Circadian changes in cardiovascular function during the progression of diabetes mellitus in the diabetes prone rat (BBDP) ( ) were studied. Age-matched diabetes-resistant rats (BBDR) served as controls. BP was recorded via telemetry in contiguous 4？hr time periods over 24 hours starting with 12 midnight to 4？am as period zero (P0). Prior to onset of diabetes BP was high at P0, peaked at P2, and then fell again at P3; BP and heart rate (HR) then increased gradually at P4 and leveled off at P5, thereby exhibiting a bipodal rhythm. These patterns changed during long-term diabetes. The cross-correlation coefficient of BP and HR was not significantly different across groups at onset, but it fell significantly at 9 months of duration of diabetes (BBDP: 0.39 ± 0.06; BBDR: 0.65 ± 0.03; ). These results show that changes in circadian cardiovascular rhythms in diabetes mellitus became significant at the late stage of the disease. 1. Introduction Circadian variations in most bodily functions have been recognized. The circadian variation enables the organism, system, and individual organs to maximize efficiency by ensuring optimal performance with minimal energy expenditure. The diurnal variation in blood pressure rhythm has been demonstrated in man [1–3] and various mammalian species [4–6]. Some variations in the circadian blood pressure patterns have been attributed to endocrine influences [7, 8] while others are thought to be of neural origin [9]. Blood pressure and heart rate are thought to vary in different ways, with diurnal changes in weather, time of day, and temperature. Circadian rhythm involves changes in autonomic function controlled by the hypothalamus and influenced by the higher brain centers. Therefore variation in circadian rhythm may also be an indicator of autonomic changes. Vinik and Erbas [10] have stressed the importance of recognizing and treating autonomic neuropathy in diabetes, but early detection of autonomic neuropathy is difficult with current assessment techniques. The search for more sensitive, less invasive, and less stressful markers of autonomic and cardiovascular dysfunction is still imperative. Young et al. [11] have reported that the heart possesses an internal circadian clock, which is associated with gene expression, metabolism, and contractile performance. They reported loss of synchronization in the phases of these circadian rhythms in streptozotocin-induced diabetes in rats. Loss of circadian rhythm of blood pressure following acute stroke has been reported in human patients [12–14]. Diabetes mellitus is known to produce
References
[1]
M. Middeke and J. Schrader, “Nocturnal blood pressure in normotensive subjects and those with white coat, primary, and secondary hypertension,” British Medical Journal, vol. 308, no. 6929, pp. 630–632, 1994.
[2]
D. Sander and J. Klingelh？fer, “Changes of circadian blood pressure patterns after hemodynamic and thromboembolic brain infarction,” Stroke, vol. 25, no. 9, pp. 1730–1737, 1994.
[3]
I. Edery, “Circadian rhythms in a nutshell,” Physiological Genomics, vol. 3, pp. 59–74, 2000.
[4]
K. Sato, F. Chatani, and S. Sato, “Circadian and short-term variabilities in blood pressure and heart rate measured by telemetry in rabbits and rats,” Journal of the Autonomic Nervous System, vol. 54, no. 3, pp. 235–246, 1995.
[5]
M. Mishina, T. Watanabe, S. Matsuoka et al., “Diurnal variations of blood pressure in dogs,” Journal of Veterinary Medical Science, vol. 61, no. 6, pp. 643–647, 1999.
[6]
V. Gross, A. F. Milia, R. Plehm, T. Inagami, and F. C. Luft, “Long-term blood pressure telemetry in AT receptor-disrupted mice,” Journal of Hypertension, vol. 18, no. 7, pp. 955–961, 2000.
[7]
J. Widimsky Jr., M. Krsek, and J. Marek, “Altered circadian blood pressure rhythm in endocrine diseases,” Experimental and Clinical Cardiology, vol. 1, pp. 108–112, 1996.
[8]
M. Middeke, M. Kluglich, and H. Holzgreve, “Circadian blood pressure rhythm in primary and secondary hypertension,” Chronobiology International, vol. 8, no. 6, pp. 451–459, 1991.
[9]
D. P. F. Duarte, V. L. Silva, A. M. Jaguaribe, D. P. Gilmore, and C. P. Da Costa, “Circadian rhythms in blood pressure in free-ranging three-toed sloths (Bradypus variegatus),” Brazilian Journal of Medical and Biological Research, vol. 36, no. 2, pp. 273–278, 2003.
[10]
A. I. Vinik and T. Erbas, “Recognizing and treating diabetic autonomic neuropathy,” Cleveland Clinic Journal of Medicine, vol. 68, no. 11, pp. 928–944, 2001.
[11]
M. E. Young, C. R. Wilson, P. Razeghi, P. H. Guthrie, and H. Taegtmeyer, “Alterations of the circadian clock in the heart by streptozotocin-induced diabetes,” Journal of Molecular and Cellular Cardiology, vol. 34, no. 2, pp. 223–231, 2002.
[12]
S. Jain, K. K. N. Namboodri, S. Kumari, and S. Prabhakar, “Loss of circadian rhythm of blood pressure following acute stroke,” BMC Neurology, vol. 4, pp. 1–6, 2004.
[13]
S. L. Dawson, S. N. Evans, B. N. Manktelow, M. D. Fotherby, T. G. Robinson, and J. F. Potter, “Diurnal blood pressure change varies with stroke subtype in the acute phase,” Stroke, vol. 29, no. 8, pp. 1519–1524, 1998.
