Basic research for regulation and disorder of cardiac Ca signal

在心血管疾病中，包括心肌梗死和心力衰竭，各种内源性调节剂从不同类型的细胞（例如内皮细胞）释放，并且在疾病的进展和恢复中起关键作用。在慢性充血性心力衰竭中，心肌收缩功能障碍被认为是其发病的关键过程，逆转心肌收缩功能障碍的强心药物可能是药物治疗的主要靶点。目前的治疗靶点已被公认为除了通过减少前负荷和后负荷来减轻心脏负荷外，还涉及抑制调节机制，如肾上腺素能调节、肾素-血管紧张素和醛固酮系统。在心力衰竭中，已经阐明去甲肾上腺素（NE）和内皮素-1（ET-1）的血浆水平在疾病严重程度的进展过程中升高。NE和ET-1可能调节心肌收缩功能。 ...更多信息 心力衰竭患者的心功能因此，我们研究了NE与ET-1相互作用对犬心室肌和单个心肌细胞收缩力和Ca^<2+>的调节。单独ET-1对犬心室肌无任何变力作用，但可引起依赖于NE共存浓度的复杂调节。在NE阈值浓度（10 <-10>μ <-9>mol/L ~ 10 μ mol/L）附近，ET-1可引起浓度依赖性的正性肌力作用（PIE），并增加肌丝Ca^2+敏感性。ET-1的PIE是独特的，因为它需要同时激活PKA和PKC。令人感兴趣的是，PKA的激活已被确定为将收缩力和[Ca^2+] i的关系向右移动，这意味着由于肌钙蛋白I和磷酸蛋白的磷酸化（导致SERCA 2a激活）而导致肌丝Ca^2+敏感性降低。相反，很明显PKA的激活与PKC的激活相互干扰，导致PIE与肌丝Ca^2+敏感性的增加有关。PKA抑制剂、PKC抑制剂、PLC抑制剂或β-受体阻滞剂可阻断ET-1的PIE。提示NE和ET-1的相互作用在心力衰竭患者心肌收缩调节中起重要作用。少

In cardiovascular disorders, including myocardial infarction and heart failure, various endogenous regulators are released from divergent types of cell, such as endothelial cells, and play crucial role in progress and recovery of diseases. In chronic congestive heart failure, it has been considered that the myocardial contractile dysfunction is the key process of the disorder and the cardiotonic agents that reverse the dysfunction may be the primary target of drug therapy of the disease. The current therapeutic target has been recognized to be addressed to the suppression of modulatory mechanisms, such as adrenergic regulation, rennin-angiotensin and aldosterone system, in addition to cardiac unloading by reduction of pre-load and after-load. In heart failure it has been elucidated that the plasma levels of norepinephrine (NE) and endothelin-1 (ET-1) are elevated in the course of progress of severity of the disease. It is highly likely that NE and ET-1 regulate the myocardial contracti … More lity in patients with heart failure. We investigated, therefore, the regulation of myocardial contractility and Ca^<2+> by crosstalk of NE with ET-1 in canine ventricular myocardium and single myocytes. ET-1 alone did not cause any inotropic effect on canine ventricular myocardium, but induced complex regulation depending on the co-existing concentrations of NE. In the presence of NE around threshold concentrations (10^<-10>〜10^<-9>mol/L) ET-1 elicited a concentration-dependent positive inotropic effect (PIE) in association with an increase in myofilament Ca^<2+> sensitivity. The PIE of ET-1 is unique in that it requires simultaneous activation of both PKA and PKC. It is of interest that the activation of PKA has been established to shift the relationship of contractile force and [Ca^<2+>]_i to the right to direction implying a decrease in myofilament Ca^<2+> sensitivity due to phosphorylation of troponin I and phosphlamban (leading to SERCA2a activation). In contrast, it became evident that the activation of PKA by crosstalk with PKC activation elicits a PIE in association with an increase in myofilament Ca^<2+> sensitivity. The PIE of ET-1 was abolished by the PKA inhibitor, PKC inhibitor, PLC inhibitor or β-blocker. The present results imply that the crosstalk of NE and ET-1 plays a crucial role in contractile regulation in patients with heart failure. Less