Published online before print July 30, 2007, doi: 10.1161/HYPERTENSIONAHA.107.095000
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(Hypertension. 2007;50:786.)
© 2007 American Heart Association, Inc.
XVIIth Scientific Meeting of the Inter-American Society of Hypertension |
Role of Exercise Training in Cardiovascular Autonomic Dysfunction and Mortality in Diabetic Ovariectomized Rats
From the Hypertension Unit (S.B.C.S., K.F., J.P., C.M., B.R., L.E.S., M.-C.I.), Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil; Human Movement Laboratory (K.D.A.), São Judas Tadeu University, São Paulo, Brazil; and the Nephrology Department (S.B.C.S., C.M.), Federal University of São Paulo, São Paulo, Brazil.
Correspondence to Kátia De Angelis, Human Movement Laboratory, São Judas Tadeu University, Av Taquari, 546, São Paulo, São Paulo, Brazil 03166-000. E-mail prof.kangelis{at}usjt.br
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Abstract |
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Diabetes and menopause markedly increase the risk of cardiovascular disease in women. The objective of the present study was to investigate the effects of exercise training on cardiovascular autonomic dysfunction and on total mortality in diabetic female rats undergoing ovarian hormone deprivation. Female Wistar rats were divided into ovariectomized groups: sedentary and trained controls and sedentary and trained diabetic rats (streptozotocin, 50 mg/kg IV). Trained groups were submitted to an exercise training protocol on a treadmill (8 weeks). The baroreflex sensitivity was evaluated by heart rate responses to arterial pressure changes. Heart rate variability was determined using the SD of the basal heart rate. Vagal and sympathetic tonus were evaluated by pharmacological blockade. Diabetes impaired baroreflex sensitivity (
55%), vagal tonus (68%), and heart rate variability (38%). Exercise training improved baroreflex sensitivity and heart rate variability in control and diabetic groups in relation to their sedentary groups. Trained control rats presented increased vagal tonus compared with that of sedentary ones. The sympathetic tonus was reduced in the trained diabetic group as compared with that of other studied groups. Significant correlations were obtained between heart rate variability and vagal tonus with baroreflex sensitivity. Mortality, assessed during the training period, was reduced in trained diabetic (25%) rats compared with mortality in sedentary diabetic rats (60%). Together, these findings suggest that decreases in baroreflex sensitivity and heart rate variability may be related to increased mortality in female diabetic subjects and that improved autonomic regulation induced by exercise training may contribute to decreased mortality in this population.
Key Words: exercise training • autonomic function • mortality • menopause • diabetes
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Introduction |
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Diabetes mellitus (DM) greatly increases the risk for cardiovascular disease in premenopausal and postmenopausal women.1–3 During menopause, the risk of DM increases significantly in women.4
Autonomic neuropathy is a frequent complication of DM associated with high morbidity and mortality in symptomatic patients,5 which affects the autonomic modulation of the sinus node, reducing heart rate variability (HRV) and impairing baroreflex sensitivity (BRS).6,7 Estrogen deprivation also induces autonomic impairment in fertile young woman8 and postmenopausal women,8,9 thus increasing cardiovascular risk.
Because the Women’s Health Initiative has encouraged medical practitioners to reconsider the hormone replacement therapy risks and benefits to each woman, the significance of lifestyle and its impact on cardiovascular function for menopausal management are of increasing relevance. In this sense, multiple studies have led to the rational suggestion that exercise favorably influences cardiovascular risk factors associated with pathologic situations. A recent systematic review of randomized, controlled trials reported benefits of exercise on body weight, bone constitution, muscle strength and endurance, flexibility, oxygen consumption, arterial pressure (AP), and metabolic control after menopause.10 Jurca et al11 reported an increase in HRV after 8 weeks of exercise training in postmenopausal women. We demonstrated recently that exercise training in ovariectomized (OVX) female rats improved resting hemodynamic status and BRS probably associated with oxidative stress reduction.12 Furthermore, we have used the experimental model of diabetes induced by streptozotocin (STZ) to study disorders of the autonomic control of the cardiovascular system, as well as the benefits of exercise in these dysfunctions in male rats.13–15 Indeed, we demonstrated that exercise training applied to male rats attenuated the STZ diabetic-induced impairment in cardiac function, basal hemodynamic, baroreflex, and chemoreflex control of circulation. However, the effects of exercise training on cardiovascular and autonomic function, as well as on mortality, in diabetic female rats undergoing estrogen deprivation are unknown. Therefore, the purpose of the present study was to test the hypothesis that 8 weeks of exercise training would improve autonomic control of the cardiovascular system in diabetic OVX female rats. A secondary aim was to test the hypothesis that the hemodynamic and autonomic changes induced by exercise training, if observed, would be associated with reduced mortality in diabetic OVX rats.
