从兴奋收缩耦联机制看心力衰竭正性肌力药物发展.ppt

从兴奋收缩耦联机制看心力衰竭正性肌力药物发展 田野 教授 哈医大二院心内科 提 要 兴奋-收缩耦联机制 正性肌力药的循证研究 洋地黄制剂 β-肾上腺素能受体激动剂 磷酸二酯酶抑制剂 钙增敏剂 新型正性肌力药的探索 亚硝酰氢  兴奋-收缩耦联机制 Excitation-contraction coupling Excitation-contraction (EC) coupling is a term coined in 1952 to describe the physiological process of converting an electrical stimulus to mechanical response. Cardiac excitation–contraction coupling Cardiac excitation–contraction coupling is the process from electrical excitation of the myocyte to contraction of the heart (which propels blood out). The ubiquitous second messenger Ca2+ is essential in cardiac electrical activity and is the direct activator of the myofilaments, which cause contraction. Cardiac tissue Cardiac cells The action potential moves through sarcolemma Ca2+- induced Ca2+- release The molecular basis for myocardial contraction Troponin C EF hands Thick filament proteins Regulation of thin filament in contraction Actin-myosin interaction Heart failure The SR Ca2+ store Overview of E-C coupling changes in the failing heart 正性肌力药的循证研究 Ancient treatment of heart failure 洋地黄制剂（﹥200 years） Mechanism of Action DIG 试验(1997) 总死亡率是中性 在3.5年的随访中，心衰恶化而死亡的危险性，地高辛组有降低趋势，地高辛显著降低了因心衰住院死亡的危险性28%（P0.01）。 总死亡率 因心衰住院死亡的发生率 Digitalis is without question the most valuable cardiac drug ever discovered one of the most valuable drugs in the ent-ire pharmacopoeia. The introduction of digitalis was one of the landmarks in the history of cardiac disease. Therapeutic Use 各种心脏病引起的充血性心力衰竭。 快速性室上性心律失常：心房颤动、心房扑动、房性心动过速、阵发性房室交界区心动过速、反复性心动过速。 Side effects action potential recordings from purkinje fiber cells (A) toxic doses produce oscillatory after depolorizations (B) leads to ventricular tachycardia (C) β-肾上腺素能受体激动剂 β-受体激动剂与心肌细胞膜上β-受体结合 通过G蛋白偶联激活腺苷酸活化酶(AC) 催化ATP生成cAMP cAMP促使L型钙通道开放 Ca内流增加，细胞内Ca浓度上升，起到正性肌力作用。 Direct acting sympathomimetics Therapeutic Use 对维持血压和心输出量具有重要意义，但易引起心率加快、心肌耗氧量增加，诱发心律失常和心肌受体下调, 对生存率有不良影响。 多用于紧急情况的急性心衰、难治性心衰。 磷酸二酯酶抑制剂 The different forms or subtypes of phosphodiesterase we