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1、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 ChannelsTransient Receptor Potential ChannelsA 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
2、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0.5mmHgAucott 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)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1.1.CCB CCB 较少证据显示高血压时电压依赖钙通道表达异常2
3、. ARB2. ARB和和ACEI 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 3. . 受体阻断剂受体阻断剂 降压机制至今仍不甚清楚4. 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, 2005Lifton 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
4、Cosens, D. J. 47:609-614Role of TRPM7 in hypertensionTouyz 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 MFluorescence ratio (arbitrary units)Liu DY,Zhu ZM. Am J Hypertens, 2005, 2008, J Hypertens, 2006, 2007Blank TRPC1 TRPC3 TRPC4 TRPC5 TR
5、PC6Blank TRPC1 TRPC3 TRPC4 TRPC5 TRPC6Role of TRPC3 in the pathogenesis of hypertensionIdentification of TRPC3 in the vasculature Liu, et al. Hypertension, 2009Increased expression of TRPC3 in aorta from SHR Liu, et al. Hypertension, 2009Effect of TRPC3 upregulation on angiotensin II - induced calci
6、um increase in SHRLiu, et al. Hypertension, 2009Effect of TRPC3 gene knockdown on angiotensin II induced calcium increase in SHRLiu, et al. Hypertension, 2009Angiotensin II increases TRPC3 in VSMC from SHRLiu, et al. Hypertension, 2009Effect of CCB/SKF on Angiotensin II-induced aortic contraction an
7、d calcium increase in VSMC from SHRLiu, et al. Hypertension, 2009Long term administration of AT1R antagonist telmisartan but not of calcium channel blocker amlodipine reduces TRPC3 in vivoLiu, et al. Hypertension, 2009Vasomotion occurs in arteries either spontaneously or in response to pressure, str
8、etch 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
9、 an important role for calcium influx. TRPCsCa2+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 r
10、ats 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 ca
11、uses 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 SHRImmunohistochemistry shows TRPCs distribution in m
12、esenteric arteriesIncreased expression of TRPC1, TRPC3, TRPC5 in mesenteric artery from SHRInhibition of TRPC significantly attenuates NE-induced vasomotion in SHR Inhibition of NE-induced vasomotion in mesenteric arteries from SHR by specific TRPC antibodiesTRPC1ControlControlTRPC3Specific antagoni
13、zing 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 SHRCtrAmloTelmCandEffects of ARB and CCB on TRPCs expression of mesente
14、ric arteryTRPC1TRPC3TRPC5-actinCtrCandAlmoTelmSummaryTRP Channel: Novel Therapeutic Targets for Hypertension?TRP Channel: Novel Therapeutic Targets for Hypertension?The present results point to the relevance of TRPC3 in thepathogenesis of primary hypertension. As indicated by recentliterature, expre
15、ssion of several TRP channel subtypes may bedivergent and redundant in cardiovascular diseases. Moreover,TRP channels display diverse properties, localization, andregulation 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 targe
