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1 Department of Sports
Medicine, Cardiac myocytes
produce endothelin-1 (ET-1). ET-1 has potent positive inotropic and
chronotropic effects. We investigated whether production of ET-1 in the
heart is altered by prolonged exercise in rats. Rats ran on a treadmill
for 45 min. Immediately after this exercise the heart and lungs were
quickly removed. Control rats remained at rest during this 45-min
period. Expression of preproET-1 mRNA in the heart was markedly higher
in the exercised than in the control rats. The peptide level of ET-1 in
the heart was also markedly higher in the exercised rats. Expression of endothelin type A- and type B-receptor mRNA and endothelin-converting enzyme mRNA in the heart did not differ between the groups. The peptide
level of ET-1 and the preproET-1 mRNA level in the lungs of the
exercised rats did not differ from those in the control rats. The
present results show that production of ET-1 is markedly increased
tissue specifically in the heart by exercise without appreciable
changes in endothelin-converting enzyme and endothelin receptor
expression. The present study suggests that myocardial ET-1 may
participate in modulation of cardiac function during exercise.
myocardial endothelin-1; positive inotropy; treadmill running; endothelin-converting enzyme; endothelin type A receptor; endothelin
type B receptor
CARDIAC MYOCYTES (32), as well as vascular endothelial
cells (35), produce endothelin-1 (ET-1). In addition to its potent vasocontractile effects (35), ET-1 has potent positive inotropic and
chronotropic effects on isolated heart muscles (6, 7) and induces
myocardial cell hypertrophy (30). We previously reported that the
circulating plasma concentration of ET-1 is significantly increased by
exercise (14). However, it is not known whether the production of ET-1
in the heart is altered by exercise.
It has been reported that the production of ET-1 in vascular
endothelial cells is increased by some humoral factors (such as ANG II
and arginine vasopressin) (2) and mechanical factors (such as shear
stress and endothelial stretching) (31, 37). In cultured ventricular
myocytes it has also been shown that the expression of preproET-1 mRNA
is increased by ANG II (8) or mechanical stretching (34). Therefore,
production of ET-1 in the heart in vitro may also be regulated by
neurohumoral and mechanical factors. Using an in vivo model of rats
with cardiac hypertrophy, we previously reported that production of
ET-1 was markedly increased in the hypertrophied heart because of a
hemodynamic pressure overload due to aortic banding (36) or pulmonary
hypertension (20). We also reported that production of ET-1 in the
heart is markedly increased in rats with chronic heart failure (25,
26). These results suggested that the production of ET-1 in the heart
is altered in some pathological conditions in vivo. However, it is not
known whether production of ET-1 in the heart is altered by physical
stress, e.g., prolonged exercise.
We investigated whether the production of ET-1 in the rat heart and
lungs is altered by prolonged exercise. Rats ran on a treadmill for 45 min. Immediately after this exercise the heart and lungs were quickly
removed, and the preproET-1 mRNA expression and the peptide ET-1 level
of these organs were determined. We also studied whether the
expressions of endothelin type A
(ETA)- and B
(ETB)-receptor mRNA in the heart
and lungs are altered by prolonged exercise. ET-1 is formed from its
precursor Big ET-1 by endothelin-converting enzyme (ECE) (22). The
biological activity of Big ET-1 is negligible, suggesting that ECE is a
key enzyme in the biosynthesis pathway of ET-1 (10). Therefore, the
expression of ECE mRNA in the heart and lungs was also studied in rats
performing prolonged exercise.
Animals and protocol.
Fifteen male Wistar rats (7 wk old) were obtained from Clea Japan
(Tokyo, Japan) and cared for according to the Guiding
Principles for the Care and Use of Animals based on the
Helsinki Declaration of 1964. The rats were maintained on a 12:12-h
light-dark cycle and received food and water ad libitum. All rats were
familiarized with running on a motor-driven treadmill 5 days/wk, over a
4-wk period, until they were capable of running 25 m/min for 45 min at
no incline (0% grade). The running time and the speed of the treadmill
were increased gradually over the 4-wk period from 10 min at 10 m/min
to 45 min at 25 m/min. Systolic arterial pressure and heart rate of the
animals were measured with a tail-cuff sphygmomanometer (model PS-100,
Riken Kaihatsu, Kanagawa, Japan) on the day before the experiment. The
body weight of the animals was also measured on the day before the
experiment. On the day of the experiment the rats were randomly divided
into two groups. In one group, eight animals ran on a treadmill (0%
grade) for 45 min at a speed of 25 m/min (the exercised group).
