Poor Wheel-Running Exercise Can Decrease Blood Pressure through Hormonal Control and Increase Endurance Exercise Capacity in Middle-Aged Normal Rats


The aim of this study was to examine the effects of voluntary wheel-running (WR) on body weight (BW), waist circumference, mesenteric fat mass (MFM), adipocyte size, circulating cytokines/hormones, blood pressure (BP) and exercise endurance capacity in 11-month-old normal rats. Three-week WR with about 0.2 km of daily running distance caused a gradual loss in BW despite an increased intake of food/water. MFM decreased as daily running distance increased. Moreover, there was a positive correlation between MFM and BW, waist circumference or adipocyte size. On the other hand, WR significantly decreased systolic/diastolic BPs, and increased endurance exercise capacity. WR rat sera contained lower concentrations of angiotensin II, aldosterone, vasopressin and endothelin-1 and higher concentration of brain natriuretic peptide compared with sedentary rat sera. Thus, WR-induced reduction in resting BPs may be accomplished by attenuated vasoconstriction, enhanced vasodilatation and reduction in blood volume. In addition, circulating vascular endothelial growth factor and interleukin-6 were higher in WR rats, suggesting angiogenesis, anti-inflammation and insulin-sensitization. These results support a prevalent idea that daily light-exercise is a potential strategy for preventing metabolic syndrome.

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Sakata, S. , Hanaoka, T. , Ishizawa, R. , Iwami, K. , Takada, Y. , Imagita, H. , Minematsu, A. , Waki, H. and Nakatani, A. (2015) Poor Wheel-Running Exercise Can Decrease Blood Pressure through Hormonal Control and Increase Endurance Exercise Capacity in Middle-Aged Normal Rats. Journal of Biosciences and Medicines, 3, 10-24. doi: 10.4236/jbm.2015.38002.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Despres, J.-P. and Lemieux, I. (2006) Abdominal Obesity and Metabolic Syndrome. Nature, 444, 881-887.
[2] Kahn, S.E., Hull, R.L. and Utzschneider, K.M. (2006) Mechanisms Linking Obesity to Insulin Resistance and Type 2 Diabetes. Nature, 444, 840-846.
[3] National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (2001) Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA, 285, 2486-2497.
[4] Grundy, S.M., Cleeman, J.I., Daniels, S.R., Donato, K.A., Eckel, R.H., Franklin, B.A., Gordon, D.J., Krauss, R.M., Savage, P.J., Smith Jr., S.C., Spertus, J.A. and Costa, F. (2005) Diagnosis and Management of the Metabolic Syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation, 112, 2735-2752.
[5] Wellen, K.E. and Hotamisligil, G.S. (2005) Inflammation, Stress, and Diabetes. Journal of Clinical Investigation, 115, 1111-1119.
[6] Tilg, H. and Moschen, A.R. (2006) Adipocytokines: Mediators Linking Adipose Tissue, Inflammation and Immunity. Nature Reviews Immunology, 6, 772-783.
[7] Wellen, K.E. and Hotamisligil, G.S. (2003) Obesity-Induced Inflammatory Changes in Adipose Tissue. Journal of Clinical Investigation, 112, 1785-1788.
[8] Weisberg, S.P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R.L. and Ferrante Jr., A.W. (2003) Obesity Is Associated with Macrophage Accumulation in Adipose Tissue. Journal of Clinical Investigation, 112, 1796-1808.
[9] Xu, H., Barnes, G.T., Yang, Q., Tan, G., Yang, D., Chou, C.J., Sole, J., Nichols, A., Ross, J.S., Tartaglia, L.A. and Chen, H. (2003) Chronic Inflammation in Fat Plays a Crucial Role in the Development of Obesity-Related Insulin Resistance. Journal of Clinical Investigation, 112, 1821-1830.
[10] Hu, F.B., Sigal, R.J., Rich-Edwards, J.W., Colditz, G.A., Solomon, C.G., Willett, W.C., Speizer, F.E. and Manson, J.E. (1999) Walking Compared with Vigorous Physical Activity and Risk of Type 2 Diabetes in Women. A Prospective Study. JAMA, 282, 1433-1439.
[11] Bassuk, S.S. and Manson, J.E. (2005) Epidemiological Evidence for the Role of Physical Activity in Reducing Risk of Type 2 Diabetes and Cardiovascular Disease. Journal of Applied Physiology, 99, 1193-1204.
