Low-Intensity Exercise Training Attenuates Cardiac β-Adrenergic Tone During Exercise in Spontaneously Hypertensive Rats
Abstract Acute and chronic exercise decrease peripheral sympathetic nerve activity, but the effect of exercise training of varying intensity on the sympathetic control of heart rate of spontaneously hypertensive rats has not yet been described. The effect of low and high intensities of exercise training on the vagal and sympathetic activities that control heart rate at rest and during dynamic exercise at 0.5, 0.8, and 1.0 mph for 4 minutes per stage was investigated in sedentary (SED, n=11), high-intensity (HT, n=12), and low-intensity exercise–trained (LT, n=13) spontaneously hypertensive rats. Exercise training was performed on a treadmill for 60 minutes, 5 days per week for 18 weeks, at 55% maximum oxygen consumption for the LT group and 85% for the HT group. Vagal and sympathetic activities were studied after administration of methylatropine (3 mg/kg) and propranolol (4 mg/kg), respectively. The LT group had a significantly lower heart rate (at 0.5, 0.8, 1.0 mph versus rest: 410±7, 426±7, 464±9, and 295±6 beats per minute [bpm], respectively) than the HT (440±6, 453±7, 474±5, and 315±4 bpm) and the SED (474±11, 500±11, 523±10, and 327±3 bpm) groups. Sympathetic effect (LT: 84±10, 88±12, 105±12, and 9±4; HT: 123±8, 125±7, 133±7, and 34±7; SED: 130±13, 143±12, 150±10, and 38±7 bpm) and sympathetic tonus (LT: 125±6, 121±5, 112±6, and 91±6; HT: 145±9, 136±6, 142±8, and 118±7; SED: 136±6, 129±6, 132±7, and 118±8 bpm) were significantly decreased by low-intensity exercise training. In conclusion, low- but not high-intensity exercise training causes resting bradycardia and attenuation of tachycardiac response during progressive dynamic exercise in spontaneously hypertensive rats. This effect can be attributed to a significantly decreased β-adrenergic tone that controls heart rate.
Neurovegetative changes promoted by exercise training have been documented in different species.1 2 3 4 However, the actual effects caused by different exercise-training intensities on vagal and sympathetic nerve activities that control heart rate in spontaneous hypertension at rest and during dynamic exercise have not yet been clarified. It has been shown that an acute session of exercise is sufficient to reduce plasma norepinephrine levels5 and neuromuscular sympathetic activity in hypertensive individuals.6 More recently, it has been demonstrated that exercise training significantly decreases renal sympathetic nerve activity in normotensive rats7 and neuromuscular sympathetic activity in humans.8 We also observed that moderate exercise training in normotensive rats caused a significant decrease in vagal and sympathetic tonus that controls heart rate, even though the major mechanism explaining resting bradycardia was not the cardiac innervation but a significant alteration in the pacemaker cell activity.4 In addition, we observed that exercise training in normotensive rats attenuated vagal withdrawal and sympathetic activation during dynamic exercise, which explained the lower tachycardiac response in trained rats.9
It has been observed that the initial stage of hypertension is associated with activation of sympathetic activity, cardiac output, and heart rate.10 11 Because exercise training causes a diminishment of sympathetic nerve activity in both heart and peripheral tissue in normotensive rats7 9 and humans,8 we decided to study the chronic effect of exercise on sympathetic nerve activity that controls heart rate in SHR.
Previous studies have demonstrated that varying intensities of exercise training have different effects on arterial blood pressure in SHR12 and humans,13 suggesting that the neurovegetative changes produced by exercise training in spontaneous hypertension could be influenced by the intensity of training. Therefore, the purpose of the present investigation was to study the effect of low and high intensities of exercise training on sympathetic and vagal controls of heart rate at rest and during dynamic exercise of progressive intensity in SHR.
Thirty-six male SHR (Paulista Medical School, Brazil; 90 to 110 g body weight) were fed standard laboratory chow and water ad libitum (2 to 3 rats per cage) in a temperature-controlled room (22°C) with a 12-hour light/dark cycle. The animals were divided randomly into three groups: sedentary (n=11), LT (n=13), and HT (n=12).
Exercise training was performed on a motor treadmill for 60 minutes, 5 days per week for 18 weeks, at 55% of V̇o2max for the LT rats and 85% of V̇o2max for the HT rats. The sedentary rats were handled every day; 3 days per week they were also submitted to short 5-minute periods of exercise on the motor treadmill at 0.5 mph to become accustomed to the experimental procedures.
