Vol. 276, Issue 3, H970-H975, March 1999
Hypotension induced by exercise is associated with enhanced
release of adenyl purines from aged rat artery
M.
Hashimoto1,
K.
Shinozuka2,
Y.
Tanabe1,
S.
Gamoh1,
T.
Hara1,
M. S.
Hossain1,
Y. M.
Kwon2,
M.
Kunitomo2, and
S.
Masumura1
1 Department of Physiology,
Shimane Medical University, Izumo, Shimane 693-8501; and
2 Department of Pharmacology,
Faculty of Pharmaceutical Science, Mukogawa Women's University,
Nishinomiya 663-8179, Japan
 |
ABSTRACT |
To determine
whether the antihypertensive effects of exercise are associated with
release of ATP and its metabolites from arteries, we assayed blood
pressure and the release of adenine nucleotides and nucleosides from
the caudal arteries of exercised and sedentary aged
hypercholesterolemic rats. Exercise on a treadmill for 12 wk
significantly decreased the rise in systolic and diastolic blood
pressure by 7.5 and 15.9%, respectively, with advanced age. The
concentrations of oleic, linoleic, and linolenic acids in the caudal
artery decreased significantly with exercise, demonstrating an
association between exercise and the unsaturation index of caudal
arterial fatty acids. The amounts of total adenyl purines released by
the arterial segments from exercised rats, both spontaneously and in
response to norepinephrine, were significantly greater by 80.0 and
60.7%, respectively, than those released by tissues from sedentary
rats. These results suggest that exercise alters the membrane fatty
acid composition in aged rats as well as the release of ATP from
vascular endothelial cells and that these factors are associated with
the regression of the rise in blood pressure normally observed with
advanced age.
adenosine 5'-triphosphate release; blood pressure; arterial
fatty acids
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INTRODUCTION |
EXERCISE DECREASES blood
pressure in hypertensive animals and humans (13, 28) at least partially
by inducing body weight loss and changes in prostaglandin metabolism
(19). We showed (15) that treadmill exercise slightly increases the
endothelium-dependent relaxation responses to ACh in thoracic aortas
isolated from young rats but does not affect those from older rats. In
addition, chronic exercise enhances endothelium-dependent
vasodilatation (8, 36) and increases the expression of endothelial
nitric oxide (NO) synthase (9, 30). Taken together, these findings
suggest that exercise may affect vascular mechanical responses by
altering endothelial cell functions.
Using endothelial cells isolated from rat caudal arteries, we (16)
showed that the amount of ATP released in response to 
1-adrenoceptor stimulation
decreases with advancing age and that this extracellular ATP, together
with its metabolites, participates in blood pressure changes associated
with aging. ATP causes vasodilatation by stimulating the release of
NO/endothelium-derived relaxing factor from endothelial cells (11) and
by hyperpolarizing smooth muscle cells (25). Adenosin enhances
vasodilatation by direct action on vascular endothelial (21) and smooth
muscle (4) cells. These purines derive primarily from endothelial cells
and, to a lesser extent, from smooth muscle cells (32). In addition, ATP, which rapidly degrades to ADP, AMP, and adenosine in vascular tissues, probably by ectonucleotidases, is thought to be the origin of
released purines (29). On the other hand, a high rate of ATP breakdown,
such as occurs during exercise, results in high levels of adenosine
(1). Therefore, if elevated postexercise adenine nucleotides and
adenosine in extracellular spaces of vascular tissues persist as part
of the body's adaptation to exercise, the antihypertensive effect of
exercise on blood pressure may be associated with an augmentation of
ATP release from vascular beds.
In patients with hypercholesterolemia, arterial vascular responses are
frequently altered, with both conduit and resistance vessels
manifesting impaired endothelial cell functions (5). In
addition, an association between hypertension and hypercholesterolemia was observed in a number of populations (34) and in aged rats (15, 16).
To clarify the beneficial effects of exercise, we assayed the release
of adenine nucleotides and nucleosides from the caudal arteries of aged
rats and correlated the release of ATP and its metabolites with the
effect of exercise on blood pressure and serum cholesterol.
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MATERIALS AND METHODS |
Animals.
