Autonomic Nervous System, Inflammation, and Diabetes: Mechanisms and Possible InterventionsView this Special Issue
Research Article | Open Access
Dynamic Aerobic Exercise Induces Baroreflex Improvement in Diabetic Rats
The objective of the present study was to investigate the effects of an acute aerobic exercise on arterial pressure (AP), heart rate (HR), and baroreflex sensitivity (BRS) in STZ-induced diabetic rats. Male Wistar rats were divided into control () and diabetic () groups. AP, HR, and BRS, which were measured by tachycardic and bradycardic (BR) responses to AP changes, were evaluated at rest (R) and postexercise session (PE) on a treadmill. At rest, STZ diabetes induced AP and HR reductions, associated with BR impairment. Attenuation in resting diabetes-induced AP (R: versus PE: mmHg) and HR (R: versus PE: bpm) reductions and BR dysfunction (R: versus PE: bpm/mmHg) was observed in the postexercise period. In conclusion, the hemodynamic and arterial baro-mediated control of circulation improvement in the postexercise period reinforces the role of exercise in the management of cardiovascular risk in diabetes.
Diabetes mellitus is commonly associated with a large number of complications. Patients with diabetes are particularly prone to disorders affecting the control of the cardiovascular system, including microangiopathy, atherosclerosis, hypertension, and autonomic neuropathy. It has been frequently reported that diabetes can affect both somatic and autonomic nerves. Autonomic neuropathy is the most serious complication of diabetes in terms of morbidity and mortality [1–3].
Baroreflex dysfunction observed in diabetic subjects has important clinical implications, because the arterial baroreceptors constitute an important system that acts against wide oscillations in arterial pressure (AP), acting on both the sympathetic and parasympathetic limbs of the autonomic nervous system. Additionally, clinical trials have shown an association between baroreflex dysfunction and morbidity and mortality [3–5].
Studies using experimental models have been conducted to investigate the mechanisms of autonomic cardiovascular reflex dysfunction in diabetes [6–13]. We have demonstrated that, in the course of streptozotocin-(STZ-) induced experimental diabetes, baroreflex control of circulation was impaired [7, 9, 11–13]. Also, we have previously demonstrated the benefits of exercise training in diabetes-induced cardiovascular, tonic and reflex autonomic dysfunction in rats [10–13]. Furthermore, Loimaala et al.  have demonstrated that 12 months of exercise training applied to type 2 diabetic patients without autonomic neuropathy-induced improvement in baroreflex sensitivity (BRS). In fact, studies have demonstrated that physical activity delays or improves the hemodynamic and metabolic dysfunction observed in diabetes and should be considered in prevention and treatment of this disease [15, 16]. However, there is little data on the effects of acute exercise (a single exercise bout) on diabetics, especially on hemodynamics and BRS.
Although cardiovascular effects of acute exercise have been studied in nondiabetic and hypertensive rats [17–19], they have not been investigated in diabetic rats. Hence, a more complete understanding of acute exercise and the health benefits that it may promote, for example, in the postexercise period, could provide useful information to help prevention, management, and treatment of the diabetes mellitus. Therefore, the objective of the present study was to investigate the effects of a single bout of dynamic aerobic exercise on HR, AP, and BRS in STZ-induced diabetic rats.
Male Wistar rats (3 mo, 200–300 g) were obtained from the breeding facility of the University of Sao Judas Tadeu (São Paulo, Brazil). Rats received standard laboratory chow and tap water ad libitum and were housed in temperature-controlled rooms (22°C) under a 12:12 h dark-light cycle. All animal protocols were approved by the Experimental Animal Use Committee of the University of Sao Judas Tadeu and were conducted in accordance with the National Research Council’s guide for the care and use of laboratory animals. Rats were randomly assigned to control (C, ) or diabetic (D, ) groups.
Diabetes was induced by a single intravenous injection of STZ (50 mg/kg; Sigma, St. Louis, MO, USA) after an overnight fast (8–10 h). Control rats received only vehicle (10 mM citrate buffer, pH 4.5) after a similar fasting period. Blood glucose was measured to confirm the diabetic-induced hyperglycemia 29 days after STZ injection (Accu-Check Instant test, Roche, Brazil). The resting and acute exercise hemodynamic evaluations started 30 days after either STZ or citrate buffer administration [6, 7, 9–13].
