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1 Department of Veterinary Biomedical Sciences, 2 Veterinary Diagnostic Laboratory, and 3 Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri 65211
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We tested the hypothesis that short-term exercise (STEx) training and the associated increase in pulmonary blood flow during bouts of exercise cause enhanced endothelium-dependent vasorelaxation in porcine pulmonary arteries and increased expression of endothelial cell nitric oxide synthase (eNOS) and superoxide dismutase-1 (SOD-1) protein. Mature, female Yucatan miniature swine exercised 1 h twice daily on a motorized treadmill for 1 wk (STEx group, n = 7); control pigs (Sed, n = 6) were kept in pens. Pulmonary arteries were isolated from the left caudal lung lobe, and vasomotor responses were determined in vitro. Arterial tissue from the distal portion of this pulmonary artery was processed for immunoblot analysis. Maximal endothelium-dependent (ACh-stimulated) relaxation was greater in STEx (71 ± 5%) than in Sed (44 ± 6%) arteries (P < 0.05), and endothelium-independent (sodium nitroprusside-mediated) responses did not differ. Sensitivity to ACh was not altered by STEx training. Immunoblot analysis indicated a 3.9-fold increase in eNOS protein in pulmonary artery tissue from STEx pigs (P < 0.05) with no change in SOD-1 or glyceraldehyde-3-phosphate dehydrogenase protein levels. We conclude that STEx training enhances ACh-stimulated vasorelaxation in pulmonary arterial tissue and that this adaptation is associated with increased expression of eNOS protein.
pulmonary circulation; nitric oxide synthase; superoxide dismutase; acetylcholine; endothelium
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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EXERCISE TRAINING IS ASSOCIATED with endothelial adaptations in different circulatory beds of several species (4, 10, 19). Many studies have focused on the effects of exercise on coronary vasomotion because exercise has been demonstrated to reduce the risk of death due to coronary artery disease or stroke (20). Exercise training for 7 days enhanced ACh-induced dilation of canine coronary arteries via increased release of nitric oxide (NO) (19), and ACh-stimulated nitrite production from coronary vessels was increased after 10 days of training (16). In addition, mRNA expression of endothelial cell nitric oxide synthase (eNOS) was increased in aortic endothelial cells of dogs exercised for 10 days (16), indicating an adaptation in gene expression after exercise training. Thus in vivo studies have confirmed enhanced endothelial function in coronary vessels and increased production of endothelium-derived NO following short-term exercise (STEx) training.
Exercise is also beneficial in rehabilitation of patients with chronic obstructive pulmonary disease (COPD), although the physiological mechanisms responsible for reduced symptomatology have not been identified. In COPD patients, exercise-induced improvements in the clinical disease state have been ascribed to alterations in skeletal muscle energetics that result in a reduction in symptoms and clinical signs (7, 8) or to improvements in ventilatory capacity (18) or efficiency (3). Although pulmonary vascular dysfunction may also contribute to clinical signs in patients with interstitial lung disease (5), few experimental studies have analyzed the effects of exercise training on the pulmonary circulation.
In the present study, we tested the hypothesis that STEx would enhance endothelium-dependent dilation and increase eNOS protein content in pulmonary arteries of miniature swine. Enhanced endothelium-dependent relaxation was theorized to represent a beneficial adaptation to exercise. We have previously shown that endothelium-dependent vasorelaxation of pulmonary arterial rings was not altered by 16 wk of exercise training (chronic training) in normal pigs (6). However, other investigations indicate that the length of the training protocol can impact the development of adaptations in vascular function. In the miniature swine model used here, exercise training for 1 wk resulted in enhanced relaxation to bradykinin in brachial artery rings (10), whereas chronic training for 16-20 wk did not (9). Therefore, we tested the hypothesis that STEx training would also be associated with augmented endothelium-dependent relaxation in pulmonary arteries of pigs.