All animal experiments were performed in accordance with the Guidelines
for Animal Experimentation of Shimane Medical University, compiled from
the Guidelines for Animal Experimentation of the Japanese Association
for Laboratory Animal Science. Female Wistar rats (100-105 wk old)
were fed a normal laboratory diet [F1 diet (in g/kg): 50 carbohydrate, 213 protein, 51 lipid, 31 fiber, 575 nitrogen-free
extract, and 80 water; total energy 42 kcal/g, Funabashi Farm, Chiba,
Japan], maintained at 23 ± 2°C in relative humidity of 50 ± 10% with automatic lighting from 0800 to 2000, and
weighed. Systolic blood pressure (SBP) and mean blood
pressure were measured by the tail-cuff plethysmographic method
(UR-1000, Ueda, Tokyo, Japan), and the diastolic blood pressure (DBP)
was calculated as previously described (16). The rats were then fed a
high-cholesterol diet (F1 diet containing 1% cholesterol and 1%
cholic acid, Funabashi Farm) and randomly divided into two groups. One
group (11 exercised rats) was exercised 1 h/day, 5 days/wk, on a
treadmill with a gradient of 10° at 5-15 m/min during the
first 4 wk and at 15 m/min over the next 8 wk (15). The other group (17 sedentary rats) was only handled for 2-3 min daily, 5 days/wk for
12 wk. The rats were kept in small individual cages (20 cm long × 14 cm wide × 14 cm high).
Within at least 24 h of the last run and after an 18-h overnight
fasting period, the rats were weighed and their blood pressure was
measured by the plethysmographic method. The rats were anesthetized with pentobarbital sodium (65 mg/kg ip); blood was collected from the
inferior vena cava into heparinized syringes, transferred to
polyethylene tubes containing 1 mmol/l EDTA, and centrifuged for 20 min
(3,000 rpm) at 4°C.
Plasma samples were assayed for platelet contamination with an
automated hematology analyzer
(<103/µl; K-2000, Toa Medical
Electronics, Kobe, Japan), and plasma levels of ATP, ADP, AMP, and
adenosine were measured by HPLC with fluorescence detection.
Tissue preparation and purine release.
Tissue preparation and purine release were carried out as previously
described (16). After blood collection, we removed a maximal segment
~(8-13 cm, 20-30 mg wet wt) of the caudal artery, cleaned
it of connective tissue while taking care not to damage the
endothelium, and suspended the segment in a water-jacketed organ
chamber containing 2.0 ml of modified Krebs solution (in mmol/l: 110 NaCl, 4.6 KCl, 2.5 CaCl2, 24.8 NaHCO3, 1.2 KH2PO4, 1.2 MgSO4, and 5.6 glucose,
equilibrated with 95% O2-5%
CO2) at 37°C for 60 min; the
solution was replaced every 3 min during the last 30 min.
After the 60-min equilibration period, the bathing solution was
collected by draining the organ chamber every 3 min. After the first
sampling to determine spontaneous release for 3 min, the tissue was
stimulated with 1 µmol/l norepinephrine for 3 min and the bathing
solution (stimulation sample) was collected. The samples were processed
for determination of ATP, ADP, AMP, and adenosine by HPLC fluorescence.
After the release experiments, the arteries were stored in
80°C until total fatty acids were measured.
Plasma cholesterol and nitrogen oxide concentrations.
Concentrations of total and free cholesterol in plasma were determined
with the Cholesterol E-test and Free Cholesterol E-test kits (Wako Pure
Chemical, Osaka, Japan), respectively. The plasma nitrogen oxide (NOx;
nitrite/nitrate) concentration was assayed by a modification of the
method of Misko et al. (24). Briefly, plasma was incubated with NADPH
and Aspergillus niger nitrate reductase (Sigma Chemical, St. Louis, MO) and subsequently with 2,3-diaminonaphthalene (Dojindo Labs, Kumamoto, Japan). Fluorescence intensity was measured with a Hitachi 850 fluorescence spectrometer (Hitachi, Tokyo, Japan). Nitrite standards (>98% pure, Sigma
Chemical) were freshly prepared.
Fatty acid content of plasma and tissue samples.