All animals were progressively adapted to exercise (10 min/day at 0.3 km/h) for 5 days (23 to 27 days after STZ or buffer injection) on a treadmill before the start of the acute exercise protocol. After adaptation, both control and diabetic rats were submitted to a dynamic aerobic exercise session on a treadmill with a gradual 0.3 km/h speed increase, that is, from 0.3 km/h to 0.9 km/h (three minutes at each load stage) .
Twenty-eight days after STZ-diabetes induction, rats were anaesthetized (ketamine-xylazine 80 : 40 mg/kg ip), and a polyethylene-tipped Tygon cannulas (4 cm of PE-08 connected to 2 cm of PE-50) filled with heparinised saline solution were inserted into the common carotid artery and jugular vein for direct measurements of arterial pressure and drug administration, respectively. Hemodynamic measurements were carried out in conscious and active rats 48 hours after catheters implantation (30 days after STZ or buffer injection). The arterial cannula was connected to a transducer (Kent Instrumental, USA) and AP signals were recorded using a microcomputer equipped with an analog-to-digital converter (CODAS, 2-kHz sampling frequency, Dataq Instruments, USA). The AP and the heart rate (HR) were recorded at rest (20 min) [6, 7, 9–13, 19]. Immediately after, increasing doses of phenylephrine and sodium nitroprusside were given sequentially as bolus injections to produce at least four pressure responses, ranging from 5 to 40 mmHg at rest. Peak increases or decreases in MAP after phenylephrine or sodium nitroprusside injections and the corresponding peak reflex changes in HR were recorded for each dose of the drug. A time interval between doses was necessary for blood pressure and heart rate to return to baseline. Beat-to-beat analysis was performed to quantify changes in MAP and HR as previously described. BRS was evaluated by two methods: linear regression and mean index. The linear regression method reported values derived from fitting sensitivity indices to through points corresponding to all changes in HR related to the induced changes in MAP [12, 13]. The mean index method related maximum changes in HR to the maximum changes in MAP after each dose of vasoactive drugs .
At least 2 hour after AP and BRS resting evaluations, the animals were submitted to acute exercise protocol on a treadmill. The AP was recorded during the postexercise period (5–25 minutes after the exercise ended) and the BRS was evaluated as described above in the postexercise period (started 30 min after exercise).
Data are expressed as means ± SEM. Student’s unpaired t-test (glycemia and body weight) and two-way ANOVA (hemodynamic and BRS evaluations) were used to compare groups, followed by the Student-Newman-Keuls test. Significance level was established at .
STZ-induced diabetic rats presented hyperglycemia (C: 97 ± 12 versus D: 362 ± 24 mg/dL, ) and reduced body weight (C: 303 ± 5 versus D: 246 ± 12 g, ).
STZ diabetes significantly reduced systolic AP, diastolic AP, MAP (), and HR () when compared with control rats (Table 1).
|Values are means ± SEM. * versus controls in similar state; † versus diabetics at rest. Systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), heart rate (HR).|
As can be seen in Table 1, acute dynamic aerobic exercise induced attenuation in diabetic resting hypotension and bradycardia () during the recovery period (5–25 min after exercise). No differences in AP were observed between diabetic rats and control groups during the postexercise period (). However, HR remained reduced in diabetic rats in relation to control rats in the period ().
The BRS evaluation demonstrated that the baroreflex tachycardic responses elicited by sodium nitroprusside were not significantly reduced in diabetic rats in relation to controls at rest (). However, the baroreflex bradycardic responses evaluated by linear regression () or mean index methods () were significantly reduced in diabetic animals as compared to controls at rest (Table 2).
|Values are means ± SEM. * versus controls in similar state; † versus diabetics at rest. Bradycardic reflex response (BR), tachycardic reflex response (TR).|
Acute dynamic aerobic exercise did not alter baroreflex tachycardic responses in diabetic rats (). However, exercise induced a significant increase in bradycardic reflex responses evaluated by linear regression () or mean index methods () in diabetic rats in the postexercise period as compared to diabetic resting values. In control rats, BRS did not significantly differ between rest and postexercise () (Table 2).
