1、ACEI机制之我见,吴平生南方医科大学南方医院,1. Perico Int J Clin Pract Suppl 111; 14,对RAAS的传统认识,缓激肽释放,血管扩张NO生成凋亡激肽释放,RAAS中血管紧张素和醛固酮是发挥生物作用的效应分子,血管紧张素,是强大的血管收缩物质（仅次于内皮素）是强大的促细胞增殖物质（通常在血压升高前引起血管和心肌肥厚）是重要的生理物质（生长发育、水电平衡等生理功能的必需物）等,醛固酮,保钠排钾，水钠储留促细胞增殖反射性抑制肾素分泌等,Plasma Renin Activity Levels in Hypertensive Persons:(10.1016/j
2、.amjhyper.2003.08.015,ESH/ESC 2013 RASI药物优先适用的情况,这些与血压高/细胞增殖有关常见的合并症,8 .G. Mancia et al.Journal of Hypertension 2013;31:1281-1357,左心室肥厚微量白蛋白尿肾功能不全既往卒中既往心肌梗死,心衰预防房颤ESRD/蛋白尿代谢综合征糖尿病,RASI对血管收缩和细胞增殖的靶点,应用ACEI之后,血管紧张素原,血管紧张素 I,肾素,血管紧张素 II,ACEI,AT3,AT1,AT2,ACE,Lee et al. Neurohormonal reactivation in hear
3、t failure patients on chronic ACE inhibitor therapy: a longitudinal study. European Journal of Heart Failure 1 1999 401406,卡托普利导致AngII逃逸,血管紧张素原,血管紧张素,血管紧张素,AT2,AT1,肾上腺素释放,炎症反应,VAP释放,凋亡,NO生成,血管扩张,肾素,ACE,Perico Int J Clin Pract Suppl 111; 14,Ang-( 1-7),缓激肽,ARB,对RAAS的传统认识,醛固酮生成,缓激肽释放,培哚普利显著降低AngII，而ARB
4、升高AngII,p 0.001.,p =0.008.,58%,300%,24例非糖尿病CKD患者，随机接受DRI或ARB治疗，并检测RAAS不同组成的浓度， 分析验证ARB治疗可能会升高AngII的假设。,通过动物研究，分析培哚普利治疗对血管内皮功能的影响，同时检测不同RAAS成分的浓度。,Frontiers in Pharmacology, 2017, 8.Ann Med. 2017 Apr 17:1-9.,ACEI治疗前后AngII水平 fmol/ml,ACE2的发现,1898 年Tigerstedt发现,血管紧张素原,血管紧张素 I,肾素,血管紧张素 II,ACE,AT3,AT1,AT2
5、,Ang(1-7),2000年Donoghue等发现,Ang(1-9),ACE2,在病理情况下，ACE/ACE2升高,倍数差异,NDM：非糖尿病1M DM：诱导出现糖尿病后1个月,实时反转录-聚合酶链式反应（RT-PCR）分析RAS系统视网膜mRNA的表达情况,糖尿病 vs. 非糖尿病，ACE/ACE2比值升高10倍,Journal of the American Society of Gene Therapy, 2012, 20(1):28-36.,血管紧张素II和血管紧张素-(1-7)的平衡调节,如图所示为RAS受体调节轴： ACE-AngII-AT1 受体和ACE2-Ang-(1-7)-
6、Mas 受体。ACEs在平衡这些轴的活动中发挥关键作用。当ACE抑制Ang形成Ang时，ACE2水解Ang产生Ang-(1-7)AVE 0991, HPCD/Ang-(1-7), CGEM856和CGEM857是Ang-(1-7)类似物， Mas激动剂和 XNT 是ACE2催化剂,Hypertension. 2010 February ; 55(2): 207213.,ACE2 和Ang-(1-7) 在RAS中扮演血管保护的角色,2016 ESH,培哚普利增加ACE2活性具有RASS调节作用,Huang ML, Li X, Meng Y, Xiao B, Ma Q, Ying SS, Wu P
7、S, Zhang ZS. Upregulation of angiotensin-converting enzyme (ACE) 2 in hepatic fibrosis by ACE inhibitors. Clin Exp Pharmacol Physiol. 2010 ;37(1):e1-6.Chao-Sheng Lo,* Fang Liu,* Yixuan Shi et al: Dual RAS blockade normalizes angiotensin-converting enzyme-2 expression and prevents hypertension and tu
8、bular apoptosis in Akita angiotensinogen-transgenic mice. Am J Physiol Renal Physiol 2012,302: F840F852.,Ramipril not augmented cardiac ACE2 expression,Ramipril and valsartan improved remodelling (P0.05), with no additional effect of dual therapy. Although ramipril inhibited ACE, and valsartan block
9、ed the angiotensin receptor, neither treatment alone nor in combination augmented cardiac ACE2 expression.Burchill LJ, Velkoska E, Dean RG, Griggs K, Patel SK, Burrell LM. Combination renin-angiotensin system blockade and angiotensin-converting enzyme 2 in experimental myocardial infarction: implica
