背景：高血壓病人冬季血壓明顯高於夏季，同時冬季也為心血管疾病發生率與死亡率的高峰期。此外，許多原發性高血壓病人有睡眠障礙問題，於低溫環境下可能更為嚴重而導致更高心血管疾病發生風險。這些現象皆與自主神經調控有關，但機轉仍不明確。目標：探討心循環自主神經及感壓反射於高血壓患者之低溫引發血壓上升之可能角色，與低溫下睡眠結構與品質的影響與自主神經的關係。材料與方法：十周自發性高血壓大鼠 (spontaneously hypertensive rat, SHR) 及正常血壓對照大鼠 (Wistar-Kyoto rat, WKY) 手術埋設記錄電極。術後七天，大鼠放置於環境溫度控制箱記錄，一天六小時每次施予一種溫度：23、18、15oC。每隻大鼠其環境溫度以隨機方式介入。利用環境溫度控制器與無線生理遙測系統記錄腦電波、肌電波、心電、環境溫度及血壓訊號，並分析睡眠結構、自主神經功能及感壓反射靈敏度 (baroreflex sensitivity, BRS) 變化。結果：室溫下SHR與WKY相比，於睡醒各期平均血壓 (MAP) 皆顯著較高及感壓反射靈敏度皆明顯較低，且特別於睡眠時出現自主神經失調。與環境溫度23oC相比，無論是WKY或SHR，環境低溫下 (18oC及15oC) 於睡醒各期都會引發MAP上升、副交感神經活性 (HF) 下降，而低溫造成交感神經活性 (BLF) 上升及BRS降低則好發於睡眠時期。環境低溫下SHR與WKY相比，於MAP及BLF顯著較高且HF及BRS明顯較低。此外，環境低溫也使得SHR睡眠中斷次數增加，且與自主神經變化有關。結論：原本睡眠時自主神經失調及感壓反射靈敏度缺陷之SHR，於低溫環境睡眠時交感神經活性增強與BRS減弱，且睡眠中斷也受低溫影響更趨嚴重，這些現象可能為高血壓病人冬季高心血管疾病的原因。

Background: Hypertensive patients had higher blood pressure (BP) in winter than in summer. Additionally, the attacks of cardiovascular disease also peaked in winter. Hypertensive patients with sleep disorders were under a higher risk for cardiovascular disease when exposed to low ambient temperature (Ta). The autonomic nervous system is proposed to involve in these processes, yet the underlying mechanism remains undetermined. Materials and Methods: 10 weeks old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rat (SHR) were implanted with recording electrodes. After seven days of recovery from the surgery, the rat was put in an air conditioned chamber in exposure to a random combination of ambient temperatures (Ta, 23, 18, and 15oC) for three days (six hours a day, one temperature for one day). Electroencephalogram (EEG) and activity were used to classify active waking (AW), quiet sleep (QS) and paradoxical sleep (PS). Autonomic activities were assessed using spectral analysis of heart rate variability and arterial pressure variability. Baroreflex sensitivity (BRS) was assessed by the slopes of the regression lines of the mean arterial pressure (MAP) and RR interval pairs that ascended (BrrA) or descended (BrrD) successively. Results: At room temperature (23oC) SHR exhibited sympathovagal imbalance during sleep and had higher MAP and lower BRS than WKY across wake and sleep. In exposure to low Ta (18oC and 15oC), both WKY and SHR showed elevated MAP and decreased HF throughout wake and sleep and had higher BLF and lower BRS especially during sleep. At low Ta SHR had significantly higher MAP and BLF and lower HF and BRS than WKY. Additionally, the increased interruptions during QS in SHR were more prominent at low Ta, and correlated with BLF and HF during QS and HF during AW. Conclusion: The worse sleep quality, abnormal sleep-related sympathovagal imbalance and impaired BRS in SHR are deteriorated at low Ta, and may explain the cold-induced cardiovascular events in hypertensive patients.