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Methods |
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Animals
Experiments were performed on female virgin Wistar rats (249±4 g) from the animal care facility of the University of São Paulo. The rats received standard laboratory chow and water ad libitum. They were housed in individual cages in a temperature-controlled room (22°C) with a 12-hour dark/light cycle. All of the rats were treated similarly in terms of daily manipulation. All surgical procedures and protocols used were approved by University of Sao Paulo Ethical Committee and were conducted in accordance with National Institutes of Health Guide for the Care and Use of Laboratory Animals. The rats were randomly assigned to 1 of 4 groups of OVX rats: sedentary control (SO; n=8), trained control (TO; n=8), sedentary diabetic (SDO; n=20), and trained diabetic (TDO; n=16). Mortality was investigated during the last 8 weeks of protocol in all of the animals and assessment began after ovariectomy (1 week), avoiding the influence of anesthesia or surgical procedure stress. Other evaluations were performed in all of the nondiabetic rats and in 7 rats of each diabetic group.
Diabetes
Animals were made diabetic by a single injection of STZ (50 mg/kg IV; Sigma Chemical Co) dissolved in citrate buffer (pH 4.5) after 6 hours of fasting. Blood samples (50 µL) were collected to measure glycemia 72 hours after the STZ injection and at the end of the protocol with a Gluco test (Advantage, Roche Laboratories).13,15
Ovariectomy
Fifteen days after STZ injection, animals were anesthetized (80 mg/kg ketamine and 12 mg/kg xylazine IP), the oviduct was sectioned, and the ovaries were removed as described in detail elsewhere.12
Exercise Training
Sedentary and trained female rats were adapted to the treadmill (10 minutes per day; 0.3 km/h) for 1 week. All of the animals were submitted to a maximal treadmill test12,15–17 to determine aerobic capacity and exercise training intensity1 at beginning of the experiment and2 in the eighth week of the training protocol. Exercise training (1 week after ovariectomy) was performed on a motorized treadmill at low-moderate intensity ( 50% to 70% maximal running speed) for 1 hour a day, 5 days a week for 8 weeks, with a gradual increase in speed from 0.3 to 1.2 km/h.12
Cardiovascular Assessments
After the last training session (11 weeks after STZ injection), 2 catheters filled with 0.06 mL of saline were implanted into the carotid artery and jugular vein of the anesthetized rats (80 mg/kg ketamine and 12 mg/kg xylazine, IP). Rats received food and water ad libitum and were studied 1 day after catheter placement; the rats were conscious in their cages and allowed to move freely during the experiments. The arterial cannula was connected to a strain-gauge transducer (P23Db, Gould-Statham), and AP signals were recorded over a 30-minute period by a microcomputer equipped with an analog-to-digital converter board (CODAS, 2-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).12,15 HRV was determined using the SD of the basal HR recording period.