V̇o2max was measured by means of expired gas analysis during a progressive exercise test at 5-m/min increments every 4 minutes. Samples of expired gases were collected in a 20-mL syringe during the last 30 seconds of every work load. Oxygen and carbon dioxide concentrations were analyzed with the Scholander microtechnique (Godart-Statham).
After the last training session, with rats under ether anesthesia, three stainless steel electrodes (5 cm long and 0.55 mm in diameter) were implanted subcutaneously and attached to the right and the left axillary areas and dorsum as previously described in detail.4 The electrodes were used to monitor electrocardiographic results in a multichannel record (model 7754A, Hewlett-Packard) as measures of heart rate. The vagal and sympathetic activities were analyzed by intraperitoneal injections of methylatropine (3 mg/kg, Sigma Chemical Co) and propranolol (4 mg/kg, Sigma) 24 hours after the electrodes had been implanted.4 14 On the first day of study, heart rate was recorded at rest and during three different exercise intensities: 0.5, 0.8, and 1.0 mph for 4 minutes at each level. Heart rate values obtained during the last 60 seconds immediately before the beginning of the exercise and during the last 15 seconds of each exercise level were used for comparisons. On the second day of study, methylatropine was injected, and 15 minutes later the rats underwent the same protocol as on the first day. At the end of the exercise, propranolol was injected, and the exercise was repeated 15 minutes later. The last session of exercise performed under methylatropine and propranolol was used to study the behavior of intrinsic heart rate. On the third day of study, propranolol was injected 15 minutes before the exercise protocol was started. Methylatropine was injected at the end of exercise, and 15 minutes later the exercise protocol was repeated to study for the second time the behavior of intrinsic heart rate at rest and during a progressive dynamic exercise. The vagal effect was evaluated as the difference between the control heart rate and the maximum heart rate after methylatropine injection. The sympathetic effect was evaluated as the difference between the control heart rate and minimum heart rate after propranolol injection. The vagal tonus was analyzed as the difference between the intrinsic heart rate and the heart rate after propranolol injection. The sympathetic tonus was analyzed as the difference between the maximum heart rate after methylatropine injection and the intrinsic heart rate. For the purpose of the study, intrinsic heart rate was expressed as the mean value of the two measurements performed on the second and third days of the experiment.
Data are presented as mean±SEM. Data from all three groups during the experimental conditions (rest and exercise) were pooled and subjected to a multivariate analysis of repeated measures (profile analysis), with complete observations at group and exercise levels.15 Because the vagal effect did not have the same profile among groups, the multivariate analysis was followed by contrasts between means at rest and at 0.5, 0.8, and 1.0 mph. A value of P<.05 was considered statistically significant.
The LT and HT groups had a significantly (P<.05) higher V̇o2max than the sedentary group after exercise training (92±9 and 94±7 versus 72±8 mL O2 · kg−1 ·min−1, respectively), whereas the values of all groups were similar before training (96±8, 102±7, and 99±8 mL O2·kg−1·min−1, respectively).
The heart rate data of sedentary, HT, and LT groups at rest and during exercise performed at 0.5, 0.8, and 1.0 mph are presented in Table 1⇓. Heart rate increased progressively from rest to 1.0-mph exercise in all groups (P<.05), but it was attenuated by exercise training (Fig 1⇓). Heart rates of both LT and HT groups were significantly lower than those of the sedentary group during all experimental conditions (rest and exercise). Heart rate values were still significantly lower in the LT group than in the HT group.
The vagal effect data, analyzed as the difference between the maximal heart rate after methylatropine administration and the control heart rate, are presented in Table 1⇑. The vagal effect decreased significantly from rest to 1.0-mph exercise in all groups (P<.05). There was no significant difference among groups at rest. During exercise at 0.5, 0.8, and 1.0 mph, however, both LT and HT rats had a significantly lower vagal effect than sedentary rats, but no significant difference was found between exercised groups (Table 1⇑, Fig 2⇓). These results indicate that the vagal withdrawal during progressive exercise was significantly reduced after low- and high-intensity exercise training.
The sympathetic effect data, analyzed as the difference between the control heart rate and the minimal heart rate after administration of propranolol, are presented in Table 1⇑. The sympathetic effect increased significantly from rest to 1.0-mph exercise in all groups (P<.05). LT rats had a significantly lower sympathetic effect than both sedentary rats and HT rats during all experimental conditions (rest and exercise), but no significant difference was observed between sedentary rats and HT rats (Table 1⇑, Fig 2⇑). These data indicate that only low-intensity exercise training attenuated the increase of sympathetic activity during progressive exercise.