目錄 I
中文摘要 V
英文摘要 VI
研究背景介紹 1
高血壓病人心血管疾病與環境低溫的關係 1
高血壓之自主神經功能異常與睡眠問題 1
低溫下造成自主神經活性與睡眠結構之變化 2
睡醒時自主神經功能的調節變化 3
自主神經於心血管調控 4
感壓反射於心血管調控 4
心率變異性 4
血壓變異性 5
目的 6
重要性 6
研究假說 7
研究材料與方法 8
動物處理 8
血壓電極埋設手術 8
遙測系統埋設手術操作 8
實驗流程 9
環境溫度控制 9
訊號收集 10
訊號分析 10
睡眠型式分析 11
心電訊號處理 11
心電及血壓訊號頻譜分析 12
頻譜分析判讀 12
感壓反射評估 12
統計分析 13
實驗結果 14
環境低溫引發平均動脈壓上升及心跳間距下降 14
WKY 14
環境低溫造成自主神經功能的變化 15
環境低溫造成感壓反射靈敏度的變化 15
環境低溫對睡眠結構的影響 16
環境低溫下睡眠與自主神經的相關性 16
討論 17
本論文之發現 17
低溫對於正常血壓大鼠之自主神經活性與感壓反射靈敏度之影響 17
低溫對於高血壓大鼠之自主神經活性與感壓反射靈敏度之影響 18
低溫對於正常血壓大鼠之睡眠的影響 19
低溫對於高血壓大鼠之睡眠的影響 19
低溫下正常血壓大鼠睡眠與自主神經活性之相關變化 19
低溫下高血壓大鼠睡眠與自主神經活性之相關變化 20
本論文之限制 20
結論 21
附圖 22
參考文獻 34

1. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Eur Heart J 17: 354-381, 1996.
2. Busek P, Vankova J, Opavsky J, Salinger J, and Nevsimalova S. Spectral analysis of the heart rate variability in sleep. Physiol Res 54: 369-376, 2005.
3. Cerri M, Ocampo-Garces A, Amici R, Baracchi F, Capitani P, Jones CA, Luppi M, Perez E, Parmeggiani PL, and Zamboni G. Cold exposure and sleep in the rat: effects on sleep architecture and the electroencephalogram. Sleep 28: 694-705, 2005.
4. Chambers JB, Williams TD, Nakamura A, Henderson RP, Overton JM, and Rashotte ME. Cardiovascular and metabolic responses of hypertensive and normotensive rats to one week of cold exposure. Am J Physiol Regul Integr Comp Physiol 279: R1486-1494, 2000.
5. Cui J, Wilson TE, and Crandall CG. Baroreflex modulation of muscle sympathetic nerve activity during cold pressor test in humans. Am J Physiol Heart Circ Physiol 282: H1717-1723, 2002.
6. Enquselassie F, Dobson AJ, Alexander HM, and Steele PL. Seasons, temperature and coronary disease. Int J Epidemiol 22: 632-636, 1993.
7. Esler M, Jennings G, Biviano B, Lambert G, and Hasking G. Mechanism of elevated plasma noradrenaline in the course of essential hypertension. J Cardiovasc Pharmacol 8 Suppl 5: S39-43, 1986.
8. Fagius J, and Kay R. Low ambient temperature increases baroreflex-governed sympathetic outflow to muscle vessels in humans. Acta Physiol Scand 142: 201-209, 1991.
9. Foley DJ, Monjan AA, Izmirlian G, Hays JC, and Blazer DG. Incidence and remission of insomnia among elderly adults in a biracial cohort. Sleep 22 Suppl 2: S373-378, 1999.
10. Jehn M, Appel LJ, Sacks FM, and Miller ER, 3rd. The effect of ambient temperature and barometric pressure on ambulatory blood pressure variability. Am J Hypertens 15: 941-945, 2002.
11. Judy WV, Watanabe AM, Henry DP, Besch HR, Jr., Murphy WR, and Hockel GM. Sympathetic nerve activity: role in regulation of blood pressure in the spontaenously hypertensive rat. Circ Res 38: 21-29, 1976.
12. Julius S. Effect of sympathetic overactivity on cardiovascular prognosis in hypertension. Eur Heart J 19 F14-F18, 1998.