[12] Overton, J.M., Tipton, C.M., Matthes, R.D. and Leininger, J.R. (1986) Voluntary Exercise and Its Effects on Young SHR and Stroke-Prone Hypertensive Rats. Journal of Applied Physiology, 61, 318-324.
[13] LaPier, T.L.K., Swislocki, A.L.M., Clark, R.J. and Rodnick, K.J. (2001) Voluntary Running Improves Glucose Tolerance and Insulin Resistance in Female Spontaneously Hypertensive rats. American Journal of Hypertension, 14, 708- 715.
[14] Kinnick, T.R., Youngblood, E.B., O’keefe, M.P., Saengsirisuwan, V., Teachey, M.K. and Henriksen, E.J. (2002) Selected Contribution: Modulation of Insulin Resistance and Hypertension by Voluntary Exercise Training in the TG(m- REN2)27 Rat. Journal of Applied Physiology, 93, 805-812.
[15] Kohno, H., Furukawa, S., Naito, H., Minamitani, K., Ohmori, D. and Yamakura, F. (2002) Contribution of Nitric Oxide, Angiotensin II and Superoxide Dismutase to Exercise-Induced Attenuation of Blood Pressure Elevation in S- pontaneously Hypertensive Rats. Japanese Heart Journal, 43, 25-34.
[16] Haskell-Luevano, C., Schaub, J.W., Andreasen, A., Haskell, K.R., Moore, M.C., Koerper, L.M., Rouzaud, F., Baker, H.V., Millard, W.J., Walter, G., Litherland, S.A. and Xiang, Z. (2009) Voluntary Exercise Prevents the Obese and Diabetic Metabolic Syndrome of the Melanocortin-4 Receptor Knockout Mouse. The FASEB Journal, 23, 642-655.
[17] Laye, M.J., Rector, R.S., Warner, S.O., Naples, S.P., Perretta, A.L., Uptergrove, G.M., Laughlin, M.H., Thyfault, J.P., Booth, F.W. and Ibdah, J.A. (2009) Changes in Visceral Adipose Tissue Mitochondrial Content with Type 2 Diabetes and Daily Voluntary Wheel Running in OLETF Rats. The Journal of Physiology, 587, 3729-3739.
[18] Mikus, C.R., Rector, R.S., Arce-Esquivel, A.A., Libla, J.L., Booth, F.W., Ibdah, J.A., Laughlin, M.H. and Thyfault, J.P. (2010) Daily Physical Activity Enhances Reactivity to Insulin in Skeletal Muscle Arterioles of Hyperphagic Otsuka Long-Evans Tokushima Fatty Rats. Journal of Applied Physiology, 109, 1203-1210.
[19] Rector, R.S., Uptergrove, G.M., Borengasser, S.J., Mikus, C.R., Morris, E.M., Naples, S.P., Laye, M.J., Laughlin, M.H., Booth, F.W., Ibdah, J.A. and Thyfault, J.P. (2010) Changes in Skeletal Muscle Mitochondria in Response to the Development of Type 2 Diabetes or Prevention by Daily Wheel Running in Hyperphagic OLETF Rats. The American Journal of Physiological Society: Endocrinology and Metabolism, 298, E1179-E1187.
[20] Zachwieja, J.J., Hendry, S.L., Smith, S.R. and Harris, R.B.S. (1997) Voluntary Wheel Running Decreases Adipose Tissue Mass and Expression of Leptin mRNA in Osborne-Mendel Rats. Diabetes, 46, 1159-1166.
[21] Bradley, R.L., Jeon, J.Y., Liu, F.-F. and Maratos-Flier, E. (2008) Voluntary Exercise Improves Insulin Sensitivity and Adipose Tissue Inflammation in Diet-Induced Obese Mice. The American Journal of Physiological Society: Endocrinology and Metabolism, 295, E586-E594.
[22] Patterson, C.M., Dunn-Meynell, A.A. and Levin, B.E. (2008) Three Weeks of Early-Onset Exercise Prolongs Obesity Resistance in DIO Rats after Exercise Cessation. American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 294, R290-R301.
[23] Gollisch, K.S.C., Brandauer, J., Jessen, N., Toyoda, T., Nayer, A., Hirshman, M.F. and Goodyear, L.J. (2009) Effects of Exercise Training on Subcutaneous and Visceral Adipose Tissue in Normal- and High-Fat Diet-Fed Rats. The American Journal of Physiological Society: Endocrinology and Metabolism, 297, E495-E504.