Increased eNOS in response to training has been demonstrated in various
species (4, 16, 19), although the effect of exercise
training on eNOS protein content has not been previously investigated
in the pulmonary circulation. We hypothesized that STEx and the
associated increase in pulmonary blood flow during exercise bouts would
increase eNOS protein in pulmonary arterial tissue. Because the
efficacy of NO can be reduced by the presence of superoxide anion
(O2
·) in the vascular environment, we also
hypothesized that STEx would increase superoxide dismutase-1 (SOD-1),
thus increasing the availability of NO by decreasing
O2· concentrations. Previous work in coronary
arterioles has demonstrated that increased flow upregulates eNOS and
SOD-1 mRNA expression (22). Therefore, in addition to
physiological studies, we tested the hypothesis that increased blood
flow associated with STEx would increase the relative expression of
SOD-1 protein levels in pulmonary artery tissue from STEx pigs relative
to sedentary controls (Sed).
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Exercise training. Mature, female Yucatan miniature swine were divided into Sed and STEx groups. STEx pigs were acclimated to a low-speed motorized treadmill (Quinton); Sed pigs remained in pens. Each day for 7 days, pigs in the STEx group ran two bouts of exercise on the treadmill, each consisting of 1 h at 3.5 mph, 0% grade. The second bout of exercise occurred at least 4 h after completion of the first bout. Routine biochemical profiles and complete blood counts were performed on each group of pigs to investigate potential differences in systemic health.
The efficacy of training was assessed by comparing heart-to-body weight ratios and skeletal muscle oxidative capacity of Sed and STEx pigs (4, 9, 14). Muscle samples were taken from the triceps brachii and deltoid, frozen in liquid nitrogen, and stored at
70°C
until processed for spectrophotometric determination of citrate
synthase activity (17).
Isolation and preparation of pulmonary arteries. Pigs were sedated with ketamine (25 mg/kg im) and xylazine (2 mg/kg im), anesthetized with pentobarbital sodium (30 mg/kg iv), and administered heparin (2,000 U/kg iv). The heart was removed by transection of the great vessels, and lungs were immediately placed in ice-cold Krebs solution containing (in mM) 131.5 NaCl, 5.0 KCl, 1.2 MgCl2 · 6H2O, 2.5 CaCl2 · 2H2O, 1.2 NaH2PO4 · H2O, 11.2 glucose, and 20.8 NaHCO3 for vessel isolation.
Pulmonary arteries (2- to 3-mm outer diameter) were located by their position medial to the bronchi. Lobar pulmonary arteries to the left caudal lung lobe were identified, and the first ventrally oriented artery was carefully isolated. These pulmonary arteries were cut into four ring segments, each 2-3 mm in length, for determination of vasoreactivity. Vessel area was calculated from internal and outer diameter and ring length, which was recorded in millimeters for each vascular ring. The distal portion of this pulmonary artery was processed for Western blot analysis.Contractile and relaxation responses.
Pulmonary artery rings were mounted between two stainless steel wires
connected to a force transducer (ETH-200/400 Series, CB Science, Dover,
NH) to measure developed tension and to a micrometer microdrive, which
allowed stretch of the vessel by known increments. Arterial rings were
stretched to a passive tension of 1.0 g for 1 h while they
equilibrated in individual 20-ml baths containing Krebs solution at
37°C and continuously bubbled with 95% O2-5% CO2. Krebs solution contained propranolol (3 × 106 M) to oppose 
2-adrenergic
receptor-mediated vasorelaxation. Isometric tension (in grams) was
continuously recorded by a computer acquisition system (MacLab, CB
Sciences, Milford, MA). Individual length-tension curves were generated
for each arterial ring to determine optimal ring length. Vessels were
progressively stretched by increments of 10% of the outer diameter and
exposed to 30 mM KCl for successive tension determinations. The optimal
length for a given artery (Lmax) was defined as
the length at which contractile force evoked by KCl failed to increase
by >10% of the previous measurement. Vessels were stabilized at
Lmax for 30 min before experimentation.
8 to 104 M, in half-log doses) was then
examined by cumulative addition of stock solutions to vessel baths.
Response to contractile agonists was expressed as the developed change
in tension (in grams) from resting tension.
Arteries were washed until they returned to resting tension and then
were precontracted with the EC50 of NE (5.75 × 107 M) and stabilized for 20 min. Preliminary experiments
indicated that NE resulted in stable contraction for >150 min in these
porcine pulmonary arteries. The presence of endothelium was confirmed by observing >60% relaxation to a single dose of bradykinin
(106 M) after NE precontraction. Arterial rings that did
not exhibit relaxation to bradykinin were discarded.