13. Kawada T, Shishido T, Inagaki M, Tatewaki T, Zheng C, Yanagiya Y, Sugimachi M, and Sunagawa K. Differential dynamic baroreflex regulation of cardiac and renal sympathetic nerve activities. Am J Physiol Heart Circ Physiol 280: H1581-1590, 2001.
14. Krauchi K, Cajochen C, Werth E, and Wirz-Justice A. Warm feet promote the rapid onset of sleep. Nature 401: 36-37, 1999.
15. Krauchi K, Gasio PF, Vollenweider S, Von Arb M, Dubler B, Orgul S, Flammer J, and Stutz EZ. Cold extremities and difficulties initiating sleep: evidence of co-morbidity from a random sample of a Swiss urban population. J Sleep Res 17: 420-426, 2008.
16. Kumar D, Mallick H, and Kumar V. Ambient temperature that induces maximum sleep in rats. Physiology & Behavior article in press: 2009.
17. Kuo TBJ, Lai CJ, Shaw FZ, Lai CW, and Yang CCH. Sleep-related sympathovagal imbalance in SHR. Am J Physiol Heart Circ Physiol 286: H1170-H1176, 2004.
18. Kuo TBJ, Lin T, Yang CCH, Li CL, Chen CF, and Chou P. Effect of aging on gender differences in neural control of heart rate. Am J Physiol 277: H2233-H2239, 1999.
19. Kuo TBJ, Shaw FZ, Lai CJ, Lai CW, and Yang CCH. Changes in sleep patterns in spontaneously hypertensive rats. Sleep 27: 406-412, 2004.
20. Kuo TBJ, Shaw FZ, Lai CJ, and Yang CCH. Asymmetry in sympathetic and vagal activities during sleep-wake transitions. Sleep 31: 311-320, 2008.
21. Kuo TBJ, and Yang CCH. Altered frequency characteristic of central vasomotor control in SHR. Am J Physiol Heart Circ Physiol 278: H201-H207, 2000.
22. Kuo TBJ, and Yang CCH. Sleep-related changes in cardiovascular neural regulation in spontaneously hypertensive rats. Circulation 112: 849-854, 2005.
23. Kuo TBJ, Yang CCH, and Chan SH. Transfer function analysis of ventilatory influence on systemic arterial pressure in the rat. Am J Physiol 271: H2108-H2115, 1996.
24. Li JY, Kuo TBJ, Hsieh SS, and Yang CCH. Changes in electroencephalogram and heart rate during treadmill exercise in the rat. Neurosci Lett 434: 175-178, 2008.
25. Lin YT, Kuo TBJ, Yang CCH. Role of autonomic modulations on ambient temperature related body temperature and sleep structure changes. 2008.
26. Lusardi P, Zoppi A, Preti P, Pesce RM, Piazza E, and Fogari R. Effects of insufficient sleep on blood pressure in hypertensive patients: a 24-h study. Am J Hypertens 12: 63-68, 1999.
27. Mahapatra AP, Mallick HN, and Kumar VM. Changes in sleep on chronic exposure to warm and cold ambient temperatures. Physiol Behav 84: 287-294, 2005.
28. Marchant B RK, Stevenson R, Wilkinson P, Timmis AD Circadian and seasonal factors in the pathogenesis of acute myocardial infarction: the influence of environmental temperature. British Heart Journal 69: 385-387, 1993.
29. Masuda Y. Role of the parasympathetic nervous system and interaction with the sympathetic nervous system in the early phase of hypertension. J Cardiovasc Pharmacol 36 S61-64, 2000.
30. Meir H, Kryger TR, and Dement. WC. Temperature, thermoregulation, and sleep. 4th ed. Philadelphia: Elserier saunders. 2005.
31. Minami J, Kawano Y, Ishimitsu T, Yoshimi H, and Takishita S. Seasonal variations in office, home and 24 h ambulatory blood pressure in patients with essential hypertension. J Hypertens 14: 1421-1425, 1996.
32. Modesti PA, Morabito M, Bertolozzi I, Massetti L, Panci G, Lumachi C, Giglio A, Bilo G, Caldara G, Lonati L, Orlandini S, Maracchi G, Mancia G, Gensini GF, and Parati G. Weather-related changes in 24-hour blood pressure profile: effects of age and implications for hypertension management. Hypertension 47: 155-161, 2006.