[24] Matsumura, Y., Kita, S. and Okui, T. (2001) Potentiation by Endothelin-1 of Vasoconstrictor Response in Stroke-Prone Spontaneously Hypertensive Rats. European Journal of Pharmacology, 415, 45-49.
[25] Skurk, T., Alberti-Huber, C., Herder, C. and Hauner, H. (2007) Relationship between Adipocyte Size and Adipokine Expression and Secretion. The Journal of Clinical Endocrinology and Metabolism, 92, 1023-1033.
[26] Miyazaki, S., Izawa, T., Ogasawara, J., Sakurai, T., Nomura, S., Kizaki, T., Ohno, H. and Komabayashi, T. (2010) Effect of Exercise Training on Adipocyte-Size-Dependent Expression of Leptin and Adiponectin. Life Sciences, 86, 691-698.
[27] Steppan, C.M., Balley, S.T., Bhat, S., Brown, E.J., Banerjee, R.R., Wright, C.M., Patel, H.R., Ahima, R.S. and Lazar, M.A. (2001) The Hormone Resistin Links Obesity to Diabetes. Nature, 409, 307-312.
[28] Rosen, E.D. and Spiegelman, B.M. (2006) Adipocytes as Regulators of Energy Balance and Glucose Homeostasis. Nature, 444, 847-853.
[29] Kim, M., Oh, J.K., Sakata, S., Liang, L., Park, W.J., Hajjar, R.J. and Lebeche, D. (2008) Role of Resistin in Cardiac Contractility and Hypertrophy. Journal of Molecular and Cellular Cardiology, 45, 270-280.
[30] Pradhan, A.D., Manson, J.E., Rifai, N., Buring, J.E. and Ridker, P.M. (2001) C-Reactive Protein, Interleukin 6, and Risk of Developing Type 2 Diabetes Mellitus. The Journal of the American Medical Association, 286, 327-334.
[31] Ridker, P.M., Stampfer, M.J. and Rifai, N. (2001) Novel Risk Factors for Systemic Atherosclerosis. A Comparison of C-Reactive Protein, Fibrinogen, Homocysteine, Lipoprotein(a), and Standard Cholesterol Screening as Predictors of Peripheral Arterial Disease. The Journal of the American Medical Association, 285, 2481-2485.
[32] Ridker, P.M., Buring, J.E., Cook, N.R. and Rifai, N. (2003) C-Reactive Protein, the Metabolic Syndrome, and Risk of Incident Cardiovascular Events. An 8-Year Follow-Up of 14719 Initially Healthy American Women. Circulation, 107, 391-397.
[33] Van Gaal, L.F., Mertens, I.L. and De Block, C.E. (2006) Mechanisms Linking Obesity with Cardiovascular Disease. Nature, 444, 875-880.
[34] Pedersen, B.K. and Febbraio, M.A. (2008) Muscle as an Endocrine Organ: Focus on Muscle-Derived Interleukin-6. Physiological Reviews, 88, 1379-1406.
[35] Kiyonaga, A., Arakawa, K., Tanaka, H. and Shindo, M. (1985) Blood Pressure and Hormonal Responses to Aerobic Exercise. Hypertension, 7, 125-131.
[36] Jennings, G., Nelson, L., Nestel, P., Esler, M., Korner, P., Burton, D. and Bazelmans, J. (1986) The Effects of Changes in Physical Activity on Major Cardiovascular Risk Factors, Hemodynamics, Sympathetic Function, and Glucose Utilization in Man: A Controlled Study of Four Levels of Activity. Circulation, 73, 30-40.
[37] Urata, H., Tanabe, Y., Kiyonaga, A., Ikeda, M., Tanaka, H., Shindo, M. and Arakawa, K. (1987) Antihypertensive and Volume-Depleting Effects of Mild Exercise on Essential Hypertension. Hypertension, 9, 245-252.
[38] Campbell, D.J. and Habener, J.F. (1987) Cellular Localization of Angiotensinogen Gene Expression in Brown Adipose Tissue and Mesentery: Quantification of Messenger Ribonucleic acid Abundance Using Hybridization in Situ. Endocrinology, 121, 1616-1626.
[39] Frederich, R.C., Kahn, B.B., Peach, M.J. and Flier, J.S. (1992) Tissue-Specific Nutritional Regulation of Angiotensinogen in Adipose Tissue. Hypertension, 19, 33-344.
