechanisms underlying these changes, as well as their functional implications, remain to be determined.
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ACKNOWLEDGEMENTS |
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The expert technical assistance of Julie Allen is gratefully acknowledged.
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FOOTNOTES |
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This study was supported by National Heart, Lung, and Blood Institute Grant HL-39443.
Address for reprint requests and other correspondence: N. C. Gonzalez, Dept. of Molecular and Integrative Physiology, Univ. of Kansas Medical Center, Kansas City, KS 66160-7401 (E-mail: ngonzale{at}kumc.edu).
1 This supplemental material may be found at http://jap.physiology. org/cgi/content/full/90/6/2057.
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.
Received 22 February 2001; accepted in final form 29 May 2001.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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T. Bupha-Intr and J. Wattanapermpool Cardioprotective effects of exercise training on myofilament calcium activation in ovariectomized rats J Appl Physiol, May 1, 2004; 96(5): 1755 - 1760. [Abstract] [Full Text] [PDF]
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F. Favret, K. K. Henderson, J.-P. Richalet, and N. C. Gonzalez Effects of exercise training on acclimatization to hypoxia: systemic O2 transport during maximal exercise J Appl Physiol, October 1, 2003; 95(4): 1531 - 1541. [Abstract] [Full Text] [PDF]
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