Assessment of cardiac excitation-contraction coupling and effect of positive inctropic agent on Ca^<2+> regulating function of sarcoplasmic reticulum in heart failan

在心动过速诱导的心力衰竭（HF）中，LV功能与从LV肌肉中提取的肌浆网（SR）功能平行评估。首先，在心力衰竭中，米力农或多巴酚丁胺的正性肌力作用减弱，而正性肌力作用则得到良好保留。HF时SR Ca^<2+>-ATP酶对cAMP的敏感性增强，可能与其维持正性营养有关。第二，HF时，SR（ryanodine receptor，RyR）的Ca^2+释放通道发生了显著的异常Ca^2+渗漏，其中FK结合蛋白/RyR的化学计量比降低。这种RyR结合的FKBP12.6的部分损失似乎通过蛋白质构象变化诱导通道性质的不稳定性。这导致显著的Ca^2+渗漏，这可能是Ca^2+超负荷的原因，从而导致舒张功能障碍以及收缩功能障碍。第三，在HF中，FKBP 12.6和RyR之间相互作用的改变诱导了RyR通道特性的不稳定性，并导致RyR的Ca^2+释放功能受损。

In tachycardia-induced heart failure (HF), LV function was assessed in parallel with the function of sarcoplasmic reticulum (SR) taken from LV muscle. First, in HF, positive inotropic effects of milrinone or dobutamine were decreased, whereas positive lusitropic effects were well preserved. The enhancement of the sensitivity of SR Ca^<2+>-ATPase on cyclic AMP was observed in HF, which might be involved in this preservation of positive lusitropy. Second, a prominent abnormal Ca^<2+> leak occurred through the Ca^<2+> release channel of the SR (ryanodine receptor ; RyR) in HF, in which the stoichiometry of FK binding protein per RyR was decreased. This partial loss of RyR-bound FKBP12.6 seems to induce an instability in the channel's properties through a protein conformational change. This leads to a prominent Ca^<2+> leak, which is a possible cause of Ca^<2+> overload and hence diastolic dysfunction, as well as of systolic dysfunction. Third, in HF the altered interaction between FKBP12.6 and RyR induced an instability of RyR-channel properties and a resulting impairment of the Ca^<2+>-release function of RyR.