Sequential bolus injections (0.1 mL) of increasing doses of phenylephrine (0.25 to 32 µg/kg) and sodium nitroprusside (0.05 to 1.6 µg/kg) were given to induce 
4 pressure responses (for each drug) ranging from 5 to 40 mm Hg. A 3- to 5-minute interval between doses was necessary for AP 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. BRS was evaluated by a mean index, calculated by the ratio between changes in HR to the changes in MAP, allowing a separate analysis of reflex bradycardia and reflex tachycardia. The mean index was expressed as beats per minute per millimeter of mercury, as described elsewhere.12,15,18
After BRS assessment, AP and HR were continuously recorded at a basal state and after methylatropine (3 mg/kg, IV) injection (<0.2 mL). Because the HR response to these drugs reaches its peak within 3 to 5 minutes, this time interval was allowed to elapse before HR measurement. Atenolol (8 mg/kg, IV) was injected (<0.2 mL) 10 minutes after methylatropine, and again the response was evaluated after simultaneous blockade with atenolol and methylatropine. On the subsequent day, the sequence of injections was inverted (first atenolol and then methylatropine). The intrinsic HR was evaluated after simultaneous blockade with atenolol and methylatropine. Sympathetic tonus was determined as the difference between maximum HR after methylatropine injection and intrinsic HR. Vagal tonus was obtained by the difference between the lowest HR after atenolol injection and intrinsic HR.13,19
Statistical Analysis
Data are reported as mean±SEM, and ANOVA (1- or 2-way) was used to compare groups, followed by the Student-Newman-Keuls test. Pearson correlation was used to study the association between variables. Survival curve was estimated by using the Kaplan-Meier method and compared by using the log-rank test. The significance level was established as P<0.05.
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Results |
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During the protocol, all of the rats given STZ presented severe hyperglycemia compared with controls. Diabetic rats had higher glycemia at the end of the protocol compared with their initial values (Table 1).
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The TO rats presented reduced body weight in relation to SO rats at the end of the protocol. After the training period, body weight was reduced in both diabetic groups compared with nondiabetic groups; however, TDO rats showed an increase in body weight compared with their respective sedentary peers (SDO; Table 1).
The animals submitted to exercise training (TO and TDO) had an increase in the maximum speed of running compared with the sedentary groups (SO and SDO) after 8 weeks of exercise training. In addition, SDO rats showed reduced maximum speed of running in relation to SO rats at the end of the protocol (Table 1).
As can be seen in Table 2, exercise training induced a reduction in systolic, diastolic, and MAP and resting bradycardia in nondiabetic rats. The SDO group presented reduced AP and HR compared with the SO group. Exercise training applied to diabetic rats attenuated resting bradycardia but did not change AP. HR was similar between trained groups.
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HRV was reduced in SDO rats (13±1.3 bpm) in relation to SO rats (18±1.5 bpm). Trained groups (TO and TDO) had an increase in HRV (23±1 bpm in TO and 21±1.2 bpm in TDO) compared with the sedentary groups (Figure 1A).
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BRS evaluated by bradycardic responses to AP rises was impaired in SDO rats (–0.9±0.1bpm/mm Hg) in relation to SO rats (–1.4±0.12 bpm/mm Hg). However, tachycardic responses to AP falls were similar between sedentary groups (2.7±0.35 bpm/mm Hg in SO and 2.7±0.6 bpm/mm Hg in SDO). The tachycardic responses (4.7±0.48 bpm/mm Hg in TO and 4.6±0.2 bpm/mm Hg in TDO) and the bradycardic responses (–1.98±0.1 bpm/mm Hg in TO and –1.7±0.09 bpm/mm Hg in TDO) evoked by baroreflex during AP falls and rises, respectively, were improved in trained animals compared with the sedentary animals (Figure 1B).
Exercise training induced an increase in vagal tonus in TO compared with SO animals. Vagal tonus was decreased in SDO rats in relation to SO rats. No difference was observed in vagal tonus between the TDO and the SO groups. Sympathetic tonus was similar between sedentary groups and was decreased in the TDO group compared with that in other studied groups. The intrinsic HR was similar between normoglycemic groups. The SDO group had a reduction in intrinsic HR in relation to that in the SO group. Exercise training increased intrinsic HR in diabetic rats, although it remained lower in TDO as compared with SO and TO groups (Table 2).
Correlation analysis involving all of the study animals showed a significant relationship between HRV and bradycardic (r=–0.7; P<0.02) and tachycardic (r=0.75; P<0.001) responses induced by AP increases and falls, respectively (Figure 2A and 2B), indicating that animals with higher BRS had higher HRV. In addition, vagal tonus was correlated with bradycardic (r=–0.7; P<0.03) and tachycardic (r=0.7; P<0.01) responses to AP changes, showing that rats with higher vagal tonus demonstrated higher BRS (Figure 2C and 2D).