10、tions for future therapeutic directions. Clin Sci (Lond). 2012 Dec;123(11):649-58.,关于醛固酮逃逸,1. Perico Int J Clin Pract Suppl 111; 14,RAASI治疗后醛固酮水平应该下降,缓激肽释放,血管扩张NO生成凋亡激肽释放,After an initial suppression/blockade of Ang II/aldosterone, the plasma levels of these 2 compounds often return to normal or eve
11、n rise above pretreatment levels: the so-called Ang II/aldosterone escape. Given the Ang II/aldosterone escape during RAAS blocker treatment, usually occurring within days-weeks after drug initiation,for many years it was argued that the more blockade, the better, to keep the levels of these active
12、components (or their activity) low.,在启动抑制AngII/醛固酮之后,这两个成分的血浆水平往往恢复正常,甚至超过治疗前的水平:所谓AngII/醛固酮逃逸。RAAS阻滞治疗期间AngII/醛固酮逃逸通常发生在药物启动后的数天至数周内,多年来，人们在争论阻滞越多，使这些活性成分(或他们的活性)越低越好。,ANGII/醛固酮逃逸的定义,Luuk te Riet, Joep H.M. van Esch, Anton J.M. et. Al. Hypertension ReninAngiotensinAldosterone System Alterations. Ci
13、rc Res 2015;116:960-975,不仅是血浆还有组织的ANGII/醛固酮逃逸,Effects of long-term enalapril and losartan therapy of hypertension on cardiovascular aldosterone.Li S1,Wu P,Zhong S,Guo Z,Lai W,Zhang Y,Liang X,Xiu J,Li J,Liu Y.Author informationPlasma aldosterone escape is found during long-term angiotensin-converting
14、 enzyme inhibitor therapy. Evidence for aldosterone production in cardiovascular tissues raised the question of whether or not aldosterone escape occurs in these tissues.CONCLUSION:This study provides the first evidence that long-term angiotensin-converting enzyme inhibition therapy induces aldoster
15、one escape in hypertensive cardiovascular tissues. Horm Res.2001;55(6):293-7.,Brugts. JJ. et al. Expert Rev. Cardiovasc. Ther. 2009; 7 (4), 345-360.,DD5010-11,组织亲和力*,培哚普利高脂溶性充分抑制组织RAAS活性,*组织亲和力：决定ACEI对组织ACE的抑制作用,10%的RAAS分别在循环，90%分布在组织,培哚普利独特的调节作用,组织渗透，Ang II逃逸少，醛固酮逃逸少（兼利尿作用）缓激肽/Ang II增加(包括组织中)激活ACE2
16、活性， 降解Ang II，增加Ang-(1-7),缓激肽通过活化B2受体发挥心血管保护效应,Curr. Med. Chem. Cardiovascular & Hematological Agents, 2005, 3, 33-44,高血压患者缓激肽浓度下降约25%,、,采用新的标记技术检测正常人及高血压等心血管疾病患者的血浆缓激肽浓度,25%,年龄（岁）,血清缓激肽浓度fmol/ml,1,此图根据研究改编,Lancet 1998; 351: 169397 Folia Pharmacologica Japonica Vol. 82 (1983) No. 2 P 159-169,培哚普利8mg重
17、建RAAS-KKS平衡 -抑制AngII、升高缓激肽至正常水平,PERTINENT研究，入选45例健康对照和EUROPA研究中的87例CAD患者，测量受试者在基线和安慰剂或培哚普利8mg治疗1年时的血浆缓激肽水平，评价培哚普利对缓激肽的影响。,培哚普利抑制AngII至正常,培哚普利升高缓激肽至正常,Cardiovasc Res. 2007 Jan 1;73(1):237-46.,+20%,雅施达8mg显著升高Ang1-7，带来更多的获益, p 0.001,95%,通过动物研究，分析培哚普利治疗对血管内皮功能的影响，同时检测不同RAAS成分的浓度。,Frontiers in Pharmacolo
18、gy, 2017, 8.,培哚普利8mg重建RAAS-KKS平衡 -显著升高Ang1-7，带来更多的获益,ACEI治疗前后Ang1-7水平（fmol/ml）,培哚普利8mg重建RAAS-KKS平衡，确保更卓越心血管保护,Frontiers in Pharmacology, 2017, 8(183).中华心血管病杂志,2012, 40(8):697-701.,58%,Conditional knockout of collecting duct bradykinin B2 receptors exacerbates angiotensin II-induced hypertension duri