Fatty acid levels in plasma were assayed by a modification of the
one-step reaction of Lepage and Roy (20). A mixture of 100 µl of
plasma, 2 ml methanol-toluene (4:1, vol/vol, containing 10 µg of
tricosanoic acid as an internal standard), and 200 µl of acetyl
chloride was incubated at 100 for 60 min; 6% aqueous potassium
carbonate containing 10% sodium chloride was then added, and the whole
mixture was shaken for 10 min at room temperature and centrifuged at
1,800 g for 5 min. The toluene phase,
containing the fatty acid methyl esters, was directly subjected to gas
chromatography (GC) on a model 5890 II gas chromatograph
(Hewlett-Packard, Avondale, PA) equipped with a flame ionization
detector and an automatic sampler (model 7673) and utilizing a 25-m × 0.25-mm ID fused-silica column (DB-WAX P/N 122-7032, J & W
Scientific, Folsom, CA) programmed from 100 to 180°C at 20/min, 180 to 240°C at 2°C/min, 240 to 260°C at 4°C/min, and at
260°C for 5 min. The identities of the peaks were established by
comparison with the peaks of reference compounds and, in part, by JMS-D
300 gas chromatography-mass spectrometry (Jeol, Tokyo, Japan).
Fatty acid levels in caudal arteries were measured by a similar
procedure. The stored caudal arteries (10-20 mg), transferred to a
capsule precooled in liquid N2,
were crushed using an amalgam mixer (UT-1600, Sharp, Osaka, Japan) and
suspended in 200 µl of phosphate-buttered saline [Dulbecco's
PBS()] containing 0.005% butylated
hydroxytoluene. The fatty acid content of 100 µl of this
suspension was analyzed by GC as described above.
Fatty acid content was expressed as milligrams per deciliter of plasma
or micrograms per gram of tissue wet weight. The average degree of
fatty acid unsaturation (the unsaturation index) was calculated as the
average number of double bonds per fatty acid residue multiplied by 100.
Statistical analysis.
Results are expressed as means ± SE. Data were evaluated by
regression analysis and by paired and unpaired Student's
t-tests, using the computer program
Stat View II (Abacus Concepts, Berkeley, CA). A level of
P < 0.05 was accepted as
statistically significant.
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RESULTS |
Body weight, food intake, and cardiovascular parameters.
We observed no significant difference in body weight before and after
treadmill exercise or food intake during the experimental period
between exercised and sedentary rats (Table
1). The SBP and DBP of sedentary aged rats
increased significantly after 12 wk; however, the blood pressure of
exercised rats did not change. Exercise increased heart weight
significantly (P < 0.05), and the
heart rate showed a tendency to decrease (0.05 < P < 0.1) (Table 1).
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Table 1.
Body weight, food intake, systolic and diastolic blood pressure, heart
weight, and heart rate in sedentary and exercised aged rats with
hypercholesterolemia
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During the experiments, the mortality of exercised rats was 0 of 11 and
that of nonexercised rats 1 of 17. Therefore, it is unlikely that the
mortality would be increased by the exercise in the present experiments.
Plasma cholesterol and NOx concentrations.
Although the level of total and free cholesterol tended to be lower in
the plasma of exercised rats than in that of sedentary rats, the
difference was not statistically significant (Table 2). In addition, plasma NOx concentrations
in aged rats were not affected by exercise (Table 2).
Fatty acid profiles in plasma and caudal arteries.
In plasma, exercise did not produce a significant decrease in linoleic
or linolenic acid (Table 3). Also, neither
the other fatty acids (palmitic acid, oleic acid, arachidonic acid,
eicosapentaenoic acid, and docosahexaenoic acid) nor the unsaturation
index, a measurement of the average number of double bonds (35),
altered significantly with exercise.
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Table 3.
Effect of exercise training on levels of plasma and caudal arterial
fatty acids in aged rats with hyperlipidemia
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In the caudal arteries of these aged rats, the concentrations of oleic
acid, linoleic acid, and linolenic acid decreased significantly with
exercise (P < 0.05), but the other
fatty acids did not alter significantly (Table 3). On the other hand,
exercise significantly increased the unsaturation index
(P < 0.05) of caudal arterial fatty
acids (Table 3).
Release of adenine nucleotides and nucleosides from caudal artery.
Measurement of the amount of adenine nucleotides and nucleosides
spontaneously released from the caudal arteries over a 3-min period
demonstrated a significantly higher release of total adenyl purines
(ATP, ADP, AMP, and adenosine) from the arteries of exercised rats than
from those of sedentary rats (Fig. 1).