Arterial rings were washed until they returned to resting tension;
5.75 × 107 M NE was then added to vessel baths.
Endothelium-dependent relaxation was determined through cumulative
addition of ACh stock solutions to the vessel bath (final concentration
of ACh: 1010 to 104 M, in half-log doses).
Percent relaxation for each dose of ACh was determined as percent
reduction in NE-induced tension. Arterial rings were washed until they
returned to resting tension; 5.75 × 107 M NE was
then added to each vessel bath. Tension was stabilized for 20 min, and
relaxation to sodium nitroprusside (SNP; bath concentration of SNP:
1010 to 104 M, in half-log doses) was
determined to assess endothelium-independent relaxation. Maximal
relaxation was identified through incubation in modified Krebs solution
containing no calcium and 2 mM EGTA.
Immunoblot analysis.
Pulmonary arterial tissue distal to the rings used in physiology
studies was processed for Western blotting. Preliminary studies indicated that these two adjacent segments of pulmonary artery did not
express different amounts of eNOS protein (data not shown). Pulmonary
artery tissue (50-100 mg) that had been cleaned of adventitia was
placed in 0.5 ml of ice-cold Tris-buffered extraction buffer containing
50 mM Tris, 0.1 mM EDTA, 0.1 mM EGTA, 0.1% -mercaptoethanol, 1 mM
phenylmethylsulfonyl fluoride, 1 µM pepstatin A, 2 µM leupeptin, 20 mM CHAPS, and 10% vol/vol glycerol at pH 7.4. Tissue was homogenized while on ice and then ultracentrifuged at 100,000 g for 30 min. Protein content of the supernatant was determined with the
Bradford protein assay using bovine serum albumin as the standard
(2); the supernatant was maintained at 70°C until
analyzed through Western blotting.
Immunohistochemistry. To confirm the localization of eNOS to the endothelium, some pulmonary arterial rings were fixed in zinc paraformaldehyde (Anatech LTD, Battle Creek, MI) for 24 h and imbedded in paraffin blocks. For processing, blocks were deparaffinized; 5-µm sections were then cut with an automated microtome, and sections were floated onto positively charged slides (Fisher, St. Louis, MO). Slides were steamed in citrate buffer at pH 6.0 (Dako target retrieval solution S1699, Carpintiera, CA) for 20 min to achieve antigen retrieval and then cooled for 20 min. The Dako auto stainer (Dako DC3400) was used for immunohistochemical staining. Sequential Tris buffer and water wash steps were performed after each protocol in the automated staining process. Sections were incubated in avidin biotin two-step blocking solution (Dako X590) to inhibit background staining and in 3% hydrogen peroxide to inhibit endogenous peroxidase. Nonserum protein block (Dako X909) was applied to prohibit nonspecific protein binding, and slides were incubated in primary mouse monoclonal IgG1 anti-eNOS antibody (Transduction Laboratories N30020) at 1:800 dilution for 60 min. After the appropriate washing steps were completed, slides were incubated in biotinylated anti-mouse link secondary antibody in PBS containing 15 mM sodium azide and peroxidase-labeled streptavidin (Dako LSAB+ kit, peroxidase, K0690). Diaminobenzidene (Dako) applied for 5 min allowed visualization of eNOS antibody staining. Slides were counterstained in Mayer's hematoxylin stain for 1 min, dehydrated, and coverslipped.
Histological sections of brachial artery were used as positive controls for eNOS staining of the endothelium. For negative controls, histological sections of lung tissue were prepared as described above, but incubation in primary antibody was excluded from the protocol.Solutions.
All chemicals were obtained from Sigma Chemical unless otherwise noted.
Krebs solution was made fresh daily, equilibrated at 37°C, bubbled
with 95% O2-5% CO2 for 20 min, and adjusted
to pH 7.4 before use. Stock solutions of bradykinin (Bachem California, Torrance, CA), ACh, and NE dissolved in distilled, deionized water were
made in a single batch and stored at 20°C until use. Dilutions used
in experiments were made fresh daily using Krebs solution as a diluent.
NE was kept covered and on ice throughout the experiment to prevent
oxidative degradation. SNP was made fresh daily in Krebs solution and
was kept in the dark immediately before addition to the bath.
Data analysis.
