瞬时受体电位通道高血压治疗的新靶点

瞬时受体电位通道瞬时受体电位通道 -高血压治疗的新靶点高血压治疗的新靶点 Transient Receptor Potential Channels A novel target for treatment of Hypertension 祝之明祝之明 第三军医大学全军高血压代谢病中心第三军医大学全军高血压代谢病中心 重庆市高血压研究所重庆市高血压研究所 大坪医院高血压内分泌科大坪医院高血压内分泌科 高血压高血压危险因素 CVD事件 高血压是心血管事件链的重要环节高血压是心血管事件链的重要环节 血脂异常 冠心病冠心病 糖尿病 肾脏损害 肥胖 脑卒中 代谢综合征代谢综合征 外周血管病 不良生活方式 心功能不全 高血压的非药物干预高血压的非药物干预 限盐可致血压下降 3-5mmHg, 减肥致血压下降个体差异大，荟萃分析肥胖者 2年，体重下降 1kg, 血压下降 0.5mmHg Aucott L, et al. Hypertension, 2005,45:1035-1041 高血压的药物治疗高血压的药物治疗 高血压的药物治疗高血压的药物治疗 (Drugs related to RAAS) 降压效应难于完全用药理机制解释降压效应难于完全用药理机制解释 1.CCB 较少证据显示高血压时电压依赖钙通道表达异常 2. ARB和和 ACEI 较少证据显示高血压时组织与循环 RAS异常，拮抗 RAS与组织 ATR、 AngII改变不平行 3. 受体阻断剂受体阻断剂 降压机制至今仍不甚清楚 4. 噻嗪类利尿剂噻嗪类利尿剂 难以证实低剂量的效应与利尿钠有关 细胞钙是血管功能调控的重要信号分子 钙信号调节异常是高血压血管阻力增高的重要特征 Hilgers RHP and Webb RC. Exp Biol Med, 2005 Lifton RP, Cell, 2001 OShanghnessy KM, JCI, 2004 钠盐摄取是影响血压最重要的环节因素之一， 细胞钠水潴留对高血压发生有重要影响 Cosens, D. J. 47:609-614 Role of TRPM7 in hypertension Touyz RM. Am J Physiol, 290: R73R78, 2006. 高血压病人和 SHR单核细胞 TRPC3表达上调，其介导的钙内流增加 M TRPC1 TRPC3 TRPC4 TRPC5 TRPC6 GAPDH M Fluorescence ratio(arbitrary units) Liu DY,Zhu ZM. Am J Hypertens, 2005, 2008, J Hypertens, 2006, 2007 Blank TRPC1 TRPC3 TRPC4 TRPC5 TRPC6 Role of TRPC3 in the pathogenesis of hypertension Identification of TRPC3 in the vasculature Liu, et al. Hypertension, 2009 Increased expression of TRPC3 in aorta from SHR Liu, et al. Hypertension, 2009 Effect of TRPC3 upregulation on angiotensin II - induced calcium increase in SHR Liu, et al. Hypertension, 2009 Effect of TRPC3 gene knockdown on angiotensin II induced calcium increase in SHR Liu, et al. Hypertension, 2009 Angiotensin II increases TRPC3 in VSMC from SHR Liu, et al. Hypertension, 2009 Effect of CCB/SKF on Angiotensin II-induced aortic contraction and calcium increase in VSMC from SHR Liu, et al. Hypertension, 2009 Long term administration of AT1R antagonist telmisartan but not of calcium channel blocker amlodipine reduces TRPC3 in vivo Liu, et al. Hypertension, 2009 Vasomotion occurs in arteries either spontaneously or in response to pressure, stretch or application of vasoconstrictor agonists, which is associated with slow oscillations of smooth muscle membrane potential and of intracellular calcium concentrations. Vasomotion may also be enhanced by oscillations of transplasmamembrane calcium influx. TRP channels have been described to play an important role for calcium influx. TRPCs Ca2+ What is pathophysiological relevance of vasomotion ? In several experimental models of hypertension an increased vasomotion of arteries had been described. Lefer et al. observed enhanced vasomotion of cerebral arterioles in spontaneously hypertensive rats compared to normotensive rats (Lefer et al., 1990). An increased vasomotion was observed in segments of posterior cerebral arteries and in mesenteric arteries from spontaneously hypertensive stroke-prone rats compared to Wistar-Kyoto rats(Osol Tsai et al., 1995). Vasomotion of coronary artery causes cardiac ischemia. Norepinephrine (NE) caused a rapid vasonconstriction and followed by synchronized oscillations of vascular tone (vasomotion) in mesenteric artery rings from SHR Increased NE-induced vasomotion in mesenteric artery rings from SHR Immunohistochemistry shows TRPCs distribution in mesenteric arteries Increased expression of TRPC1, TRPC3, TRPC5 in mesenteric artery from SHR Inhibition of TRPC significantly attenuates NE-induced vasomotion in SHR Inhibition of NE-induced vasomotion in mesenteric arteries from SHR by specific TRPC antibodies TRPC1 Control Control TRPC3 Specific antagonizing TRP Channel subtypes significantly reduced vasomotion Inhibition of NE-induced calcium increase in mesenteric arteries from SHR by specific TRPC antibodies Effects of ARB and CCB on vasomotion and systolic blood pressure in SHR Ctr Amlo TelmCand Effects of ARB and CCB on TRPCs expression of mesenteric artery TRPC1 TRPC3 TRPC5 -actin Ctr CandAlmo Telm Summary TRP Channel: Novel Therapeutic Targets for Hypertension? The present results point to the relevance of TRPC3 in the pathogenesis of primary hypertension. As indicated by recent literature, expression of several TRP channel subtypes may be divergent and redundant in cardiovascular diseases. Moreover, TRP channels display diverse properties, localization, and regulation as a result of their assembly into distinct homomeric and heteromeric channel complexes. However, TRP channels will be fascinating targets to elucidate novel pathogenic mechanisms in hypertension, and TRP channels will be new therapeutic targets for cure of hypertension. ACKNOWLEDGMENS Center for Hypertension and Metabolic Diseases, Third Military Medical University, Chongqing Ma Liqun, Liqun Ma, Zhidan Luo, Tingbing Cao, Dachun Yang, Shundao Ma, Zhencheng Yan, Lijuan Wang,