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1、第 24 章 肾素-血管紧张素醛固酮系统抑制药,华中科技大学同济医学院药理学系,主讲教师 金满文,2010年10月,Inhibitors of the renin-angiotensin-aldosterone system,1/70,本次课要求掌握的内容,2.ACE抑制药的药理作用、作用机理、主要的临床应用和不良反应。,2/70,3.全面比较AT1受体拮抗药与ACE抑制药在药理作用、作用机理、临床应用和不良反应方面的异同。,4.通过本章学习，你对靶点发现、确认及与药物研发的关系有何心得？,1.RAAS抑制药分类及各类的主要代表药。,hypertension, congestive heart
2、 failure, myocardial infarction, and diabetic nephropathy,Pathophysiology,Renin-Angiotensin-Aldosterone System,RAAS,3/70,renin-angiotensin-aldosterone system,History,Components of RAAS,Functions and Effects of RAAS,(RAAS),4/70,In 1898, Tiegerstedt and Bergman found that crude saline extracts of the
3、kidney contained a pressor substance that they named renin.,History,1898, Tiegerstedt 和 Bergman 发现肾脏的盐水粗提物含有加压物质，他们将其命名为“肾素”。,5/70,Tigerstedt R, Bergman PG: Niere und Kreislauf 肾脏和循环. Skand Arch Physiol 1898; 8:223-271.,1934, Goldblatt 证明收缩肾血管可产生持续的高血压 (renal hypertension),In 1940, Braun-Menendez(Ar
4、gentina), Page and Helmer (USA) 分别报道肾素是酶，产生缩血管物质，前者称其为hypertensin ，后者称其为angiotonin.,大约20年后，将此过程中的升压物质命名为血管紧张素angiotensin，血浆中的底物称为 血管紧张素原angiotensinogen.,7/70,In the mid-1950s, a decapeptide and an octape-ptide were recognized. The octapeptide was shown to be the more active form.,decapeptide,octapep
5、tide,angiotensin-converting enzyme(ACE),enzyme,(Angiotensin I),(Angiotensin II),in 1957, synthesized by Schwyzer and Bumpus,8/70,In the early 1970s, important physiological and pathophysiological roles for the RAAS were revealed.,上个世纪七十年代早期，开始认识RAAS的重要的生理和病理生作用。,Physiological roles,Pathohysiological
6、 roles,Pharmacological intervention,9/70,Thirst,Converting,enzyme,Pressor effect,Sympathetic,stimulation,ADH secretion,Converting enzyme antagonist Captopril enalapril,enalkiren,Remikiren Aliskiren,Renin inhibitor,Ang II receptor Antagonist losartan,Aldosterone secretion,Renin,Components of RAAS,Ald
7、osterone secretion,Ang III,Ang IV,Ang 1-7,10/70,。,Angiotensin (3-8),AT4,Ang IV,Ang(1-7) receptor,AT1,AT2,?,Phe-His,8 9,GG 11th, 2006,11/70,Angiotensin Receptors (AT),12/70,Extrinsic Local RAAS,Local (Tissue) RAAS (局部或组织RAAS),Intrinsic Local RAAS,The traditional view of the RAAS is that of a classica
8、l endocrine system. Renin(kidney) angiotensinogen(liver),ACE,This traditional view is an oversimplification that must be expanded to include local RAAS (tissue) .,Ang I,Ang II,Aldosterone(kidney),Biological effects,13/70,Extrinsic Local RAAS (take up) Circulating renin of renal origin can be taken u
9、p by the arterial wall and by other tissues.,动脉壁和其他组织从循环中摄取肾源性肾素，激活局部的RAAS。,14/70,许多组织（脑、血管、心脏、肾脏、肾上腺）表达肾素、血管紧张素原、转换酶的mRNA，源于这些组织的细胞培养可产生肾素、血管紧张素原、转换酶、Ang I, II, and III.,Intrinsic Local RAAS (de novo synthesis) Many tissuesincluding the brain, blood vessels, heart, kidney, and adrenal glandexpress
10、mRNAs for renin, angiotensino-gen, and/or ACE, and various cells cultured from these tissues produce renin, angioten-sinogen, ACE, and Ang I, II, and III.,15/70,Functions and Effects of the RAAS,17/70,.,Altered Peripheral Resistance,I. Direct vasoconstriction 直接收缩血管 II. peripheral noradrenergic neur
11、otransmission A.NE release 增加NE释放 B.NE reuptake 减少NE再摄取 C.vascular responsiveness 增加血管反应性 III.sympathetic discharges (CNS) 增强交感中枢输出 IV.release of catecholamines from adrenal Medulla,Rapid Pressor Response 快加压反应,Mechanism,Result,.,Altered Renal Function,I. Direct Na+ reabsorption in proximal tubule I
12、I. Release of aldosterone from adrenal cortex （ Na+ reabsorption and K+ excretion) III. Altered renal hemodynemics: A. Direct renal vasoconstriction B.noradrenergic neurotransmission in kidney C.renal sympathetic tone (CNS),Slow Pressor Response 慢加压反应,Mechanism,Result,19/70,.,Altered Cardiovascular
13、structure,I. Non-hemodynamically mediated effects: expression of proto-oncogenes production of growth factors synthesis of extracellular matrix proteins II. Hemodynamically mediated effects: afterload (cardiac) wall tension (vascular),Vascular and cardiac hypertrophy & remodelling 血管和心脏肥厚、重构,Mechani
14、sm,Result,Thirst,Converting,enzyme,Pressor effect,Sympathetic,stimulation,ADH secretion,Converting enzyme Antagonist 1981 captopril enalapril,Ang II receptor Antagonist 1995 losartan telmisartan,Aldosterone secretion,MR antagonist spirolactone eplerenone 2002,Renin,Renin inhibitor remikiren remikire
15、n Aliskiren 2007,INHIBITORS OF THE RAAS,20/70,21/70,RAAS抑制药上市时间,1981, captopril(ACEI),1995, losartan(ARB),2002, eplerenone(MRA),2007, alisliren(RI),on the market,上市,Thirst,Converting,enzyme,Pressor effect,Sympathetic,stimulation,ADH secretion,Converting enzyme antagonist Captopril enalapril,remikire
16、n,Renin inhibitor,Ang II receptor Antagonist losartan telmisartan,Aldosterone secretion,MR antagonist Spirolactone eplerenone,Renin,remikiren aliskiren,补进展,INHIBITORS OF THE RAAS,22/70,23/70,ACE Inhibitors (Angiotensin Converting Enzyme Inhibitors ),In the 1960s, Ferreira and colleagues found that the venoms of pit vipers (颊窝毒蛇)contain factors that intensify responses to bradykinin