Data are presented as means ± SE. Contractile tension was
calculated by subtracting resting tension from tension measured after
each addition of drug. A concentration-response curve was constructed
by plotting developed tension against log NE concentration, and the
concentration that resulted in half-maximal contraction was defined as
the EC50. This value was interpolated from regression on
points taken from the linear portion of the log concentration-response curve and was expressed as a percentage of the maximal response (using
Basica IC50). Relaxation was expressed as percent
reduction from precontracted tension induced by 5.75 × 107 M NE (EC50) at each dose added.
IC50 was defined as the drug concentration resulting in
half-maximal relaxation. This value was determined by interpolation on
each log concentration-response curve by using the same computer
regression program (Basica IC50).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Indexes of exercise training.
STEx pigs had a significantly greater heart-to-body weight ratio
(4.84 ± 0.14) than did Sed (4.24 ± 0.51) pigs
(P < 0.05). Body weight did not differ between Sed
(37.4 ± 1.4 kg) and STEx (35.8 ± 8.1 kg) pigs
(P = 0.64). In pigs that had undergone exercise training, there was a trend toward increased citrate synthase activity
in the lateral and long heads of the triceps (P = 0.06-0.08) (Table 1).
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Characteristics of pulmonary arteries. Arterial rings from Sed and STEx pigs did not differ in physical dimensions or percent stretch required to reach Lmax. Outer diameter of pulmonary arterial rings was 2.54 ± 0.07 mm in Sed pigs and 2.51 ± 0.07 mm in STEx pigs. Passive tension necessary to attain Lmax also did not differ between arteries of Sed and STEx pigs.
Contractile and relaxation responses.
Response to 80 mM KCl did not differ in arteries from Sed (3.85 ± 0.50 g) and STEx (3.40 ± 0.42 g) pigs
(n = 7, P = 0.50). The
concentration-response relationship to NE did not differ between arteries from Sed and STEx pigs (P = 0.32), and
contractile tension to EC50 concentration of NE (5.75 × 107 M) was similar in pulmonary arteries from Sed
(2.11 ± 0.28 g) and STEx (1.55 ± 0.29 g) pigs
(n = 7, P = 0.19).
107 M ACh than arteries from Sed
pigs (P < 0.05) (Fig.
1), but sensitivity to ACh did not differ
between groups, as indicated by similar IC50 concentrations
for Sed (7.23 ± 0.65 × 108 M) and STEx
(8.41 ± 1.8 × 108 M) arteries
(P = 0.58). Previous experiments on arteries denuded of
endothelium confirmed that the response to ACh was endothelium dependent (6).
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8 M) and STEx (IC50 = 15.00 ± 5.95 × 108 M) arteries (P = 0.33).
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Immunoblot analysis of short-term training effects.
Immunoblot analysis for eNOS protein content was performed on samples
from six Sed and six STEx pigs, and immunoreactive eNOS was detected in
tissue from five Sed and four STEx pigs. Densitometry readings were
similar for samples run in triplicate. Figure
3A displays protein expression
for eNOS in pulmonary arterial tissue from Sed (lanes
2-5) and STEx (lanes 6-9) pigs. Lane
10 represents reaction of eNOS antibody with bovine aortic
endothelial cells, a positive control sample. In this representative
blot, increased expression of immunoreactive eNOS protein is evident in
pulmonary artery tissue from STEx pigs. Figure 3, B and
C, illustrates a 3.9-fold increase in eNOS protein in
samples obtained from STEx pigs compared with Sed controls
(P = 0.01).
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Immunohistochemistry.
Immunohistochemistry revealed that eNOS staining was confined to the
endothelium in the pulmonary arteries of Yucatan swine (Fig.
6). Nonspecific staining was absent, and
eNOS reactivity was absent from other cellular layers of these
arteries. In the absence of incubation with primary antibody to eNOS,
no immunoreactivity was detected.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We have previously reported that chronic exercise training (16 wk) does not alter vasorelaxation in pulmonary arteries of normal pigs (6). The primary purpose of this study was to test the hypothesis that STEx training results in enhanced endothelium-dependent vasorelaxation and increased expression of eNOS and SOD-1 protein in pulmonary arteries. Our hypothesis was supported by the finding that ACh-induced relaxation is enhanced and eNOS protein levels are increased 3.9-fold in pulmonary arterial tissue of pigs that have completed a short-term training protocol. Although levels of SOD-1 protein are 58% higher in pulmonary arterial tissue from STEx pigs relative to Sed controls, the difference is not statistically significant. GAPDH protein content is also unaltered by exercise, indicating that exercise training has a selective effect on eNOS protein production in these pulmonary arteries.