33. Owens NC, Ootsuka Y, Kanosue K, and McAllen RM. Thermoregulatory control of sympathetic fibres supplying the rat's tail. J Physiol 543: 849-858, 2002.
34. Papanek PE, Wood CE, and Fregly MJ. Role of the sympathetic nervous system in cold-induced hypertension in rats. J Appl Physiol 71: 300-306, 1991.
35. Pedulla M, Silvestri R, Lasco A, Mento G, Lanuzza B, Sofia L, and Frisina N. Sleep structure in essential hypertensive patients: differences between dippers and non-dippers. Blood Press 4: 232-237, 1995.
36. Picotti GB, Carruba MO, Ravazzani C, Bondiolotti GP, and Da Prada M. Plasma catecholamine concentrations in normotensive rats of different strains and in spontaneously hypertensive rats under basal conditions and during cold exposure. Life Sci 31: 2137-2143, 1982.
37. Prejbisz A, Kabat M, Januszewicz A, Szelenberger W, Piotrowska AJ, Piotrowski W, Piwonski J, Makowiecka-Ciesla M, Widecka K, Patera B, Bieniaszewski L, Narkiewicz K, Tykarski A, Piejko A, Grodzicki T, Czerwienska B, and Wiecek A. Characterization of insomnia in patients with essential hypertension. Blood Press 15: 213-219, 2006.
38. Sabharwal R, Coote JH, Johns EJ, and Egginton S. Effect of hypothermia on baroreflex control of heart rate and renal sympathetic nerve activity in anaesthetized rats. J Physiol 557: 247-259, 2004.
39. Schwartz S, McDowell Anderson W, Cole SR, Cornoni-Huntley J, Hays JC, and Blazer D. Insomnia and heart disease: a review of epidemiologic studies. J Psychosom Res 47: 313-333, 1999.
40. Seals DR, and Esler MD. Human ageing and the sympathoadrenal system. J Physiol 528: 407-417, 2000.
41. Sei H, and Morita Y. Effect of ambient temperature on arterial pressure variability during sleep in the rat. J Sleep Res 5: 37-41, 1996.
42. Sheth T, Nair C, Muller J, and Yusuf S. Increased winter mortality from acute myocardial infarction and stroke: the effect of age. J Am Coll Cardiol 33: 1916-1919, 1999.
43. Somers VK, Dyken ME, Mark AL, and Abboud FM. Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med 328: 303-307, 1993.
44. Spencer FA, Goldberg RJ, Becker RC, and Gore JM. Seasonal distribution of acute myocardial infarction in the second National Registry of Myocardial Infarction. J Am Coll Cardiol 31: 1226-1233, 1998.
45. Trinder J, Kleiman J, Carrington M, Smith S, Breen S, Tan N, and Kim Y. Autonomic activity during human sleep as a function of time and sleep stage. J Sleep Res 10: 253-264, 2001.
46. Wallin BG, Thompson JM, Jennings GL, and Esler MD. Renal noradrenaline spillover correlates with muscle sympathetic activity in humans. J Physiol 491 881-887, 1996.
47. Winnicki M, Canali C, Accurso V, Dorigatti F, Giovinazzo P, and Palatini P. Relation of 24-hour ambulatory blood pressure and short-term blood pressure variability to seasonal changes in environmental temperature in stage I hypertensive subjects. Results of the Harvest Trial. Clin Exp Hypertens 18: 995-1012, 1996.
48. Wolk R, Gami AS, Garcia-Touchard A, and Somers VK. Sleep and cardiovascular disease. Curr Probl Cardiol 30: 625-662, 2005.
49. Yang CCH, Lai CW, Lai HY, and Kuo TBJ. Relationship between electroencephalogram slow-wave magnitude and heart rate variability during sleep in humans. Neurosci Lett 329: 213-216, 2002.
50. Yang CCH , Shaw FZ, Lai CJ, Lai CW, and Kuo TBJ. Relationship between electroencephalogram slow-wave magnitude and heart rate variability during sleep in rats. Neurosci Lett 336: 21-24, 2003.