[14]
J. T. Korpelainen, K. A. Sotaniemi, H. V. Huikuri, and V. V. Myllyl？, “Circadian rhythm of heart rate variability is reversibly abolished in ischemic stroke,” Stroke, vol. 28, no. 11, pp. 2150–2154, 1997.
[15]
A. I. Vinik, R. E. Maser, B. D. Mitchell, and R. Freeman, “Diabetic autonomic neuropathy,” Diabetes Care, vol. 26, no. 5, pp. 1553–1579, 2003.
[16]
D. L. Eckberg, S. W. Harkins, J. M. Fritsch, G. E. Musgrave, and D. F. Gardner, “Baroreflex control of plasma norepinephrine and heart period in healthy in healthy subjects and diabetic patients,” The Journal of Clinical Investigation, vol. 78, pp. 366–374, 1986.
[17]
M. Lishner, S. Akselrod, V. Mor Avi, O. Oz, M. Divon, and M. Ravid, “Spectral analysis of heart rate fluctuations. A non-invasive, sensitive method for the early diagnosis of autonomic neuropathy in diabetes mellitus,” Journal of the Autonomic Nervous System, vol. 19, no. 2, pp. 119–125, 1987.
[18]
K. K. Hicks, E. Seifen, J. R. Stimers, and R. H. Kennedy, “Effects of streptozotocin-induced diabetes on heart rate, blood pressure and cardiac autonomic nervous control,” Journal of the Autonomic Nervous System, vol. 69, no. 1, pp. 21–30, 1998.
[19]
C. N. Anigbogu and S. A. Adigun, “Blood pressure, heart rate and autonomic reflexes in Plasmodium berghei malaria infection,” Nigerian Quarterly J of Hospital Medicine, vol. 6, pp. 47–51, 1996.
[20]
National Research Council, Guide for the Care and Use of Laboratory Animals, National Academy Press, Washington, DC, USA, 1996.
[21]
B. R. Baldridge, D. E. Burgess, E. E. Zimmerman, et al., “Heart rate-arterial blood pressure relationship in conscious rat before vs. after spinal cord transaction,” American Journal of Physiology, vol. 283, pp. R748–R756, 2002.
[22]
C. N. Anigbogu, R. O. Speakman, D. L. Silcox, et al., “Extended longitudinal analysis of arterial blood pressure and heart rate in unanesthetized rats with type 1 diabetes mellitus and in age-matched controls,” submitted to American Journal of Physiology.
[23]
M. E. Young, P. Razeghi, and H. Taegtmeyer, “Clock genes in the heart: characterization and attenuation with hypertrophy,” Circulation Research, vol. 88, no. 11, pp. 1142–1150, 2001.
[24]
F. Damiola, N. Le Minli, N. Preitner, B. Kornmann, F. Fleury-Olela, and U. Schibler, “Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus,” Genes and Development, vol. 14, no. 23, pp. 2950–2961, 2000.
[25]
S. Yamazaki, R. Numano, M. Abe et al., “Resetting central and peripheral circadian oscillators in transgenic rats,” Science, vol. 288, no. 5466, pp. 682–685, 2000.
[26]
R. T. Dowell, F. L. Atkins, and S. Love, “Integrative nature and time course of cardiovascular alterations in the diabetic rat,” The Journal of Clinical Investigation, vol. 78, pp. 366–374, 1986.
[27]
S. Ramanadham and T. E. Tenner Jr., “Chronic effects of streptozotocin diabetes on myocardial sensitivity in the rat,” Diabetologia, vol. 29, no. 10, pp. 741–748, 1986.
[28]
E. Dobrzynski, D. Montanari, J. Agata, J. Zhu, J. Chao, and L. Chao, “Adrenomedullin improves cardiac function and prevents renal damage in streptozotocin-induced diabetic rats,” American Journal of Physiology, vol. 283, no. 6, pp. E1291–E1298, 2002.
[29]
M. E. Young, C. R. Wilson, P. Razeghi, P. H. Guthrie, and H. Taegtmeyer, “Alterations of the circadian clock in the heart by streptozotocin-induced diabetes,” Journal of Molecular and Cellular Cardiology, vol. 34, no. 2, pp. 223–231, 2002.
[30]
N. Akiyama, K. Okumura, Y. Watanabe et al., “Altered acethlcholine and norepinephrine concentrations in diabetic rat hearts. Role of parasympathetic nervous system in diabetic cardiomyopathy,” Diabetes, vol. 38, no. 2, pp. 231–236, 1989.
[31]
X. Li, R. D. Tanz, and K. S. K. Chang, “Effect of age and methacholine on the rate and coronary flow of isolated hearts of diabetic rats,” British Journal of Pharmacology, vol. 97, no. 4, pp. 1209–1217, 1989.
[32]
K. A. Kimball, R. H. Kennedy, and E. Seifen, “Diabetes and the control of cardiac pacemaking activity,” The FASEB Journal, vol. 5, article A1257, 1991.
[33]
D. C. Randall, D. E. Burgess, E. E. Zimmerman, et al., “BP and HR cross correlations in rat before vs after spinal cord transection,” The FASEB Journal, vol. 15, article A1145, 2001.
[34]
L. Brown, D. Brown, D. Randall, and C. Knapp, “Correlation of arterial pressure, heart rate and physical activity in rats,” Federation Proceedings, vol. 46, article A1252, 1987.