[40] Massiera, F., Bloch-Faure, M., Ceiler, D., Murakami, K., Fukamizu, A., Gasc, J.-M., Quignard-Boulange, A., Negrel, R., Ailhaud, G., Seydoux, J., Meneton, P. and Teboul, M. (2001) Adipose Angiotensinogen Is Involved in Adipose Tissue Growth and Blood Pressure Regulation. The FASEB Journal, 15, 2727-2729.
[41] Yiannikouris, F., Karounos, M., Charnigo, R., English, V.L., Rateri, D.L., Daugherty, A. and Cassis, L.A. (2012) Adipocyte-Specific Deficiency of Angiotensinogen Decreases Plasma Angiotensinogen Concentration and Systolic Blood Pressure in Mice. American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 302, R244- R251.
[42] Tipton, C.M., Sebastian, L.A., Overton, J.M., Woodman, C.R. and Williams, S.B. (1991) Chronic Exercise and Its Hemodynamic Influences on Resting Blood Pressure of Hypertensive Rats. Journal of Applied Physiology, 71, 2206- 2210.
[43] Veras-silva, A.S., Mattos, K.C., Gava, N.S., Brum, P.C., Negrao, C.E. and Krieger, E.M. (1997) Low-Intensity Exercise Training Decreases Cardiac Output and Hypertension in Spontaneously Hypertensive Rats. American Journal of Physiology, 273, H2627-H263.
[44] Sun, M.-W., Qian, F.-L., Wang, J., Tao, T., Guo, J., Wang, L., Lu, A.-Y. and Chen, H. (2008) Low-Intensity Voluntary Running Lowers Blood Pressure with Simultaneous Improvement in Endothelium-Dependent Vasodilatation and Insulin Sensitivity in Aged Spontaneously Hypertensive Rats. Hypertension Research, 31, 543-552.
[45] Sun, D., Huang, A., Koller, A. and Kaley, G. (1994) Short-Term Daily Exercise Activity Enhances Endothelial NO Synthesis in Skeletal Muscle Arterioles of Rats. Journal of Applied Physiology, 76, 2241-2247.
[46] Spier, S.A., Delp, M.D., Meininger, C.J., Donato, A.J., Ramsey, M.W. and Muller-Delp, J.M. (2004) Effects of Ageing and Exercise Training on Endothelium-Dependent Vasodilatation and Structure of Rat Skeletal Muscle Arterioles. The Journal of Physiology, 556, 947-958.
[47] Masuo, K., Mikami, H., Ogihara, T. and Tuck, M.L. (2000) Weight Gain-Induced Blood Pressure Elevation. Hypertension, 35, 1135-1140.
[48] Haynes, W.G., Sivitz, W.I., Morgan, D.A., Walsh, S.A. and Mark, A.L. (1997) Sympathetic and Cardiorenal Actions of Leptin. Hypertension, 30, 619-623.
[49] Shek, E.W., Brands, M.W. and Hall, J.E. (1998) Chronic Leptin Infusion Increases Arterial Pressure. Hypertension, 31, 409-414.
[50] Mueller, P.J. and Hasser, E.M. (2006) Putative Role of the NTS in Alterations in Neural Control of the Circulation Following Exercise Training in Rats. American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, 290, R383-R394.
[51] Michelini, L.C. and Stern, J.E. (2009) Exercise-Induced Neuronal Plasticity in Central Autonomic Networks: Role in Cardiovascular Control. Experimental Physiology, 94, 947-960.
[52] Waki, H., Gouraud, S.S., Bhuiyan, M.E.R., Takagishi, M., Yamazaki, T., Kohsaka, A. and Maeda, M. (2013) Transcriptome of the NTS in Exercise-Trained Spontaneously Hypertensive Rats: Implications for NTS Function and Plasticity in Regulating Blood Pressure. Physiological Genomics, 45, 58-67.
[53] Holloszy, J.O. and Coyle, E.F. (1984) Adaptations of Skeletal Muscle to Endurance Exercise and Their Metabolic Consequences. Journal of Applied Physiology, 56, 831-838.
[54] Holloszy, J.O. (2011) Regulation of Mitochondrial Biogenesis and GLUT 4 Expression by Exercise. Comprehensive Physiology, 1, 921-940.
