(Hypertension. 1999;34:768-772.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Exercise Reverses Peripheral Insulin Resistance in Trained L-NAME–Hypertensive Rats
From the Laboratory of Cardiovascular Physiology, Department of Physiology (K.D.A., G.G., J.F., P.D'A., V.L.A., L.R.P., T.G.F., M.C.I.), Basic and Health Science Institute, University of Rio Grande do Sul, Brazil; and the Hypertension Unit, Heart Institute (M.C.I.), São Paulo, Brazil.
Correspondence to Maria Cláudia Irigoyen, MD, PhD, Hypertension Unit, Heart Institute, São Paulo, Brazil, Av Enéas de Carvalho Aguiar, 44, São Paulo, São Paulo 05403-000. E-mail hipirigoyen{at}incor4.incor.usp.br
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Abstract |
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Abstract—Several studies have demonstrated an increase in peripheral resistance to insulin associated with hypertension. To assess the hemodynamic and metabolic effects of exercise training, normotensive and N
-nitro-L-arginine methyl
ester (L-NAME)–hypertensive male Wistar rats were submitted to
low-intensity treadmill exercise training for 10 weeks and compared
with their sedentary controls. Blood pressure signals were obtained and
processed with a data acquisition system (CODAS, 1 kHz) to evaluate
mean arterial pressure, heart rate, autonomic control of
heart rate, and baroreflex sensitivity. Exercise training induced a
nonsignificant 6.5-mm Hg decrease in mean arterial
pressure in trained hypertensive rats (163±9 mm Hg) compared
with sedentary hypertensive rats (169.5±5.5 mm Hg). The
hypertensive groups showed impairment of baroreflex function in
response to changes in arterial pressure compared with
sedentary controls. Furthermore, exercise training improved the
tachycardic response to decreasing arterial pressure and
reduced intrinsic heart rate in trained control rats compared with all
other groups. Sedentary hypertensive rats presented a decrease
in body weight compared with normotensive animals. Basal evaluation of
the glucose/insulin ratio showed increased insulin resistance in
sedentary (28.4±3) and trained (23.5±2.7) hypertensive rats compared
with sedentary control rats (40.5±3). However, the glucose/insulin
ratio evaluated during the exercise session in trained rats showed an
improvement in insulin resistance (54.5±5 for control rats and 44±9
for hypertensive rats). In conclusion, L-NAME–induced hypertension is
accompanied by an increase in insulin resistance in rats. The
improvement in peripheral insulin sensitivity during
exercise and the body weight gain observed in trained hypertensive rats
may support the positive role of physical activity in the management
of hypertension.
Key Words: insulin resistance • hypertension • exercise • autonomic nervous system • baroreceptors
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Introduction |
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Hypertension is a multifaceted medical and health problem related to morphological and functional changes in the cardiovascular system and autonomic control in humans and animals.1 There is now convincing evidence that nitric oxide (NO) is an important molecular messenger that plays a critical role in vascular relaxation, neuronal transmission, and immune modulation.2 The importance of NO for cardiovascular homeostasis is demonstrated by acute3 4 5 and chronic6 inhibition of NO synthase by N
-nitro-L-arginine
methyl ester (L-NAME), which leads to arterial
hypertension. Changes in autonomic mechanisms7 8 and
baroreflex sensitivity9 10 involved in
cardiovascular control in hypertension induced by NO
blockade have been observed. Moreover, several studies have suggested
that NO blockade is frequently associated with changes in
peripheral resistance to insulin action.11 12 13
Previous studies have demonstrated that abrogation of NO release by an
NO synthase inhibitor prevents the action of insulin
involved in increasing blood flow to skeletal
muscle.14 15 On the other hand, exercise training has been advocated in the management of hypertension because numerous studies in humans have associated lower resting blood pressure with an improvement of glucose homeostasis.16 17 18 In our laboratory, exercise training (10 weeks) applied to young, spontaneously hypertensive rats (SHR) improved baroreflex function and reduced resting arterial pressure (AP).19 20 Moreover, we demonstrated that exercise training improved the peripheral action of insulin and oxidative stress in aged, normotensive rats.21
Data from animal and human studies have provided conflicting results about the efficiency of physical training in reducing the consequences of hypertension,1 depending on animal species, age, time course, or mechanisms involved in the hypertension process. Also, there are no literature data about the effects of exercise on experimental hypertension induced by chronic inhibition of NO synthase. Therefore, the aim of the present study was to investigate the hemodynamic and metabolic changes induced by exercise training in L-NAME–hypertensive rats.