The intrinsic heart rate values, obtained after blockade of methylatropine and propranolol, increased significantly (P<.05) during exercise in all groups (Table 2⇓). No significant difference between sedentary rats and LT rats was observed during all experimental conditions (rest and exercise), but the values were significantly higher in sedentary rats compared with HT rats.
The vagal tonus values, analyzed as the difference between the intrinsic heart rate and minimal heart rate after administration of propranolol, decreased significantly (P<.05) from rest to 1.0-mph exercise in all groups (Table 2⇑). However, no significant difference among groups was observed during all experimental conditions (rest and exercise).
The sympathetic tonus values, analyzed as the difference between the maximal heart rate after methylatropine administration and the intrinsic heart rate, increased significantly (P<.05) from rest to 1.0-mph exercise in all groups (Table 2⇑). LT rats had a significantly lower sympathetic tonus than both sedentary rats and HT rats during all experimental conditions (rest and exercise), whereas no significant difference was observed between HT rats and sedentary rats (Fig 3⇓). Therefore, both sympathetic tonus and sympathetic effect were attenuated in the LT group during dynamic exercise of progressive intensity.
The major findings of the present investigation on the effects of exercise training in SHR are (1) resting bradycardia and attenuation of tachycardia during dynamic exercise of progressive intensity are significantly more pronounced after low-intensity than after high-intensity exercise training, (2) low-intensity but not high-intensity exercise training causes a significant decrease of sympathetic nerve activity at rest and during progressive exercise, (3) both low and high intensities of exercise training attenuate vagal withdrawal during dynamic exercise, and (4) low and high intensities of exercise training produce no change in the behavior of intrinsic heart rate.
The higher V̇o2max in the LT and HT rats shows the effectiveness of the present exercise training.
The present data show that in SHR exercise training significantly decreases heart rate at rest and during exercise. However, in contrast to other observations in normotensive rats4 and normotensive humans,2 resting bradycardia cannot be explained by a decrease in intrinsic heart rate, since no significant difference in intrinsic heart rate was found between LT rats and sedentary rats at rest (Table 2⇑). Indeed, it can be attributed to a decrease in sympathetic drive to the heart in LT rats, since both sympathetic effect and sympathetic tonus were significantly reduced, whereas no significant change was found in vagal effect and vagal tonus. In agreement with other studies in normotensive rats9 and normotensive humans,16 17 the increase in heart rate response during exercise in SHR was mainly due to a progressive withdrawal of vagal activity and a progressive increase of sympathetic activity during exercise. Furthermore, in the present study, vagal effect and tonus decreased significantly when the exercise intensity increased, whereas sympathetic effect and tonus increased significantly. Exercise training attenuated the tachycardiac response during exercise because a lower sympathetic activity is released simultaneously with increased vagal activity. These data agree with our previous observation that in normotensive trained rats9 cardiac acceleration was significantly attenuated at 0.8 and 1.0 mph. Similar results were also found in dogs18 and in men.19 Varying exercise intensity exerted different effects on the cardiac sympathetic functions at rest and during exercise. We found that resting bradycardia and attenuation of tachycardiac response were more intense after low- than after high-intensity exercise training, probably because sympathetic effect and sympathetic tonus were significantly less pronounced in the LT rats.