Shepherd and Gollnick (29) reported that this intensity (25 m/min) of
treadmill running in rats is ~78% of maximal oxygen consumption. The
other seven animals remained at rest during this 45-min period (the
control group).
ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References
METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References
80°C for
measurement of plasma epinephrine and norepinephrine concentrations by
radioenzymatic assay, for a mature ET-1 peptide assay by a
sandwich-enzyme immunoassay (EIA), and for determination of preproET-1
mRNA expression by RT-PCR analysis. In these organs (i.e., heart and
lungs), the expressions of ECE mRNA and
ETA- and
ETB-receptor mRNA were also
determined by RT-PCR analysis. The control animals were killed ~24 h
after their last bout of exercise, i.e., at the same time point as the
exercised rats.
Sandwich-EIA for determination of plasma, heart, and lung ET-1
levels.
Each blood sample was placed into a chilled tube containing aprotinin
(300 kallikrein-inhibiting units/ml) and EDTA (2 mg/ml) and centrifuged
at 3,000 g for 15 min at 4°C. The
plasma was stored at 80°C until use. The plasma ET-1
concentration was measured by a sandwich-EIA, as previously described
(14, 15, 18, 19, 21, 26). Briefly, plasma (1 ml) was acidified with 3 ml of 4% acetic acid, and immunoreactive ET-1 was extracted with a
Sep-Pak C18 cartridge (Waters,
Milford, MA). The elutes were reconstituted with 0.25 ml of assay
buffer and subjected to a sandwich-EIA for ET-1. The sandwich-EIA for
ET-1 was carried out as described previously with the immobilized mouse
monoclonal antibody AwETN40, which recognizes the amino-terminal
portion of ET-1, and peroxidase-labeled rabbit anti-ET-1
carboxyl-terminal peptide fragment 15-21, Fab' (14, 15, 18,
19, 26). The intra- and interassay coefficients of variation of the
ET-1 assay were 11 and 13%, respectively (17).
80°C, were homogenized with a Polytron homogenizer (model
PT10SK/35, Kinematica, Lucerne, Switzerland) for 60 s in 10 volumes of
1 mol/l acetic acid containing 10 µg/ml pepstatin (Peptide Institute,
Osaka, Japan) and immediately boiled for 10 min. After it was chilled
the homogenate was centrifuged at 20,000 g for 30 min at 4°C, and the
supernatant was stored at 80°C until it was used. The
supernatant was subjected to a sandwich-EIA for ET-1.
RT-PCR to determine levels of preproET-1 mRNA, ECE mRNA, and ETA- and ETB-receptor mRNA in heart and lungs. The expression of preproET-1 mRNA in the left ventricle and lungs was analyzed by RT-PCR. The expressions of ECE mRNA and ETA- and ETB-receptor mRNA in the left ventricle and lungs were also determined by RT-PCR. The expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA was determined as an internal control. Semiquantitative RT-PCR were performed according to the method described by Firsov et al. (3) with a minor modification (see below).
Total tissue RNA was isolated by acid guanidinium thiocyanate-phenol-chloroform extraction with Isogen (Nippon Gene, Toyama, Japan) according to the manufacturer's instructions. The tissue was homogenized in Isogen (100 mg tissue/1 ml Isogen) with the Polytron tissue homogenizer. The precipitated RNA was extracted with chloroform, precipitated with isopropanol, and washed with 75% (vol/vol) ethanol. The resulting RNA was resolved in diethyl pyrocarbonate-treated water, treated with DNase I (Takara, Shiga, Japan), and extracted again by Isogen to eliminate the genomic DNA. The RNA concentration was determined spectrophotometrically at 260 nm. Total tissue RNA (10 µg) was primed with 0.05 µg of oligo d(pT)12-18 and reverse transcribed by avian myeloblastosis virus RT using a first-strand cDNA synthesis kit (Life Sciences). The reaction was performed at 43°C for 60 min. The cDNA was diluted in a 1:10 ratio, and 1 µl was used for PCR. Each PCR reaction contained 10 mM Tris · HCl (pH 8.3), 50 mM KCl, 1.5 mM MgCl2, dNTP at 200 µM each, gene-specific primer at 0.5 µM each, and 0.025 U/µl Taq polymerase (Takara). The gene-specific primers were synthesized according to the published cDNA sequences for each of the following: preproET-1, ECE, ETA and ETB receptors, and GAPDH. The sequences of the oligonucleotides have been described previously (11, 13) and were shown as follows: preproET-1, 5'-TCTTCTCTCTGCTGTTTGTG-3' (sense) and 