STEx training did not alter contractile responses to activation of voltage-gated calcium channels. This contrasts with findings in chronically trained pigs, in which increased contraction to 80 mM KCl was noted in pulmonary arteries of exercised pigs compared with Sed controls (6). In addition, contraction to EC50 levels of NE and relaxation to SNP in pulmonary arteries from Sed and STEx pigs were similar, indicating that STEx training had no effect on measured vascular smooth muscle functional responses within the pulmonary circulation. The sole difference in vascular reactivity of pulmonary artery rings between Sed and STEx pigs was enhanced endothelium-dependent relaxation in pigs that completed STEx training.
STEx training produces similar functional adaptations in the coronary circulation of the dog, in which 7-10 days of exercise training resulted in enhanced epicardial coronary artery dilation associated with greater release of NO (19). Sessa et al. (16) also reported increased eNOS gene expression in the aorta of dogs trained for 10 days, indicating that STEx training is associated with endothelial adaptations in conduit-sized arteries. Our experiments provide support for enhanced endothelium-dependent pulmonary arterial vasorelaxation and increased eNOS protein content following short-term training in the pulmonary arteries examined here.
Previous work by other investigators has implicated a role for altered expression of eNOS in the time dependence of training-induced improvements in endothelium-dependent vasorelaxation. Delp and Laughlin (4) studied the time course of exercise-induced adaptations in aortic tissue of the rat and found enhanced ACh-induced relaxation after 4 wk of endurance training. Aortic tissue from exercise-trained rats displayed increased eNOS protein levels coincident with improved relaxation. In our model of exercise training, exercise-induced adaptations in endothelium-dependent relaxation of pulmonary arteries appear to mimic the response reported in brachial arteries, in which relaxation was increased with the same short-term training program used in the present study (10) but was unchanged after 16 wk of exercise training (9). The different time course of endothelial adaptations in rats and pigs may be related to differences between species or vascular beds in response to exercise training.
Increased expression of eNOS protein has been illustrated in cultured endothelial cells exposed to increased shear stress (13), and increased blood flow associated with exercise is thought to impact endothelial cell function by exerting shear stress on the endothelial lining of the vessel. Pulmonary blood flow increases five- to sixfold in the exercising pig (1) and likely increases shear stress within pulmonary arteries; however, shear stress has not been measured directly in the pulmonary arteries studied here. Interestingly, short-term training augments endothelial cell production of eNOS protein and endothelium-dependent relaxation in pulmonary arteries, whereas this adaptation is not present following chronic exercise training (6). If shear stress is the stimulus for the adaptation noted, our results suggest an alteration in the stimulus-response relationship as training becomes long-term. Potential mechanisms that might alter the response to blood flow and/or shear stress would include structural remodeling of the vasculature, a decrease in the shear stress gradient sensed by endothelial cells, or decreased response to the shear stress stimulus. In the coronary circulation, conduit arteries from pigs used in this model fail to demonstrate enhanced endothelium-dependent relaxation following chronic exercise training (14); however, coronary arterioles display augmented relaxation mediated by NO (11). These resistance arterioles also have increased eNOS mRNA (21) and SOD-1 protein and mRNA content (15). In the coronary circulation, it is possible that long-term training enhances vasorelaxation and endothelium-dependent function in the microcirculation, leading to a reduction in the shear stress signal for endothelial adaptation in conduit-sized arteries. This potential mechanism has not been investigated in the pulmonary circulation.