[55] Fitzsimons, D.P., Diffee, G.M., Herrick, R.E. and Baldwin, K.M. (1990) Effects of Endurance Exercise on Isomyosin Patterns in Fast- and Slow-Twitch Skeletal Muscles. Journal of Applied Physiology, 68, 1950-1955.
[56] Sullivan, V.K., Powers, S.K., Criswell, D.S., Tumer, N., Larochelle, J.S. and Lowenthal, D. (1995) Myosin Heavy Chain Composition in Young and Old Rat Skeletal Muscle: Effects of Endurance Exercise. Journal of Applied Physiology, 78, 2115-2120.
[57] Sexton, W.L. (1995) Vascular Adaptations in Rat Hindlimb Skeletal Muscle after Voluntary Running-Wheel Exercise. Journal of Applied Physiology, 79, 287-296.
[58] Rodnick, K.J., Henriksen, E.J., James, D.E. and Holloszy, J.O. (1992) Exercise Training, Glucose Transporters, and Glucose Transport in Rat Skeletal Muscles. American Journal of Physiology, 262, C9-C14.
[59] Henriksen, E.J. and Halseth, A.E. (1995) Adaptive Responses of GLUT-4 and Citrate Synthase in Fast-Twitch Muscle of Voluntary Running Rats. American Journal of Physiology, 268, R130-R134.
[60] Hokama, J.Y., Streeper, R.S. and Henriksen, E.J. (1997) Voluntary Exercise Training Enhances Glucose Transport in Muscle Stimulated by Insulin-Like Growth Factor I. Journal of Applied Physiology, 82, 508-512.
[61] Kamei, N., Tobe, K., Suzuki, R., Ohsugi, M., Watanabe, T., Kubota, N., Ohtsuka-Kowatari, N., Kumagai, K., Sakamoto, K., Kobayashi, M., Yamauchi, T., Ueki, K., Oishi, Y., Nishimura, S., Manabe, I., Hashimoto, H., Ohnishi, Y., Ogata, H., Tokuyama, K., Tsunoda, M., Ide, T., Murakami. K., Nagai, R. and Kadowaki, T. (2006) Overexpression of Monocyte Chemoattractant Protein-1 in Adipose Tissue Causes Macrophage Recruitment and Insulin Resistance. The Journal of Biological Chemistry, 281, 26602-26614.
[62] Kanda, H., Tateya, S., Tamori, Y., Kotani, K., Hiasa, K., Kitazawa, R., Kitazawa, S., Miyachi, H., Maeda, S., Egashira, K. and Kasuga, M. (2006) MCP-1 Contributes to Macrophage Infiltration into Adipose Tissue, Insulin Resistance, and Hepatic Steatosis in Obesity. Journal of Clinical Investigation, 116, 1494-1505.
[63] Matter, C.M. and Handschin, C. (2007) RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted), Inflammation, Obesity, and the Metabolic Syndrome. Circulation, 115, 946-948.
[64] Wu, H., Ghosh, S., Perrard, X.D., Feng, L., Garcia, G.E., Perrard, J.L., Sweeney, J.F., Peterson, L.E., Chan, L., Smith, C.W. and Ballantyne, C.M. (2007) T-Cell Accumulation and Regulated on Activation, Normal T Cell Expressed and Secreted Upregulation in Adipose Tissue in Obesity. Circulation, 115, 1029-1038.
[65] Prior, B.M., Yang, H.T. and Terjung, R.L. (2004) What Makes Vessels Grow with Exercise Training? Journal of Applied Physiology, 97, 1119-1128.
[66] Bloor, C.M. (2005) Angiogenesis during Exercise and Training. Angiogenesis, 8, 263-271.
[67] Waters, R.E., Rotevatn, S., Li, P., Annex, B.H. and Yan, Z. (2004) Voluntary Running Induces Fiber Type-Specific Angiogenesis in Mouse Skeletal Muscle. American Journal of Physiology-Cell Physiology, 287, C1342-C1348.
[68] Lloyd, P.G., Prior, B.M., Yang, H.T. and Terjung, R.L. (2003) Angiogenic Growth Factor Expression in Rat Skeletal Muscle in Response to Exercise Training. The American Journal of Physiology: Heart and Circulatory Physiology, 284, H1668-H1678.
[69] Pedersen, B.K. (2009) Muscle as an Endocrine Organ: IL-6 and Other Myokines. Journal of Applied Physiology, 107, 1006-1014.

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