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Methods |
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Animal Care and Training Program
Twenty-five male Wistar rats from the Animal House of Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil, weighing 257±5 g, received standard laboratory chow and water ad libitum and were housed in individual cages in a temperature-controlled room (22°C) with a 12-hour dark/light cycle. All surgical procedures and protocols used were in accordance with the Guidelines for Ethical Care of Experimental Animals and were approved by the International Animal Care and Use Committee.
The rats were randomly assigned to 1 of 4 groups: sedentary normotensive (SC, n=5), trained normotensive (TC, n=6), sedentary hypertensive (SH, n=8), and trained hypertensive (TH, n=6). Hypertensive groups of animals were given L-NAME (Sigma Chemical Co) dissolved in drinking water (300 mg/L, or 40 mg · kg-1 · d-1) for 11 weeks.
Low-intensity exercise training was performed on a treadmill 5 days a week for 10 weeks, gradually progressing to a speed of 1.1 miles per hour (mph) for TC rats or 0.9 mph for TH rats (starting after 1 week of NO blockade) at a 3% grade for 60 minutes, as described in detail elsewhere. 19 22 23
Cardiovascular Evaluations
After the last training session, 2 catheters filled with 0.06 mL
of saline were implanted under ether anesthesia into the
femoral artery and vein (PE-10 for direct measurements of AP and drug
administration, respectively). Rats receiving food and water ad libitum
were studied 1 day after catheter placement; the rats were conscious
and allowed to move freely during experiments. The arterial
cannula was connected to a strain-gauge transducer (Narco Bio-Systems
miniature pressure transducer RP 1500), and blood pressure signals were
recorded during a 20-minute period by a microcomputer equipped with
an analog-to-digital converter board (CODAS, 1-kHz sampling frequency,
Dataq Instruments, Inc). The recorded data were analyzed on
a beat-to-beat basis to quantify changes in mean AP (MAP) and heart
rate (HR). Increasing doses of phenylephrine (0.5 to 2.0
µg/mL) and sodium nitroprusside (5 to 20 µg/mL) were given as
sequential bolus injections (0.1 mL) to produce pressure responses
ranging from 5 to 40 mm Hg.24 A 3- to 5-minute
interval between doses was necessary for blood pressure to return to
baseline. Peak increases or decreases in MAP after
phenylephrine or sodium nitroprusside injection and the
corresponding peak reflex changes in HR were recorded for each dose
of the drug. Baroreflex sensitivity was evaluated by fitting a
regression line through points relating the changes in HR to the
changes in MAP.
Vagal and sympathetic tonus and intrinsic HR (IHR) were studied22 by injecting methylatropine (3 mg/kg IV, Sigma) and propranolol (4 mg/kg IV, Sigma) in a maximal volume of 0.2 mL per injection. Resting HR was recorded while the rats were in their cages in an unrestrained state, and methylatropine was injected immediately after the recording. Because the HR response to these drugs reaches its peak within 10 to 15 minutes,22 this time interval was allowed to elapse before the HR measurement was made. Propranolol was injected 15 minutes after methylatropine, and again the response was evaluated after simultaneous blockade with propranolol and methylatropine. On the next day, the sequence of injections was reversed, first propranolol and then methylatropine. IHR was evaluated after simultaneous blockade with propranolol and methylatropine. Sympathetic tonus was determined as the difference between maximum HR after methylatropine injection and IHR. Vagal tonus was obtained by the difference between the lowest HR after propranolol injection and IHR.
On the third day, immediately after a 5-minute control AP recording, L-arginine (300 mg/kg, Sigma) was administered as an intravenous bolus, and AP was recorded for 40 minutes. The response to L-arginine was determined as the difference between the maximal decrease in MAP and the control values of MAP before injection of the drug.
Metabolic Evaluations
Body weight was monitored each week during the period of
physical activity. Blood samples were collected at rest in the fasted
state before and after 20 minutes of training on the treadmill (0.7
mph) during the 10th week from the beginning of the exercise protocol
for all groups. Plasma glucose and insulin were measured by a
colorimetric enzymatic test (Enz Color, Bio
Diagnostica) and by radioimmunoassay (ICN Pharmaceuticals,
Inc), respectively.
Data Analysis
Data are reported as mean±SEM, and 2-way ANOVA was used to
compare groups, followed by the Student-Newman-Keuls test. Correlations
were determined by linear regression analysis.