In a previous study of the effects of chronic exercise (16 wk)
training, pulmonary arterial rings from Sed and chronically trained
pigs displayed equal endothelium-dependent relaxation and relied
equally on NO for ACh-mediated relaxation (6). To determine whether chronic training altered eNOS protein content, we
performed Western blot analysis on pulmonary arterial tissue taken from
seven sedentary and seven chronically trained pigs from that study and
evaluated expression of eNOS, SOD-1, and GAPDH protein levels utilizing
similar methods to those described here. No significant differences in
protein expression of SOD-1, GAPDH, or eNOS were detected in conduit
pulmonary arterial tissue of Sed pigs and pigs that had completed 16 wk
of exercise training (Fig. 7), supporting
a time-dependent alteration in the effects of exercise training on
levels of eNOS protein that correlates with endothelium-dependent
changes in vasoreactivity. Thus both eNOS protein levels and
ACh-mediated relaxation are increased in pulmonary arteries of pigs
that have completed short-term exercise but are not different from Sed
controls following chronic exercise training. Further investigation
into the mechanisms responsible for an alteration in this adaptation
with chronic training will provide insight into the impact of exercise
training in the pulmonary circulation.
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Increased eNOS protein following STEx training could reflect increased protein production and/or decreased protein breakdown. Short-term training could augment gene expression of eNOS, or the half-life of mRNA for eNOS may be prolonged by STEx training. Evidence in the literature supports upregulation of eNOS gene expression coincident with increased eNOS protein content in response to chronic increases in blood flow (12) and increased shear stress (13). Woodman et al. (22) reported upregulation of eNOS mRNA following 2 and 4 h of high-flow conditions in perfused coronary arterioles isolated from Sed pigs. Gene expression for eNOS and SOD-1 has not currently been investigated in the pulmonary circulation of trained swine.
Pigs in this study completed a strenuous exercise protocol designed to provide maximal stimulus for exercise-induced effects on the vasculature within a short period of time. Heart-to-body weight ratio increased by 14% in STEx pigs in the absence of a change in body weight, indicating a degree of myocardial hypertrophy following STEx training similar to that seen after chronic training (9, 15, 21). However, citrate synthase activity showed only a trend toward increased activity in certain muscles, indicating that the stable adaptation of skeletal muscle to training that occurs with more protracted training protocols in this pig model (6, 21) had not been achieved. With the use of available methods, conduit-sized pulmonary arteries of STEx pigs displayed no gross changes in physical characteristics or in passive properties compared with Sed controls, suggesting that structural remodeling had not occurred in these vessels.
The level of exercise performed in these studies was carefully controlled, and application of these results to the response to exercise in patients with cardiopulmonary disease is difficult to predict. The exercise capacity achieved by individuals with heart or lung disease depends on multiple factors, and, just as exercise limitation results from a number of variables including vascular dysfunction, the effects of exercise on health status may be impacted by numerous factors including improvements in endothelial function. STEx training improves endothelial function in the pulmonary circulation, and this represents a previously unrecognized effect of exercise on cardiopulmonary function.
In conclusion, our data indicate that STEx training (1 h twice daily for 1 wk) results in increased expression of eNOS protein and enhanced ACh-mediated relaxation in the pulmonary arteries studied here. This adaptation was endothelium dependent because relaxation to SNP, a direct donor of NO to vascular smooth muscle cells, did not differ between arteries from Sed and STEx pigs. These studies complement previous findings in the pulmonary circulation of normal pigs, which demonstrate the lack of an adaptation after chronic (16 wk) exercise training (6). Together, these studies suggest that the length of training impacts the development of adaptations within the pulmonary circulation. After short-term training, eNOS protein is increased and endothelium-dependent relaxation is enhanced. With chronic training, eNOS protein is no longer increased and a functional endothelial adaptation is no longer present in these conduit-type pulmonary arteries (6), perhaps due to ultrastructural adaptations in the vasculature, adaptations in other pulmonary arteries, reduced response to shear stress, or a decrease in the gradient of shear stress encountered. Further studies are required to analyze mechanisms contributing to the time course of training effects in the pulmonary circulation and to examine induction of training-related adaptations throughout different sites within the pulmonary vasculature.
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ACKNOWLEDGEMENTS |
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We thank Pam Thorne, Tammy Strawn, Denise Holiman, and Marilyn Beissenherz for invaluable assistance with this project.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-03856 and HL-52490.
Address for reprint requests and other correspondence: L. R. Johnson, VM: Medicine and Epidemiology, School of Veterinary Medicine, Univ. of California, Davis, CA 95616-8737 (E-mail: LRJohnson{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.
Received 1 August 2000; accepted in final form 20 September 2000.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Am J Physiol Heart Circ Physiol
276:
H1058-H1063,
1999
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