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During the 8 weeks of the exercise training protocol, total mortality was higher (P<0.04) in SDO rats (12 of 20 deaths, 60% mortality) than in SO rats (no deaths). Exercise training reduced mortality among OVX diabetic rats, as demonstrated by only 4 deaths among 16 TDO rats (25% mortality; P<0.04 versus SDO; Figure 3).
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Discussion |
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This study was performed to investigate the impact of autonomic dysfunction of the cardiovascular system and its association with the incidence of mortality in diabetic female rats that underwent ovarian hormone deprivation. In addition, we aimed to study the effects of exercise training, as a nonpharmacologic approach to treating diabetes and ovariectomy induced dysfunctions. Two important insights can be gained from the present study. First, the diabetic OVX rats presented increased autonomic dysfunction and mortality compared with normoglycemic rats. Second, TDO rats showed autonomic function improvement and a lower mortality than SDO rats.
Previous reports12,20 demonstrated that ovarian hormone deprivation in rats increases AP to levels higher than that observed in intact female and male rats.12,20–23 The AP values obtained in the SO rats in the present study were also increased in relation to the values documented in previous studies in intact female or male rats. Similarly, the incidence of hypertension rises after menopause in women.24 Importantly, we also corroborated our recent finding12 that 8 weeks of exercise training induced a significant reduction in AP values in OVX rats. In normotensive postmenopausal women, results demonstrated a decrease or maintenance in AP values after training.10,25 These changes in AP may be attributed, at least in the present study, to the resting bradycardia, induced by exercise training vagal tonus increase, and the likely associated cardiac output reduction. Similar data were documented previously in trained male mice and humans.26,27
Diabetic rats, sedentary or trained, did not change AP after ovarian hormone deprivation. In accordance, McGavock et al28 showed that 10 weeks of exercise training did not change AP in normotensive postmenopausal women with type 2 DM. Similar to what we reported in male rats with STZ-induced DM,13 exercise training did not induce additional resting bradycardia in diabetic rats; HR was actually significantly higher in the diabetic trained rats. This paradoxical effect most likely resulted from a training-induced increase in intrinsic HR (see Table 2).
Baroreflex has been recognized as a marker of autonomic control and as a predictor of cardiovascular mortality.29 Indeed, abnormality of baroreceptor-cardiac reflex sensitivity in insulin-dependent diabetic patients has been associated with the development of hypertension and the increase of sudden cardiac death risk.30 Even with the demonstration of an increase in vascular sympathetic baroreflex gain in postmenopausal women undergoing long-term estrogen replacement therapy,31 the hormone therapy is actually questionable. Indeed, the benefits of estrogen replacement in diabetic women are limited,3 and the study of alternative therapies to improve BRS has important clinical implications in postmenopausal women. Control of baroreflex function has been found to be altered after exercise training in normal subjects,32 as well as in type 2 DM patients.33 Davy et al34 reported that physically active postmenopausal women have higher BRS and levels of HRV compared with age-matched, less active women. Indeed, Jurca et al11 demonstrated that 8 weeks of moderate-intensity aerobic exercise training, but not hormone replacement therapy, can increase HRV in postmenopausal women. In the present study, we demonstrated that exercise training applied to an experimental model of ovarian hormone deprivation induces improvement of BRS for AP rises and falls and HRV in control and diabetic groups. The correlations obtained between BRS and HRV suggest that the increase in reflex AP regulation, mediated by HR changes evoked by the baroreceptors, induced an enhancement in HRV in the TO groups. A similar association was reported previously by Hull et al,35 studying the effects of exercise training in dogs.