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Hemodynamic Measurements
All 14 rats given L-NAME developed severe hypertension compared with controls, although a nonsignificant 6.5-mm Hg decrease in MAP was observed in TH rats (163±9 mm Hg) compared with SH rats (169.5±5.5 mm Hg; Table 1). Control and hypertensive rats presented similar resting HR values. The hypertensive groups presented lower baroreflex sensitivity than did control rats, as expressed by the slope of the regression line (Figure 1). Moreover, exercise training increased the tachycardic response of TC rats compared with SC rats (Figure 1). The autonomic control of HR and IHR did not differ among groups, except in TC animals, which presented a lower IHR (370±6 bpm; Table 1). After blockade with propranolol, MAP increased in all groups, but no statistical difference was observed in SC rats. This increase was larger in trained rats (14±5 for normotensive and 24±4 mm Hg for hypertensive animals) than in their sedentary controls (7±4 for normotensives and 15±1 mm Hg for hypertensives).
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The response to L-arginine was higher in hypertensive rats (-24±8 mm Hg for SH and -20±11 mm Hg for TH) than in normotensive rats (-6.2±1.3 mm Hg), and a positive correlation was obtained by linear regression between resting MAP and maximum decrease in MAP after L-arginine, with a greater decrease in MAP at higher resting MAP (r=0.8; Figure 2).
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Metabolic Measurements
Plasma glucose concentration measured in the resting state was
higher in TC than in TH rats but similar to that for the SC group. On
the other hand, plasma insulin values at rest were higher in TH than in
SC rats but similar to those for the TC group. Exercise-induced
glycemia increased in hypertensive rats, and plasma insulin levels
decreased in TC and TH animals, compared with resting values. In this
situation, the normotensive groups presented similar plasma
glucose values, and the sedentary groups did not present
significant differences in plasma insulin levels. The glucose-insulin
(G/I) ratio evaluated at rest was lower in HC than in SC rats. During a
bout of exercise, the G/I ratio increased in both TC and HC groups, but
no changes were observed within the sedentary groups (Table 2). Body weight was similar in all groups
at the end of the training program (351±13 g for SC, 348±19 g for TC,
and 300±10 g for TH) except for the SH rats (284±9 g).
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Discussion |
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The main findings of the present study were that rats with L-NAME–induced hypertension showed increased peripheral insulin resistance and, when submitted to exercise training, (1) no changes in blood pressure, HR, or baroreflex sensitivity; (2) increased body weight gain; and (3) reversal of insulin resistance during a bout of exercise.
There are several conflicting studies in the literature about the effect of exercise on hemodynamic parameters of hypertensive individuals.1 7 8 9 10 The variable effects of exercise training on resting blood pressure seem to be due to a lack of standardization of how the exercise is prescribed or evaluated in different hypertensive subjects, whose physiopathological processes depend on different mechanisms of regulation.25 26 27 28 In the present study, low-intensity–trained, L-NAME–hypertensive rats showed no changes in HR and slight but nonsignificant changes in blood pressure. Previous studies have demonstrated that exercise training decreased resting HR in SHR,19 20 normotensive rats,21 and humans.1 These changes were explained by a reduced sympathetic activity to the heart in SHR and by a decrease in IHR in normotension.19 20 According to these reports, the autonomic blockade used in the present experiment induced a reduced IHR in TC rats, whereas no changes were observed in sympathetic tonus to the heart in L-NAME–hypertensive trained or untrained rats. The lack of substantial evidence for an L-NAME–dependent increase in sympathetic tonus is in agreement with other studies that showed variable results, depending on the dose and time of exposure to NO blockade.7 8 L-NAME treatment may induce variable sympathoecxitatory effects with regional differences.8 29 The previous observation that acute or chronic administration of L-arginine analogues to rats raises renal,30 31 splanchnic,32 and mesenteric33 vascular resistance seems to indicate the predominance of vasoconstrictor over vasodilator activity in the microcirculation, causing a large fraction of the arterial hypertension observed. In fact, arterial hypertension and diminished single-nephron glomerular filtration rate, which may be related to changes in renal vascular resistance, were demonstrated in rats given L-NAME orally for 2 months.34 These alterations suggest that NO plays a crucial role in the long-term regulation of systemic blood pressure in the rat. Probably the slight reduction in resting blood pressure of L-NAME–hypertensive rats after exercise training observed in this study was related to the specific changes in peripheral resistance induced by chronic exposure to L-NAME, blunting the adaptive vasodilation of the muscle vascular bed35 during and after an exercise period. Therefore, we could not expect a lowering of resting blood pressure in L-NAME–treated, trained animals, as previously described by Tipton et al36 for Dahl rats and by Gava et al19 for SHR. Different mechanisms of autonomic regulation such as baroreflex control of HR are impaired in hypertension induced by L-NAME8 9 10 and do not change after exercise training. Indeed, the improvement of the tachycardic response to AP reduction occurring in trained control rats that has been attributed to an increased sensitivity of the afferent pathway of the baroreceptors37 was not observed in TH rats. It suggests that the impairment of baroreflex sensitivity induced by L-NAME hypertension in rats was not reversed by exercise training.
