Basic research for regulation and disorder of cardiac Ca signal

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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