Treatment of these tissue samples with 1.0 µmol/l norepinephrine for
3 min increased the release of total adenyl purines; the amount
released from the arteries of exercised rats was also significantly
higher than that from the arteries of sedentary rats (Fig. 1).
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Fig. 1.
Release of adenyl purines from caudal arteries of sedentary and
exercised aged rats. Purine release was measured over 3 min. S,
sedentary rats (n = 16); Ex, exercised
rats (n = 11); NE, norepinephrine.
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Regression analysis of the relationship between the amount of adenyl
purine released in vitro and the level of arterial fatty acids showed a
significantly negative correlation between norepinephrine-induced purine release and the level of arterial oleic acid
(r = 0.393, P = 0.0316). Although there was a
significant positive correlation between purine released in response to
norepinephrine and fatty acid unsaturation index (Fig.
2), the correlation between spontaneous purine release and unsaturation index, although positive, was not
statistically significant.
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Fig. 2.
Relationship between unsaturation index of caudal arterial fatty acids
and NE-induced release of total of 4 purine compounds (ATP, ADP, AMP,
and adenosine) from caudal arteries of aged rats. Purine release was
measured over 3 min.  ,  , sedentary and exercised aged rats,
respectively.
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Plasma levels of adenine nucleotides and adenosine.
The levels of adenine nucleotides and nucleosides in plasma revealed
that in aged rats exercise did not produce a statistically significant
increase (0.05 < P < 0.1) in total
plasma concentrations of these purines (Fig.
3). Regression analysis revealed a
significant positive relationship between plasma purine levels and the
norepinephrine-induced release of adenyl purines from rat caudal
arteries (r = 0.636, P = 0.0005).
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Fig. 3.
Plasma concentrations of adenyl purines in sedentary and exercised aged
rats; n = 16 (sedentary rats) and 11 (exercised rats).
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Relationship between blood pressure and adenyl purines.
Regression analysis of the relationship between blood pressure and the
amount of plasma adenyl purines demonstrated a significantly negative
correlation between SBP and plasma purine concentration (r = 0.473,
P = 0.0147) and also a significantly
negative correlation between purine release (spontaneous or
norepinephrine-induced) and blood pressure (Table
4).
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Table 4.
Correlations between spontaneous and NE-induced release of 4 purine
compounds from caudal arteries and blood pressure in sedentary
and exercised aged rats
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DISCUSSION |
We have shown here that 12 wk of treadmill exercise depressed the rise
in SBP and DBP normally observed in hypercholesterolemic aged rats.
During exercise, one of the factors that affects arteriolar resistance
is the increased blood flow to skeletal muscles to meet the increase in
metabolic demand. Miller et al. (23) showed that increased blood flow
enhances the endothelium-dependent relaxation induced by ACh and ADP in
canine femoral arteries. In addition, the frictional force caused by an
acute increase in blood flow results in shear stress, leading to
relaxation of the underlying vascular smooth muscle (7) and to an
increase in the production of NO, an endothelium-derived relaxing
factor and a powerful vasodilator. Delp et al. (10) observed that 10 wk
of treadmill exercise enhances the sensitivity and maximal
endothelium-dependent relaxation of abdominal aortas of male
Sprague-Dawley rats to ACh. In contrast, although we found that
treadmill exercise for 12 wk produced a tendency toward increased
ACh-induced endothelium-dependent relaxation of thoracic aortas from
young female Wistar rats, the sensitivity to ACh was decreased by
exercise in aged rats (15) and was not affected in aged
hypercholesterolemic animals (data not shown).
Although other researchers have reported that NO production by coronary
circulation increases with exercise (40), our study showed that plasma
NOx concentration, an index of NO production, was not affected by
treadmill exercise. This discrepancy may be related to the strain, sex,
and/or age of the rats and/or to the relaxation
response to ACh in the vascular beds. Although NO is involved in
lowering vascular resistance locally in certain vascular beds (37),
measuring plasma NOx concentration may not be sensitive enough to
detect local changes. Further experiments are needed to clarify whether
NO participates in the blood pressure-lowering effect induced by
exercise training.
ATP is another endothelial cell factor released by increased blood flow
and shear stress (2). We also reported (32) that a large amount of ATP
is released from vascular endothelial cells by
1-adrenoceptor stimulation. ATP
and ADP induce endothelium-dependent vasodilatation in precontracted
arteries by binding to P2y
and/or P2u purinoceptors,
(6) and adenosine induces direct vasodilatation in arterial endothelial
(21) and smooth muscle cells by binding to
A2 purinoceptors (4, 6). In
addition, both ATP and adenosine acting via
P3 purinoceptors reduce
norepinephrine release from vascular sympathetic nerves (31).