An interesting finding in our experiments was the pressor effect of
propranolol, observed in the trained and hypertensive
groups. This paradoxical effect of nonselective ß-blockers could be
explained by 
-receptor–mediated vasoconstriction unopposed by
ß-receptor–mediated vasodilatation.38 In situations of
increased sympathetic activity, as in hypertension,29 this
mechanism may override the hypotensive properties of nonselective
ß-blockers. In trained rats, the elevated sensitivity of
ß-adrenoceptors39 may contribute to the pressor response
to propranolol, suggesting a major importance of these
receptors in maintaining vascular tonus in exercise, promoting high
vasodilatation when the flow demand is increased.40
Several articles have shown that NO blockade may lead to increasing resistance to the peripheral action of insulin.11 12 13 14 15 On the other hand, exercise training may reduce insulin resistance associated with lower blood pressure values.41 In the present study, we found higher resting plasma insulin associated with lower plasma glucose in hypertensive subjects, demonstrating a decrease in insulin sensitivity as expressed by an increase in the G/I ratio. However, the measurements performed after 20 minutes of exercise as expressed by the G/I ratio indicated a significant decrease in insulin resistance in the trained groups. This finding is in agreement with other evidence showing that the increased insulin action in the trained state is due to an enhanced sensitivity to insulin.42 The physiological importance of this increased insulin sensitivity during a bout of exercise is related to the maintenance of this improvement in the postexercise period.43 Because L-NAME may block both glucose transporter translocation (glut 4) and exercise-stimulated glucose transport,44 we speculate that the improvement in the G/I ratio in TH rats (90% versus 40% for the TC group) may be related to exercise-induced changes in the NO system.
A decrease in body weight usually occurs in trained subjects,21 27 although many studies have reported unchanged body weight after a physical program.36 42 L-NAME treatment impairs body weight gain, suggesting a metabolic disorder.6 Our findings are in agreement with these data, as shown by the increase in body weight of TH rats compared with untrained animals, indicating an improvement of metabolic status in trained, hypertensive subjects.
In this study, the changed glucose homeostasis in hypertensive rats may have been related to the suppression of the vasodilatory action of endothelial NO, impairing glucose utilization by decreasing the delivery of glucose and insulin to the muscle vascular beds.35 If exercise training improves glucose utilization but does not reduce resting blood pressure or sympathetic tonus, maintaining an increased, peripheral vascular resistance in L-NAME–hypertensive rats, how can we expect improvement in flow-dependent delivery of glucose or insulin to the muscle in the exercise situation? The positive correlation (Figure 2) established between falls in blood pressure induced by L-arginine injection and resting blood pressure indicates that higher blood pressure values are associated with marked falls in AP. Moreover, when we compared the falls in AP as a percentage of resting AP, only SH rats were found to differ from normotensive rats (-14.5±0.9% versus 6.2±1.3%), suggesting that exercise training in hypertensive rats had changed NO synthase blockade (10.7±2%).
In summary, physical training did not modify resting blood pressure, HR, baroreflex attenuation, or increased peripheral insulin resistance at rest in L-NAME–hypertensive rats. However, enhanced insulin sensitivity during a bout of exercise suggests that exercise training associated with increased body weight gain and with the differences in response to L-arginine induced an improvement of hemodynamic and metabolic status in L-NAME–hypertensive rats. These data may support the importance of the role of physical activity in the management of hypertension.
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Acknowledgments |
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This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Financiadora de Estudos e Projetos (FINEP), and Fundação de Amparo a Pesquisa do Estado do Rio Grande do Sul (FAPERGS). The authors are grateful to Inbramed Ltda for its technical support in physical training equipment.
Received May 10, 1999; first decision July 1, 1999; accepted July 28, 1999.
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