Regarding the effects of acute and chronic exercise on sympathetic activity, Cléroux et al5 reported that exercise performed at 50% of V̇o2max for 45 minutes caused a significant decrease in total peripheral resistance at the recovery period, associated with a significant diminishment of plasma norepinephrine in hypertensive subjects. Floras et al6 demonstrated that an acute session of exercise provoked a significant decrease in neuromuscular sympathetic activity in hypertensive men. More recently, we demonstrated that exercise training significantly reduced renal sympathetic nerve activity in normotensive rats,7 as did Meredith et al20 in humans. Grassi et al8 showed that exercise training significantly reduced neuromuscular sympathetic activity in humans. Moreover, DiCarlo and Bishop21 verified that exercise training significantly decreased the sensitivity of the baroreflex control of renal sympathetic nerve activity in rabbits during progressive reduction of arterial blood pressure. However, the present study provides the first demonstration that low- but not high-intensity exercise training significantly decreases sympathetic nerve activity of the heart at rest and during progressive dynamic exercise in SHR. The sedentary SHR had an 18%, 22%, and 17% higher sympathetic effect at 0.5, 0.8, and 1.0 mph, respectively, than the normotensive rats we studied previously.9 The SHR subjected to high-intensity exercise training showed a tendency toward a normalization of sympathetic activity during exercise, since they had only a 14%, 10%, and 6% higher sympathetic effect than sedentary normotensive rats at 0.5, 0.8, and 1.0 mph, respectively.9 The SHR on low-intensity exercise training showed not only a striking reduction in sympathetic nerve activity but also a training adaptation very similar to that found in normotensive trained rats undergoing exercise training at approximately 60% of V̇o2max.9 The sympathetic effect at 0.5, 0.8, and 1.0 mph was 84, 88, and 105 beats per minute, respectively, in SHR and 85, 73, and 96 beats per minute, respectively, in normotensive rats.9 There is no definitive explanation of the distinct effect caused by low-intensity and high-intensity exercise training in SHR. High-intensity exercise may increase the sympathetic drive so intensively that it overcomes the benefits of exercise training, at least in SHR. The mechanisms involved in the attenuation of the sympathetic nerve activity in trained rats can be either centrally or peripherally mediated. Shyu and Thorén22 have demonstrated that spontaneous exercise in SHR caused a significant decrease in arterial blood pressure at the recovery period and that naloxone injection before exercise prevented this fall in blood pressure, suggesting a central modulation of β-endorphin release by an exercise session. We showed that exercise training significantly reduced blood pressure responsiveness to increased doses of phenylephrine.7 Similar results were observed in response to norepinephrine.8 23 These data suggest that exercise training produces α1-noradrenergic receptor hyposensitivity.
Experimental and clinical studies have proposed that environmental conditions that cause stressful stimulation in genetically susceptible subjects could represent an important factor in the development of hypertension.24 25 In addition, the initial stage of hypertension has been attributed to a state called hyperkinetic circulation, which is related to an activation of the sympathetic system and an increase in cardiac output and heart rate.10 The present results demonstrate that low-intensity exercise training in SHR decreases heart rate at rest and during a stressful condition such as exercise, which is due to a significant reduction of sympathetic nerve activity. Exercise training performed in excess of 75% of V̇o2max had no effect on resting caudal blood pressure in rats, whereas exercise training of 40% to 60% of V̇o2max lowered blood pressure.12 It has been also observed that low- and moderate-intensity training have similar 24-hour blood pressure reductions, but each training intensity may interfere with different pathogenic effects associated with distinct blood pressure profiles.13 Therefore, low-intensity exercise training has a potential usefulness, not only in preventing the development of hypertension but also in the nonpharmacological treatment of high blood pressure.
We cannot exclude some possible limitations of the present study related to the use of pharmacological blockade with propranolol (ie, the blockade may not be complete, especially during exercise). In addition, the blockade of one side of the autonomic system may cause changes in the other that would mask the relative contribution of the two divisions; also, the order in which the blockade is given can have an effect on the interpretation of sympathetic and parasympathetic effects. The significant increase in intrinsic heart rate from rest to 1.0 mph suggests an incomplete sympathetic blockade. However, the increase in intrinsic heart rate was only 33, 27, and 36 beats per minute in sedentary, HT, and LT groups, respectively. Moreover, the effectiveness of sympathetic blockade can be also evaluated by comparisons with other studies. Ji et al26 demonstrated that 30 mg/kg propranolol administered during intense exercise caused an attenuation of 25% in the exercising heart rate, whereas in the present study the attenuation was 29%, 28%, and 23% in sedentary, HT, and LT groups, respectively.
In conclusion, our data demonstrate that exercise training in SHR causes resting bradycardia and attenuation of tachycardiac response during dynamic exercise of progressive intensity. Moreover, these adaptations are much more pronounced after low-intensity than high-intensity exercise training, which can be attributed to a significant diminishment of the sympathetic nerve activity that controls heart rate. Therefore, the intensity of exercise training in SHR seems to be crucial to the adaptations of the neurovegetative system that controls heart rate at rest and during a stressful condition such as progressive dynamic exercise.
Selected Abbreviations and Acronyms
|SHR||=||spontaneously hypertensive rats|
|V̇o2max||=||maximum oxygen consumption|
This study was supported by Financiadora de Estudos e Projetos (FINEP/No. 66.93.0023.00), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP/No. 91/0545-6), and Fundação E.J. Zerbini. We also thank Katt Coelho Mattos for technical contributions and Júlia Tizue Fukushima for performing the statistical analysis throughout this study.
- Received June 18, 1995.
- Revision received August 1, 1995.
- Accepted October 16, 1995.
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