The major new insight of the present investigation is that a single bout of dynamic aerobic exercise improves diabetes-induced BRS impairment and attenuated resting hemodynamic dysfunctions. Furthermore, this study also confirms our preliminary findings that STZ-diabetes induces hypotension, bradycardia, and BRS impairment [6, 7, 9–13].
In the present study, we observed an increase in AP and HR in the postexercise period in diabetic rats. Jackson and Carrier  have suggested that the decrease in AP in STZ-induced diabetic rats at rest may be the result of a decreased cardiac output due to hypovolemia caused by hyperglycemic osmotic diuresis. However, Cohen et al.  have observed that these animals were polyuric with a high urine flow, reflecting the osmotic diuretic effects of glucose. Despite the mechanism, several studies have demonstrated impaired cardiac function in STZ-diabetic rats [3, 22–24]. In this aspect, the AP postexercise normalization in comparison to control rats in the present study could be ascribed to a better ventricular contractility and to an enhanced resting HR, as observed previously in trained diabetic rats [3, 22, 23]. Moreover, the reduction in HR in diabetic animals at rest has been attributed to changes in the sinoatrial node [3, 6, 13], although functional alterations in the cholinergic mechanism cannot be excluded as a causal factor. In this regard, the attenuation of resting bradycardia in the postexercise period in the present study may be related to changes in intrinsic HR or sympathovagal cardiac balance as previously observed in trained diabetic rats [3, 12, 13]. Regarding the physiological importance, the AP and HR changes during the recovery period in diabetic rats may reflect a transitory improvement in autonomic control of circulation and can represent a better perfusion pressure to the tissues.
Regarding BRS, it is well known that exercise training improves baroreflex control of circulation in normotensive and diabetic in animals and humans [11–14, 25–28]. Figueiroa et al.  have demonstrated that endurance exercise training reduced blood pressure without changes in heart rate variability (HRV) and BRS at rest, but training increased HRV and BRS during the recovery of acute endurance exercise, indicating an improved postexercise autonomic modulation of HR, which was similar in obese women with and without type 2 diabetes. In the present paper we demonstrated, for the first time, that a single bout of exercise restores previously impaired baroreflex-mediated bradycardic responses in sedentary diabetic rats. In this regard, it is worth emphasizing that baroreceptor cardiac reflex sensitivity abnormalities in diabetic patients increase the risk of sudden cardiac death [1, 2]; BRS improvement after each exercise session can favorably modify long-term survival as demonstrated in postmyocardial infarction patients [4, 5].
Baroreflex improvement induced by acute exercise in the present study may be associated with transitory changes in baroreceptors, in central nervous system, or in efferent fibers to the effectors organs. Although in the present paper we have not investigated these pathways, vagal function impairment in diabetic rats has been previously described by our group [6, 10, 12, 13]. Moreover, exercise training in diabetic male rats induced a 40% increase in vagal tonus as compared to sedentary STZ-rats . A similar increase in vagal function could also occur after each exercise session in sedentary diabetic rats in the present investigation, which can represent an increase in the vagal reserve used during HR responses evoked by the baroreceptors. Additionally, an increase in vascular compliance  and/or an enhancement in shear stress during exercise may induce the release of endothelial factors , increasing the arterial baroreceptor afferent sensitivity .
Diabetic autonomic neuropathy is a serious complication found in one-fourth of type 1 and one-third of type 2 diabetic patients [2, 32]. The effects of diabetic autonomic dysfunction are seen as changes in autonomic modulation of the cardiac sinus node, resulting in reduced heart rate variability, which is strongly (i.e., relative risk is doubled) correlated with an increased risk of silent myocardial ischemia and resultant mortality [2, 33]. Furthermore, reduced BRS is a well-documented indicator of increased risk for mortality and morbidity in nondiabetics and diabetics [1–5]. Given these findings, the arterial baro-mediated control of circulation improvement in the postexercise period demonstrated in the present study reinforces the role of exercise in the management of cardiovascular risk in diabetic individuals.
In conclusion, a single aerobic exercise session induced attenuation of hemodynamic impairment associated with baroreflex improvement in STZ-induced diabetic rats.
Conflict of Interests
The authors have no conflicts of interest to disclose.
This study was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP- 07/57595-5; 07/58942-0), Conselho Nacional de Pesquisa e Desenvolvimento (CNPq—482520/2009-4, 306011/2010-7), and Fundação E.J. Zerbini. M. C. Irigoyen and K. D. Angelis are recipients of CNPq Fellowship (CNPq-BPQ).