The mechanism underlying the BRS improvement induced by exercise training in diabetic OVX rats may be associated with changes in baroreceptors, in the central nervous system, or in efferent fibers to the effector organs. We have previously described vagal function impairment in diabetic rats.13,19,36,37 In the present study, exercise training increased vagal tonus in control rats. Furthermore, exercise training induced an attenuation of vagal tonus impairment in diabetic rats, because no difference was observed between TDO rats and SO rats. This improvement could lead to a vagal reserve increase used during HR responses evoked by the baroreceptors. Moreover, the upregulation of muscarinic receptors reported previously in diabetic rats36 may be exacerbated by exercise training,38,39 contributing to BRS normalization. We demonstrated recently that BRS improvement in nondiabetic trained rats is associated with reduced oxidative stress and an increase in antioxidant enzymes,12 because STZ diabetes-induced oxidative stress plays a role in diabetes-induced baroreceptor dysfunction.40 The increase in vascular compliance observed after exercise training in postmenopausal women with type 2 DM,28 as well as the exercise-induced increase in the release of endothelial factors,41 may improve the sensitivity of the arterial baroreceptor afferents, thus increasing BRS.42
One question is whether the exercise protocol used in our study was effective in enhancing aerobic physiological capacity in rats. According to the previously described association between oxygen consumption and running velocity in untrained rats,16,17 the trained female rats showed a marked increase in the estimated aerobic physiological capacity as demonstrated previously for our group in rats and mice.12,26 Furthermore, the finding of a resting bradycardia in the TO group is a good indicator of the efficacy of the exercise training protocol to produce overall fitness.
Additional information provided by our study is the demonstration of reduced body weight in TO rats. In a recent review of 9 studies of postmenopausal women, Asikainen et al10 reported that exercise training decreased body weight in these women. In the present study, the increase in body weight in TDO rats seems to indicate metabolic improvement, which could be contributing to the autonomic changes in this group. Interestingly, the final glycemia was enhanced in comparison with the initial measurement in female STZ rats, showing that ovariectomy caused changes in glucose metabolism in diabetic females. In fact, menopause has been associated with impairment in metabolic state.10,20 Although the sympathetic activity plays an important role in glucose homeostasis,43 we did not observe a reduction in fasting glycemia in the presence of reduced cardiac sympathetic tonus in TDO female rats. This finding could be associated with specific sympathetic discharge to different tissues.
Diabetic patients with normal cardiovascular reflexes have a lower incidence of mortality than do diabetic individuals with abnormal autonomic reflex function.5 In accordance with this clinical observation, in the present study, SDO rats that had exacerbated autonomic dysfunction had a higher mortality than did sedentary normoglycemic rats. La Rovere et al44 demonstrated that changes in BRS induced by 4 weeks of bicycle ergometry exercise can favorably modify long-term survival in infarcted patients. Despite the fact that we did not evaluate the cause of death, our data indicate that total mortality was markedly reduced (SDO: 60% versus TDO: 25%) in the TDO group, which exhibited improvement in autonomic function, in relation to SDO group. Together, these findings suggest that decreases in BRS and HRV may contribute to cardiovascular disease–related mortality in diabetic women and that exercise training–induced increases in BRS and HRV may reduce mortality in this population.
Perspectives
DM is one of the most significant world health problems, especially in developing countries, where the prevalence and incidence rates are higher.5,45 Clinically, type I and type II DM do not differ substantially in terms of outcome, adversely increasing cardiovascular risk. The risk of death from cardiovascular disease in women with diabetes is >3 times that of nondiabetic women.1–4 Considering that postmenopausal hormone therapy may not be effective for the prevention of CVD, especially in diabetic women, other therapeutic interventions are needed. In this way, exercise training as a tool to improve autonomic dysfunction associated with diabetes, estrogen deprivation, or both seems to be an alternative in the management of the increased risk of developing chronic complications in this condition and to reduce mortality among this population. The mechanism underling exercise training–induced improvements in autonomic function after ovarian hormone deprivation in diabetic females subjects must be investigated in future studies. Finally, experimental data obtained in the present study must be investigated in humans, providing definitive evidence of the roles of BRS and HVR in the incidence of mortality, as well as the benefits of exercise training in reducing cardiovascular risk and mortality in postmenopausal diabetic women.
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Acknowledgments |
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Sources of Funding
This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 04/0300-5 and 04/0301-1) and Conselho Nacional de Desenvolvimento Científico e Tecnológico.
Disclosures
None.
Received May 23, 2007; first decision June 10, 2007; accepted July 6, 2007.
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