19、ng high salt intake,Clin Exp Hypertens. 2016 ; 38(1): 19,Knockout of Angiotensin 17 Receptor Mas Worsens the Course of Two-Kidney, One-Clip Goldblatt Hypertension: Roles of Nitric Oxide Deficiency and Enhanced Vascular Responsiveness to Angiotensin II,Kidney Blood Press Res 2010;33:476488,缓激肽和Ang1-7
20、对组织局部作用更重要,培哚普利改善中膜厚度最佳,Massimiliano Mancini, Angela Scavone, Carmem Luiza Sartorio et al.Effect of different drug classes on reverse remodeling of intramural coronary arterioles in the spontaneously hypertensive rat. Microcirculation. 2017;24:e12298.,2013 ESC guidelines on the managementof stable c
21、oronary artery disease,European Heart Journal (2013)34, 29493003,培哚普利改善冠脉血流,Massimiliano Mancini, Angela Scavone, Carmem Luiza Sartorio et al. Effect of different drug classes on reverse remodeling of intramural coronary arterioles in the spontaneously hypertensive rat. Microcirculation. 2017;24:e12
22、298.,pre-arterioles(200-500m),large arterioles(100-200m),Smaller arterioles(40m),midium-size Arterioles(40-100m),冠脉微血管调节机制,34,1.Herrmann J, et al. Eur Heart J. 2012 Nov;33(22):2771-2782b.,冠状动脉血流量是由主动脉和毛细血管床之间的压力差驱动，并通过各种影响微循环的物理和神经因素进一步调节微循环中最重要的生理机制在于通过心脏代谢控制血管张力,神经因素去甲肾上腺素肾上腺素乙酰胆碱,主动脉近端BP,毛细血管微静脉远
23、端BP,物理因素血管外压迫LVEDPRVEDP,冠脉微血管（直径500m）:,500um-5mm的传导动脉：10%500-100m的前小动脉：25%, 100m的小动脉：55%,Roland E Schmieder， Lancet 2007; 369: 120819,AngII作为RAAS系统的核心，参与多个病理生理学过程,随着研究的深入，RAAS系统不断更新完善,Pepine CJ. Vascular Biology 2002;Vol 2,No.1 1-8.,血管完整性 PAI-1,AT2受体,AT3受体,AT4受体,？,Ang1-7是ACE2Ang1-7Mas轴的核心物质，通过激活MAS受
24、体发挥保护效应,Clinical Science (2013) 124, 443456,抑制肺部和肝脏纤维化,保护生殖功能,抑制炎症反应,抑制癌症和血管生成,保护大脑，促进学习和记忆功能,改善代谢,“200年前，人们就已经发现心外膜冠脉的阻塞性病变是导致心绞痛的原因；100年前人们发现突然的血栓形成是造成心肌梗死的原因; 可是直到近20年，我们才认识到冠脉微血管功能障碍是造成心肌缺血的重要原因”“未来冠心病治疗的突破，取决于我们对于冠脉微血管病变的理解和干预”,Camici, P. G. et al. Nat. Rev. Cardiol. 12, 4862 (2015),人们的认识过程,ACE
25、I对微血管的作用没有引起我们足够的重视,Sever P, et al. Lancet. 2005;366:895-906 ADVANCE Collaborative Group. Lancet 2007; 370: 829840 Beckett NS, et al. N Engl J Med. 2008 May 1;358(18):1887-1898 PROGRESS Collaborative Group.Lancet 2001; 358: 10331041 EUROPA Investigators. Lancet. 2003;362:782-788 Ferrari R. Arch Inte
26、rn Med. 2006;166:659-666 PEP-CHF Investigators. Eur Heart J. 2006;27:2338-2345,群多普利,依那普利,雷米普利,培哚普利,替米沙坦,氯沙坦,缬沙坦,厄贝沙坦,坎地沙坦,已发表的随机、双盲、发病率/死亡率临床试验，包括至少1000人以上的高血压、冠心病、糖尿病和心力衰竭研究,EUROPA研究结果：培哚普利8mg显著降低高、中、低危心血管风险主要终点,JACC荟萃：ACEi降低高危心血管风险患者的全因死亡优势仍显著,26项ARB或ACEi与安慰剂随机对照研究的荟萃分析，共纳入108,212例高危且无心衰患者，评估ARBs或
27、ACEis对心血管死亡、心梗、卒中、全因死亡、新发心衰和新发糖尿病的疗效,1.Savarese G,et al.JACC.2013,Journal of the American College of Cardiology.美国心脏病学杂志，心血管领域国际优秀杂志之一，影响因子14.156,2017 AHA,ARBs may be better tolerated than ACE inhibitors in black patients, with less cough and angioedema, but according to the limited available experience they offer no proven advantage over ACE inhibitors in preventing stroke or CVD in this population.,谢谢！,