5'-TAGTTTTCTTCCCTCCACC-3' (antisense); ECE, 5'-TGGTTCTGGTGACGCTTCTG-3' (sense) and 5'-CGTTCATACACGCACGGTAG-3' (antisense); ETA receptor, 5'-ATCGCTGACAATGCTGAGAG-3' (sense) and 5'CCACGATGAAAATGGTACAG-3' (antisense); ETB receptor, 5'-GAAAAGAGGATTCCCACCTG-3' (sense) and 5'-ACGAACACGAGGCATGATAC-3' (antisense); GAPDH, 5'-GCCATCAACGACCCCTTCATTG-3' (sense) and 5'-TGCCAGTGAGCTTCCCGTTC-3' (antisense). PCR was carried out using a PCR thermal cycler (model TP-3000, Takara). The cycle profile included denaturation for 15 s at 94°C, annealing for 20 s at each suitable temperature, and extension for each suitable time at 72°C. The annealing temperature was set as follows: 54°C for preproET-1, 53°C for ECE, and 58°C for ETA and ETB receptors and GAPDH. The extension time was set as follows: 1 min for preproET-1 and 30 s for ECE, ETA and ETB receptors, and GAPDH. The reaction cycles of PCR were performed in the range that demonstrated a linear correlation between the amount of cDNA and the yield of PCR products. The PCR products were the expected size, as shown by 1.5% agarose gel electrophoresis. In addition, the specificity of the amplified sequences was confirmed by restriction enzyme analysis and DNA sequencing.Semiquantitative analysis of PCR products. The amplified PCR products were electrophoresed on 1.5% agarose gels, stained with ethidium bromide, visualized by an ultraviolet transilluminator, and photographed. The photographs were scanned by CanoScan 600 (Canon, Tokyo, Japan), and the quantification was performed by computer with MacBAS software (Fuji Film, Tokyo, Japan).
Preparation of the positive-control cDNAs of preproET-1, ECE, ETA and ETB receptors, and GAPDH. The cDNAs for the verification of the semiquantitative PCR analysis were prepared from each gene PCR product of rat cDNA. Each PCR product was purified, quantified, and used as a positive-control cDNA.
Verification of the semiquantitative PCR analysis. We performed semiquantitative PCR analysis to evaluate the expression level of preproET-1 mRNA, ECE mRNA, ETA- and ETB-receptor mRNA, and GAPDH mRNA. To demonstrate that our semiquantitative PCR strategy was valid, serial dilutions of each positive-control cDNA were amplified by PCR and quantified by scanner.
Measurement of plasma epinephrine and norepinephrine concentrations. The plasma norepinephrine and epinephrine concentrations were measured using a radioenzymatic assay based on the method of Peuler and Johnson (23). Plasma samples from each animal were examined in triplicate.
Statistics. Values are means ± SE. To evaluate differences between the control and the exercised group, Student's t-test for unpaired values was used. P < 0.05 was accepted as significant.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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There were no significant differences between the control and the exercised rats in systolic arterial pressure (125 ± 3 vs. 121 ± 3 mmHg) or heart rate (379 ± 16 vs. 387 ± 8 beats/min) on the day before the animals were killed. There was no significant difference in body weight between the two groups (Table 1). Neither the left ventricular wet weight nor the lung wet weight differed significantly between the two groups (Table 1). The left ventricle and lung weight mass indexes for body weight did not differ between the two groups (Table 1). These results indicated that the physical changes induced by 4 wk of training, which was performed for familiarization with running on a treadmill, were to the same degree in the control and the exercised group.
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Immediately after the 45-min exercise or rest, plasma concentrations of epinephrine and norepinephrine were significantly greater in the exercised than in the control rats (Fig. 1). Thus the plasma epinephrine and norepinephrine concentrations were significantly increased by the prolonged exercise.
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The relationships between the amount of cDNA and the yield of PCR products are shown in Fig. 2. There was a linear correlation between the initial amount of preproET-1 cDNA and the yield of PCR products (Fig. 2A). In the cases of ECE, ETA and ETB receptors, and GAPDH, the yield of PCR products was also in proportion to the initial amount of cDNA (Fig. 2, B-E).