- D. J. Ewing, I. W. Campbell, and B. F. Clarke, “The natural history of diabetic autonomic neuropathy,” Quarterly Journal of Medicine, vol. 49, no. 193, pp. 95–108, 1980.
- A. I. Vinik and D. Ziegler, “Diabetic cardiovascular autonomic neuropathy,” Circulation, vol. 115, no. 3, pp. 387–397, 2007.
- K. De Angelis, M. C. Irigoyen, and M. Morris, “Diabetes and cardiovascular autonomic dysfunction: application of animal models,” Autonomic Neuroscience, vol. 145, no. 1-2, pp. 3–10, 2009.
- M. T. La Rovere, C. Bersano, M. Gnemmi, G. Specchia, and P. J. Schwartz, “Exercise-induced increase in baroreflex sensitivity predicts improved prognosis after myocardial infarction,” Circulation, vol. 106, no. 8, pp. 945–949, 2002.
- M. Malik, A. J. Camm, J. T. Bigger Jr. et al., “Heart rate variability. Standards of measurement, physiological interpretation, and clinical use,” European Heart Journal, vol. 17, no. 3, pp. 354–381, 1996.
- C. Y. Maeda, T. G. Fernandes, H. B. Timm, and M. C. Irigoyen, “Autonomic dysfunction in short-term experimental diabetes,” Hypertension, vol. 26, no. 6, pp. 1100–1104, 1995.
- C. Y. Maeda, T. G. Fernandes, F. Lulhier, and M. C. Irigoyen, “Streptozotocin diabetes modifies arterial pressure and baroreflex sensitivity in rats,” Brazilian Journal of Medical and Biological Research, vol. 28, no. 4, pp. 497–501, 1995.
- G. Monckton and E. Pehowich, “Autonomic neuropathy in the streptozotocin diabetic rat,” Canadian Journal of Neurological Sciences, vol. 7, no. 2, pp. 135–142, 1980.
- P. Dall'Ago, T. G. Fernandes, U. F. Machado, A. A. Belló, and M. C. Irigoyen, “Baroreflex and chemoreflex dysfunction in streptozotocin-diabetic rats,” Brazilian Journal of Medical and Biological Research, vol. 30, no. 1, pp. 119–124, 1997.
- K. L. D. De Angelis, A. R. Oliveira, P. Dall'Ago et al., “Effects of exercise training on autonomic and myocardial dysfunction in streptozotocin-diabetic rats,” Brazilian Journal of Medical and Biological Research, vol. 33, no. 6, pp. 635–641, 2000.
- A. D. Harthmann, K. De Angelis, L. P. Costa et al., “Exercise training improves arterial baro- and chemoreflex in control and diabetic rats,” Autonomic Neuroscience, vol. 133, no. 2, pp. 115–120, 2007.
- S. B. C. Souza, K. Flues, J. Paulini et al., “Role of exercise training in cardiovascular autonomic dysfunction and mortality in diabetic ovariectomized rats,” Hypertension, vol. 50, no. 4, pp. 786–791, 2007.
- C. Mostarda, A. Rogow, I. C. Silva et al., “Benefits of exercise training in diabetic rats persist after three weeks of detraining,” Autonomic Neuroscience, vol. 145, no. 1-2, pp. 11–16, 2009.
- A. Loimaala, H. V. Huikuri, T. Kööbi, M. Rinne, A. Nenonen, and I. Vuori, “Exercise training improves baroreflex sensitivity in type 2 diabetes,” Diabetes, vol. 52, no. 7, pp. 1837–1842, 2003.
- S. R. Chipkin, S. A. Klugh, and L. Chasan-Taber, “Exercise and diabetes,” Cardiology Clinics, vol. 19, no. 3, pp. 489–505, 2001.
- S. R. Colberg, R. J. Sigal, B. Fernhall et al., “Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement,” Diabetes Care, vol. 33, no. 12, pp. e147–e167, 2010.
- C. E. Negrão, E. D. Moreira, P. C. Brum, M. L. Denadai, and E. M. Krieger, “Vagal and sympathetic control of heart rate during exercise by sedentary and exercise-trained rats,” Brazilian Journal of Medical and Biological Research, vol. 25, no. 10, pp. 1045–1052, 1992.
