2012作用于内脏系统药物.ppt

? reduce CHF-associated morbidity and mortality rates ? may have a more favorable effect on quality of life 第二十三章第二十三章 肾素肾素- -血管紧张素系统药理血管紧张素系统药理 （ReninRenin angiotensinangiotensin system, RAS system, RAS） 肾素血管紧张素系统药理 一、 肾素血管紧张素系统及意义（了解） 二、 肾素血管紧张素系统阻断药 1、 血管紧张素转化酶抑制剂（ACEI） 共性（掌握） 常用的ACEI（熟悉） 2、 AT1-R阻断剂 作用特点及应用（掌握） 常用药（熟悉） 血管紧张素原 血管紧张素 血管紧张素 肾素血管紧张素系统肾素血管紧张素系统 血管紧张素转换酶 （ACEACE） AT1受体 AT2受体 1.血管收缩外周阻力 2.Ald释放 水钠潴留 3.促生长增殖心血管重构 1.与胎儿发育有关 2.激活NOS 3.部分对抗AT1的促增殖作用 肾素 Components of the RAS AngII, the most active angiotensin peptide, is derived from angiotensinogen in two proteolytic steps. renin, an enzyme released from the kidneys, cleaves the decapeptide AngI from the amino terminus of angiotensinogen (renin substrate). ACE ,removes the carboxy-terminal dipeptide of AngI to produce the octapeptide AngII. AT1 and AT2, AngII acts by binding to two heptahelical GPCRs, The understanding of the RAS has expanded in recent years. The current view of the RAS also includes a local (tissue) RAS, alternative pathways for AngII synthesis (ACE independent), formation of other biologically active angiotensin peptides (AngIII, AngIV, Ang17), additional angiotensin binding receptors (angiotensin subtypes 1, 2, and 4 AT1, AT2, AT4; Mas) that participate in cell growth differentiation, hypertrophy, inflammation, fibrosis, and apoptosis. 局部组织RAS（local tissue RAS） 部位：心肌、血管、肝、肾、血管、粘膜等 AngI AngII 自分泌、旁分泌等方式发挥作用。心血管组织中 的RAS在高血压、心血管重构、动脉粥样硬化等 发生发展过程中起重要作用。 糜酶、ACE Formation of angiotensins I-IV from the N-terminal of the precursor protein angiotensinogen Angiotensin Peptides Ang I(1-10) Ang II(1-8) AT1-R and AT2-R Ang III(2-8) AT1-R/? Ang IV(3-8) AT4-R(IRAP)/? Ang(1-7) Mas-R Current view of the reninangiotensin system cascade Abbreviations: ACE, angiotensin-converting enzyme; Ang, angiotensin; AMP, aminopeptidase; AT1, Ang II type 1 receptor; AT2, Ang II type 2 receptor; Mas, Ang(17) receptor Mas; D-Amp, dipeptidyl-. Santos R A S et al. Exp Physiol 2008;93:519-527 Schematic representation of the enzymatic pathways involved in the generation of angiotensin peptides Angiotensin Receptors Most of the known biological effects of AngII are mediated by the AT1-R. associated with hypertension, hypertrophic cardiomyopathy, and coronary artery vasoconstriction. Functional roles for the AT2 -R are less well defined, but they may counterbalance many of the effects of the AT1-R by having antiproliferative, proapoptotic, vasodilatory, natriuretic, and antihypertensive effects . The Mas-R mediates the effects of Ang(17), which include vasodilation and anti-proliferation. Deletion of the Mas gene in transgenic mice reveals cardiac dysfunction The AT4-R(IRAP) mediates the effects of AngIV. This receptor is a single transmembrane protein (1025 amino acids) that co- localizes with the glucose transporter GLUT4. AT4 receptors are detectable in a number of tissues, such as heart, vasculature, adrenal cortex, and brain regions processing sensory and motor functions . Angiotensin-Converting Enzyme (ACE, Kininase II, Dipeptidyl Carboxypeptidase二肽羧肽酶 ) pACE is an ectoenzyme and glycoprotein with an apparent molecular weight of 170,000. pACE is rather nonspecific and cleaves dipeptide units from substrates with diverse amino acid sequences. pACE is identical to kininase II, the enzyme that inactivates bradykinin and other potent vasodilator peptides. Angiotensin-Converting Enzyme 2 Two groups independently discovered a novel ACE-related carboxypeptidase, now termed ACE2 ACE2 cleaves one amino acid from the carboxyl terminal to convert AngI to Ang(19) and AngII to Ang(17). AngII is the preferred substrate for ACE2 with 400-fold higher affinity than AngI. ACE2 may serve as a counter-regulatory mechanism to oppose the effects of ACE. ACE2 regulates the levels of AngII and limits its effects by converting it to Ang(17), which binds to Mas receptors and elicits vasodilator and anti- proliferative responses . ACE2 is not inhibited by the standard ACEI and has no effect on bradykinin. The juxtaglomerular apparatus Renin release 交感神经（球 旁细胞1） 肾内压力感受 器（ 卡托普利卡托普利 福辛普利）；福辛普利）；血管神经性水肿血管神经性水肿 久用血锌降低或含久用血锌降低或含-SH-SH结构引起：结构引起： 味觉及嗅觉障碍；味觉及嗅觉障碍； ( (青霉胺青霉胺) )皮疹、粒细胞减少皮疹、粒细胞减少 畸胎：畸胎：胎儿肺、肾发育不全胎儿肺、肾发育不全, ,可能低血压引起羊水减可能低血压引起羊水减 少少 。 ACEI禁忌症 （1 1）使用）使用ACEIACEI后曾发生血管性水肿或无尿性肾后曾发生血管性水肿或无尿性肾 衰竭的患者、双侧肾动脉狭窄患者以及妊娠衰竭的患者、双侧肾