脑卒中预防的新策略研究
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摘要
目的:寻找预防脑卒中的新的作用靶点,探讨其可能的作用机制,在此基础上为脑卒中的预防提供新的治疗策略。结果和结论:(1)动脉压力感受性反射(ABR)功能作为一个独立的因子,可以预测高血压性脑卒中的发生。小剂量酮色林单纯地通过改善ABR功能,显著地延缓脑卒中的发生。(2)热量限制可以显著地延缓SHR-SP脑卒中的发生。这一作用与血压改变无关。ABR功能的改善、长寿蛋白SIRT1表达的增加可能参与这一作用。SIRT1激动剂白藜芦醇长期治疗可以延缓SHR-SP脑卒中的发生。(3)破坏ABR功能导致SD大鼠心肾组织的SIRT1表达降低,并减弱热量限制对SIRT1的增加作用。另外,破坏ABR功能减弱限制热量摄入延缓SHR-SP脑卒中死亡的作用。热量限制延缓SHR-SP脑卒中发生的作用至少部分地由ABR功能介导。
Object: To investigate the new targets for the preventing of stroke in hypertension and its mechanism, and propose the new strategies for it. Results and Conclusion: Arterial baroreflex (ABR) function is a new independent predictor for stroke incident in hypertension, and restoration of impaired baroreflex sensitivity (BRS) alone with low dose of ketanserin delayed stroke death. Caloric restriction (CR) prevents the end organ damage, extends the life span of SHR-SP, and delays the occurrence of stroke. SIRT1 expression, arterial baroreflex function and apoptosis might involve in the effects of CR on stroke death. The expression of SIRT1 was inhibited by impared ABR function by sinoaortic denervation (SAD) operation. The prolonging of life span by CR was also inhibited by impared ABR function.
Object: To investigate the new targets for the preventing of stroke in hypertension and its mechanism, and propose the new strategies for it. Results and Conclusion: Arterial baroreflex (ABR) function is a new independent predictor for stroke incident in hypertension, and restoration of impaired baroreflex sensitivity (BRS) alone with low dose of ketanserin delayed stroke death. Caloric restriction (CR) prevents the end organ damage, extends the life span of SHR-SP, and delays the occurrence of stroke. SIRT1 expression, arterial baroreflex function and apoptosis might involve in the effects of CR on stroke death. The expression of SIRT1 was inhibited by impared ABR function by sinoaortic denervation (SAD) operation. The prolonging of life span by CR was also inhibited by impared ABR function.
引文
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3. Luepker RV, Arnett DK, Jacobs DR Jr, et al. Trends in blood pressure, hypertension control, and stroke mortality: the Minnesota Heart Survey. Am J Med. 2006;119:42-49.
4. Cechetto DF, Wilson JX, Smith KE, Wloski D, Silver MD, Hachinski VC. Autonomic and myocardial changes in middle cerebral artery occlusion: stroke models in the rat. Brain Res. 1989;502:296-305.
5. Wolf-Maier K, Cooper RS, Banegas JR, et al.Hypertension prevalence and blood pressure levels in 6 European countries, Canada, and the United States. JAMA. 2003;289:2363-2369.
6. Editorial. Reducing the burden of stroke. Lancet. 2005;366:1752.
7. La Rovere MT, Pinna GD, Hohnloser SH, et al.Autonomic tone and reflexes after myocardial infarction. Baroreflex sensitivity and heart rate variability in the identification of patients at risk for life-threatening arrhythmias: implications for clinical trials. Circulation. 2001;103:2072-2077.
8. La Rovere MT, Bigger JT, Marcus FI, et al.Baroreflex sensitivity and heart rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet. 1998;351:478-484.
9. Doba N, Reis DJ. Role of central and peripheral adrenergic mechanisms in neurogenic hypertension produced by brainstem lesions in rat. Circ Res. 1974;34: 293-301.
10. Appenzeller O, Descarries L. Circulatory reflexes in patients with cerebrovascular disease. N Engl J Med. 1964;271:820-823.
11. Gross M, Circulatory reflex in cerebral ischaemia involving different vascular territories. Clin Sci. 1970;38:491-502.
12. Robinson T, James M, Youde J, Panerai R, Potter J. Cardiac baroreceptor sensitivity is impaired after acute stroke. Stroke. 1997;28:1671-1676.
13. Robinson TG, Dawson SL, Eames PJ, Panerai RB, Potter JF. Cardiac baroreceptor sensitivity predicts long-term outcome after acute ischemic stroke. Stroke. 2003; 34:705-712.
14. Fu YJ, Shu H, Miao CY, Wang MW, Su DF. Restoration of baroreflex function by ketanserin is not blood pressure dependent in conscious freely moving rats. J Hypertens. 2004;22:1165-1172.
15. Wood JG, Rogina B, Lavu S, et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature. 2004;430: 686-689.
16. Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004;305:390-392.
17. Motta MC, Divecha N, Lemieux M, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004; 116: 551-63.
18. Gasser SM, Cockell MM. The molecular biology of the SIR proteins. Gene. 2001; 279:1-16.
19. Guarente L. Sir2 links chromatin silencing, metabolism, and aging. Genes Dev. 2000; 14: 1021-1026.
20. Yamori Y, Horie R, Handa H, Sato M, Fukase M. Pathogenic similarity of strokes in stroke-prone spontaneously hypertensive rats and humans. Stroke. 1976;7:46-55.
21. Miao CY, Xie HH, Zhan LS, Su DF. Blood pressure variability is more important than blood pressure level in determination of end-organ damage in rats. J Hypertens. 2006; 24:1125-1135.
22. Xie HH, Shen FM, Miao CY, Su DF.Blood pressure, baroreflex sensitivity, and end organ damage in hybrid offspring of spontaneously hypertensive rats and Sprague-Dawley rats. Acta Pharmacol Sin. 2005; 26:1049-1056.
23. Smyth HS, Sleight P, Pichering GM. Reflex regulation of arterial pressure during sleep in man:a quantitative method of assessing baroreflex sensitivity. Circ Res.1969, 24:109-114.
24. Su DF, Chen L, Kong XB, Cheng Y. Determination of arterial baroreflex-blood pressure control in conscious rats. Acta Pharmacol Sin. 2002; 23:103-109.
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