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The expression of preproET-1 mRNA in the heart was markedly increased in the exercised rats (Fig. 3A). In the lungs the expression of preproET-1 mRNA did not differ significantly between the two groups (Fig. 3B). The peptide level of ET-1 in the heart was markedly higher in the exercised rats than in the control rats, whereas the peptide level in the lungs did not differ between the two groups (Fig. 4). These findings suggested that the production of ET-1 was increased tissue specifically in the heart by prolonged exercise. The expression of ECE mRNA in the heart did not differ significantly between the two groups (Fig. 5A). The expression of ECE mRNA in the lungs did not differ significantly between the two groups (Fig. 5B).
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The expression of neither ETA- nor ETB-receptor mRNA in the heart differed significantly between the two groups (Fig. 6). In the lungs the expression of ETA-receptor mRNA did not differ between the two groups, whereas the expression of ETB-receptor mRNA was significantly higher in the exercised rats than in the control rats (Fig. 7).
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The plasma concentration of ET-1 after prolonged exercise/rest was slightly but significantly higher (P < 0.01) in the exercised rats (0.83 ± 0.04 pg/ml) than in the control rats (0.63 ± 0.05 pg/ml). Therefore, the plasma ET-1 concentration was increased by the prolonged exercise.
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Cardiac myocytes (32) as well as vascular endothelial cells (35) produce ET-1. The present study revealed for the first time that the production of ET-1 in the rat heart is markedly increased by prolonged exercise, as evidenced by the increases in mRNA and peptide levels. We also demonstrated that expression of ECE mRNA, a key enzyme in the biosynthesis pathway of ET-1, in the heart of the exercised rats did not differ from that of the control rats. We therefore suspect that the increase in ET-1 production in the heart induced by exercise originated from an increase in preproET-1 production, which was not accompanied by any alteration of ECE mRNA. However, in the present study, because the protein level of preproET-1 was not measured, it is unclear whether the increase in ET-1 production is a result of an increase in preproET-1 protein. In the present study the expression of preproET-1 mRNA and the peptide level of ET-1 in the heart were markedly higher in the exercised rats than in the control rats, whereas those in the lungs did not differ between the two groups. These findings suggested that the production of ET-1 was tissue specifically increased in the heart by prolonged exercise.
The mechanism underlying the difference in the production of ET-1 between the heart and lungs by exercise remains to be elucidated. The production of ET-1 is thought to be regulated by multiple factors. Several endogenous substances, e.g., ANG II and arginine vasopressin, have been reported to augment the production of ET-1 in cultured endothelial cells (2). It is well known that plasma ANG II and arginine vasopressin levels are augmented during exercise. It has also been demonstrated that hemodynamic shear stress (which should be greatly augmented with the increase in blood flow during exercise) and endothelial stretching stimulate ET-1 production in cultured vascular endothelial cells (31, 37). In cultured ventricular myocytes it has also been shown that the expression of preproET-1 mRNA is increased by ANG II (8). Furthermore, it has been demonstrated that stretching of cardiac myocytes causes an increase in ET-1 expression (34). Although blood flow is increased by exercise in the lungs and in the heart, an exercise-induced increase in ET-1 production occurs only in the heart. Therefore, a factor other than changes in blood flow may be involved in the exercise-induced increase in ET-1 production in the heart. Taken together, the above observations and the present findings suggest that exercise-induced changes in neurohumoral and/or mechanical factors may contribute to increased production of ET-1 in the heart in vivo. In the heart, cardiac myocytes and vascular endothelial cells produce ET-1 (32, 35). Which cells are responsible for the increase in ET-1 production in the heart by prolonged exercise remains to be determined.
ET-1 has potent positive inotropic and chronotropic effects on isolated heart muscles in vitro (6, 7). We previously demonstrated that preproET-1 mRNA was increased in the heart under some pathological conditions in vivo: pressure overload to the left ventricle due to aortic banding (36) or pressure overload to the right ventricle due to pulmonary hypertension (20). We recently reported that the production of ET-1 in the heart is markedly increased in rats with chronic heart failure (25, 26). We also observed that acute intravenous infusion of BQ-123, an ETA-receptor antagonist, significantly reduced heart rate and myocardial contractility in rats with chronic heart failure, but not in normal rats under basal conditions, thus suggesting that endogenous ET-1 is involved in the modulation of cardiac function in rats with chronic heart failure (25, 26). These observations suggest that ET-1 helps support cardiac function in some pathological settings. Because the present study revealed that the production of ET-1 in the heart is markedly increased by exercise, we suspect that myocardial ET-1 is involved in the modulation of cardiac function during exercise. Alternatively, because ET-1 is a potent vasoconstrictor (16, 35) and prolonged exercise under conditions in the present study caused an increase in the circulating level of ET-1, it is likely that the postulated ET-1-dependent increase in cardiac output would be counteracted by an increased afterload due to elevated ET-1-dependent vascular resistance.
