从兴奋收缩耦联机制看心力衰竭正性肌力药物发展PPT.ppt

Therapeutic Use 失代偿性急性心力衰竭，伴心输出量下降和高灌注压 心脏术后心力衰竭（顿抑） 急性心肌梗死后心力衰竭 新型正性肌力药的探索 亚硝酰氢 HNO是NO的去单电子产物，HNO去质子化将产生相应的阴离子NO-。 Ribeiro da Silva MD, et al., Org Biomol Chem. 2004,2(17):2507-12. HNO直接修饰肌丝 HNO对肌浆网钙离子的重吸收和释放可不依赖于cAMP/PKA或cGMP/PKG途径，而是与巯基化合物的修饰密切相关；事实上在心肌细胞的细肌丝上也存在巯基。 HNO可能直接修饰肌丝巯基，而独立于钙转运系统。 Ingraham RH, et al. Biochemistry,1988 Aug 9;27(16):5891-8. Tocchetti CG, et al. Circulation Res. 2007,100(1):96-104. Muscle Contraction Pi release rates: 1. No Tm-Tn: 10 – 20 s-1 ; 2. + Tm-Tn no Ca2+: 0.1- 0.2 s-1 ; 3.+ Tm-Tn + Ca2+:10 – 20 s-1 Actin-myosin interaction In vitro motility assay showing the sliding of actin filaments over a myosin surface initiated by flash photolysis of caged ATP (Clive R. Bagshaw) Bers DM. Cardiac excitation-contraction coupling [J]. Nature, 2002, 415(6868): 198-205. Excitation-contraction coupling Heart failure Ryanodine receptor(RyR) Phosphorylation of RYR increase Ca2+ leak ATP-dependent pump Phospholamban(PLB) In HF Expression and activation of SERCA2 Phosphorylation of PLB Expression of β1AR ATP supply uptake↓ Re-uptake Store Release M SR SR Ca2+ srore decrease, Ca2+ transient delay The SR Ca2+ store 1 2 3 4 5 1. Reduced Ca++ trigger thru L-type channel 2. Reduced RyR function (Calcium leaks from SR) 3. Decreased sensitivity of TN-C to Ca++ 4. Reduced Ca++ uptake due to loss of SERCA function and increased Plb 5. Increased Na/Ca exchanger function 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） Digilis purpurea Purple foxglove William Withering (1741 - 1799) Digitalis 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）。 The Effect of Digoxin on Mortality and Morbidity in Patients with Heart FailureN Eng1 Med,1997;336:525-533 总死亡率 Placebo Digoxin The Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure N Eng1 Med,1997;336:525-533 因心衰住院死亡的发生率 28% P0.01 Placebo Digoxin