Adrenergic nerve stimulation induces the release of large amounts of
ATP from extraneuronal sites of blood vessels via
1-adrenoceptors (29, 38), and these released purines act as autocrine and paracrine stimulators of
blood vessel tone (39). The release of these endogenous adenyl purines
from the arteries may produce vasodilatation via
P2y, A2, and
P3 purinoceptor stimulation and
thus decrease blood pressure. Our findings of increased adenyl purine
release from the arteries of exercised rats and of an inverse
relationship between purine release and the increases in SBP and DBP
normally observed in aging rats suggest that ATP and its metabolites
ADP and adenosine, which are released from vascular endothelium, may
participate in blood pressure control in exercised rats.
Our findings showed a negative correlation between plasma adenyl purine
levels and blood pressure associated with aging (16) or exercise (this
study). Plasma concentrations of epinephrine and norepinephrine
increase during the initial stages of exercise training and are
significantly lower in trained rats at rest compared with untrained
rats (18). Purines released from the vascular endothelium act on
purinoceptors on adrenergic nerve terminals to reduce the release of
norepinephrine (33). These findings thus suggest that sympathetic
nervous activity in response to exercise may be, at least partially,
negatively regulated by the ATP released from vascular endothelial cells.
A second important finding that emerges from this study is the decrease
in fatty acids (i.e., oleic, linoleic, and linolenic acids) observed in
caudal arteries of exercised rats, resulting in an increase in the
unsaturation index. These results are consistent with those of Ohkubo
et al. (26) showing that swimming exercise markedly reduces the
linoleic acid content in both the iliac artery and the aorta, leading
to significant increases in the unsaturation index of their vascular
beds. Although daily injections of catecholamines reduce the linoleic
acid content in heart muscle, these animals also exhibit reduced body
weight (12). In contrast, we demonstrated that the decrease in fatty
acids associated with treadmill exercise had no effect on body weight
or food intake in aged rats.
Selective changes in the number and/or affinity of
1-adrenoceptors in arterial
endothelial cells appear to play an important role in altering ATP
release. Many researchers have demonstrated that changes in membrane
unsaturated fatty acid composition correlate with changes in membrane
fluidity that ultimately affect cell function. For example, after
esterification and subsequent incorporation into the cell membrane,
-3 polyunsaturated fatty acids modify the fluid mobility gradient of
the phospholipid bilayer (14, 22). Moreover, supplementation with
polyunsaturated fatty acids that increase "membrane fluidity"
enhances the coupling between 
-adrenergic receptors and adenylate
cyclase (27) and membrane-associated 5'-nucleotidase and
adenylate cyclase activities (3).
We recently showed (17) that administration of
cis-5,8,11,14,17-eicosapentaenoic acid
(EPA), an -3 polyunsaturated fatty acid, increases ATP release from
the caudal artery and arterial EPA concentration and is associated with
the repression of the blood pressure rise seen in aged
hypercholesterolemic rats. These results, together with our finding
that exercise caused an increase in the unsaturation index of fatty
acids in the caudal arteries of aged rats, suggest that the
exercise-induced enrichment of membrane lipid unsaturated fatty acids
may be associated with changes in membrane fluidity, as well as the
number and affinity of membrane
1-adrenoceptors, and that this
may lead to enhanced ATP release from rat caudal arteries. In addition,
because ATP and its metabolites can produce vasodilatation, the
enhanced ATP release from vascular endothelial cells may reduce total
peripheral resistance and blood pressure. Thus arterial endothelial
adaptations to exercise may have important implications for the
prevention and treatment of cardiovascular disease.
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ACKNOWLEDGEMENTS |
This work was supported in part by a Grant-in-Aid for Scientific
Research (C)(2) from the Ministry of Education, Science and Culture,
Japan and by a Grant for Biomedical Research from the Smoking Research
Foundation of Japan.
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FOOTNOTES |
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: S. Masumura, Dept. of Physiology, Shimane
Medical Univ., Izumo 693-8501, Japan.
Received 11 May 1998; accepted in final form 17 November 1998.
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Abstract
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