- N. S. Gava, A. C. Véras-Silva, C. E. Negrão, and E. M. Krieger, “Low-intensity exercise training attenuates cardiac β-adrenergic tone during exercise in spontaneously hypertensive rats,” Hypertension, vol. 26, no. 6, pp. 1129–1133, 1995.
- K. De Angelis, T. Ogawa, I. C. Sanches, K. V. Rigatto, E. M. Krieger, and M. C. Irigoyen, “Impairment on cardiac output and blood flow adjustments to exercise in L-NAME-induced hypertensive rats,” Journal of Cardiovascular Pharmacology, vol. 47, no. 3, pp. 371–376, 2006.
- C. V. Jackson and G. O. Carrier, “Influence of short-term experimental diabetes on blood pressure and heart rate in response to norepinephrine and angiotensin II in the conscious rat,” Journal of Cardiovascular Pharmacology, vol. 5, no. 2, pp. 260–265, 1983.
- A. J. Cohen, D. M. McCarthy, and R. R. Rossetti, “Renin secretion by the spontaneously diabetic rat,” Diabetes, vol. 35, no. 3, pp. 341–346, 1986.
- D. J. Paulson, S. J. Kopp, D. G. Peace, and J. P. Tow, “Improved postischemic recovery of cardiac pump function in exercised trained diabetic rats,” Journal of Applied Physiology, vol. 65, no. 1, pp. 187–193, 1988.
- P. M. C. DeBlieux, R. W. Barbee, K. H. McDonough, and R. E. Shepherd, “Exercise training improves cardiac performance in diabetic rats,” Proceedings of the Society for Experimental Biology and Medicine, vol. 203, no. 2, pp. 209–213, 1993.
- R. Wichi, C. Malfitano, K. Rosa et al., “Noninvasive and invasive evaluation of cardiac dysfunction in experimental diabetes in rodents,” Cardiovascular Diabetology, vol. 6, article 14, 2007.
- S. E. O'Sullivan and C. Bell, “The effects of exercise and training on human cardiovascular reflex control,” Journal of the Autonomic Nervous System, vol. 81, no. 1–3, pp. 16–24, 2000.
- P. C. Brum, G. J. Justo Da Silva, E. Dias Moreira, F. Ida, C. E. Negrão, and E. M. Krieger, “Exercise training increases baroreceptor gain sensitivity in normal and hypertensive rats,” Hypertension, vol. 36, no. 6, pp. 1018–1022, 2000.
- K. De Angelis, R. B. Wichi, W. R. A. Jesus et al., “Exercise training changes autonomic cardiovascular balance in mice,” Journal of Applied Physiology, vol. 96, no. 6, pp. 2174–2178, 2004.
- K. L. D. D'Avila, G. Gadonski, J. Fang et al., “Exercise reverses peripheral insulin resistance in trained L-NAME- hypertensive rats,” Hypertension, vol. 34, no. 4, pp. 768–772, 1999.
- A. Figueroa, T. Baynard, B. Fernhall, R. Carhart, and J. A. Kanaley, “Endurance training improves post-exercise cardiac autonomic modulation in obese women with and without type 2 diabetes,” European Journal of Applied Physiology, vol. 100, no. 4, pp. 437–444, 2007.
- C. Giannattasio, B. M. Cattaneo, A. A. Mangoni et al., “Changes in arterial compliance induced by physical training in hammer-throwers,” Journal of Hypertension, vol. 10, no. 6, pp. S53–S55, 1992.
- S. D. Katz, “The role of endothelium-derived vasoactive substances in the pathophysiology of exercise intolerance in patients with congestive heart failure,” Progress in Cardiovascular Diseases, vol. 38, no. 1, pp. 23–50, 1995.
- D. Ziegler, “Cardiovascular autonomic neuropathy: clinical manifestations and measurement,” Diabetes Reviews, vol. 7, no. 4, pp. 300–315, 1999.
- G. Jermendy, L. Toth, P. Voros, M. Z. Koltai, and G. Pogatsa, “Cardiac autonomic neuropathy and QT interval length. A follow-up study in diabetic patients,” Acta Cardiologica, vol. 46, no. 2, pp. 189–200, 1991.
Copyright © 2012 Luciana Jorge et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.