During prolonged exercise, there occurs a cardiovascular response termed "cardiovascular drift" (24), i.e., a gradual decrease in stroke volume with the decrease in plasma volume, which results from a plasma water shift into the interstitial spaces of working muscles and from sweat evaporation and a concurrent increase in the heart rate, which compensates for the decreased stroke volume. Because ET-1 has a positive chronotropic effect on the heart, the results of this study were consistent with the idea that ET-1 generated in the heart is helpful in maintaining cardiac output by increasing heart rate in cooperation with catecholamine during prolonged exercise. However, it is not clear whether cardiovascular drift occurred in the exercised rats under the conditions in the present study.
ET-1 has been shown to induce myocardial cell hypertrophy (30). Although the present study showed that the production of ET-1 in the rat heart was markedly increased by prolonged exercise, it is unclear whether the ET-1 system in the heart contributes to the hypertrophy of the myocardium by long-term exercise, i.e., in the athletic heart.
ET-1 is formed from its precursor, Big ET-1, by ECE (22). The biological activity of Big ET-1 is negligible, suggesting that ECE is a key enzyme in the biosynthesis pathway of ET-1 (10). It has been reported that the expression of ECE mRNA is increased in the vessels by vascular injury due to balloon angioplasty in rats (33), suggesting that the ECE expression is altered in some pathological conditions. In the present study the expression of preproET-1 mRNA was greatly increased in the heart of the exercised rats, whereas the expression of ECE mRNA in the heart of the exercised rats did not differ from that of the control rats. Therefore, we believe that the increase in mature ET-1 peptide in the heart induced by exercise originated from an increase in the transcription of the ET-1 gene, which was not accompanied by any alteration in the expression of ECE mRNA. In the heart rats with heart failure, we reported that preproET-1 mRNA expression increases in the absence of an increase in ECE mRNA expression (13).
There are three isopeptides of endothelin (ET-1, ET-2, and ET-3) (5,
16) and two subtypes of endothelin receptors
(ETA and
ETB) (1, 28). The affinity rank
order of endothelins for the ETA
receptor is ET-1 
ET-2 ET-3, and that for the
ETB receptor is ET-1 = ET-2 = ET-3
(27). Both subtypes of endothelin receptor have been shown to exist on
cardiac myocytes (4). We previously reported that the positive
inotropic effect of ET-1 is mediated through
ETA receptors (26). It has also
been reported that the hypertrophic effect of ET-1 on cardiocytes is
mediated through ETA receptors (8,
9, 20). We previously demonstrated that the expression of
ETA- and
ETB-receptor mRNA in the heart was
increased in rats with congestive heart failure (12), suggesting that
the expressions of ETA and
ETB receptor are altered in some conditions in vivo. In the present study, however, the expressions of
ETA- and
ETB-receptor mRNA in the hearts of
the exercise group did not differ from those of the control group.
In conclusion, we have demonstrated that the expression of preproET-1 mRNA and the mature peptide level of ET-1 in the heart were markedly higher in the exercised than in the control rats. The present study also demonstrated that the expression of ECE mRNA in the heart did not differ significantly between the two groups. The expressions of ETA- and ETB-receptor mRNA in the heart did not differ between the two groups. In the lungs the peptide level of ET-1 and the preproET-1 mRNA level in the exercised rats did not differ from those in the control rats. Thus the present study first demonstrated that the production of ET-1 was markedly increased in the rat heart tissue specifically by prolonged exercise. Because ET-1 has potent positive inotropic and chronotropic effects on the heart (6, 7), it is possible that myocardial ET-1 participates in the modulation of cardiac function during exercise.
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ACKNOWLEDGEMENTS |
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This work was supported by Grants-in-Aid for Scientific Research from Ministry of Education, Science, Sports, and Culture of Japan (8670757, 9780040, and 9770473), a grant from the Study Group of Molecular Cardiology, the Kanae Foundation for Life and Socio-Medical Science, and the Miyauchi project of the Tsukuba Advanced Research Alliance at the University of Tsukuba.
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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. §1734 solely to indicate this fact.
Address for reprint requests: T. Miyauchi, Cardiovascular Div., Dept. of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
Received 20 March 1998; accepted in final form 10 August 1998.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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