Comparative Studies of Calyculin A and Deslanoside on Rat Isolated Heart Inotropy and Their Underlying Mechanism

OBJECTIVE To investigate the inotropic effect and its underlying mechanism of calyculin A， a protein phosphatase (PP) inhibitor， compared to deslanoside， a digitalis positive inotropic agent. To provide inputs whether PP can be served as a potential therapeutic target to develop pharmacological inotropic agents in treatment of heart failure. METHODS Ex vivo study was used to record the effects of calyculin A and deslanoside on rat isolated contractilities. They were perfused to follow in order: normal perfusion solution→calyculin A（1， 4， 10 nmol/L） or normal perfusion solution→deslanoside（0.1， 1， 10 μmol/L）. Ca²⁺ transients triggered by field stimulation and by caffeine (20 mmol/L) were measured to analyze the Ca²⁺ handling effects of calyculin A (100 nmol/L) and deslanoside (10 μmol/L). RESULTS Both calyculin A (1， 4， 10 nmol/L) and deslanoside (0.1， 1， 10 μmol/L) significantly increased the left ventricular developed pressure and the peak rate of rise of left pressure (P<0.05) and decreased the heart rate (P<0.05). Calyculin A (100 nmol/L) and deslanoside (10 μmol/L) significantly increased the amplitude of Ca²⁺ transient and shortened the Ca²⁺ transient duration at 50% full recovery level (P<0.05)；Calyculin A also lowered diastolic cytoplasm Ca²⁺ concentration (P<0.05). Calyculin A (100 nmol/L) significantly increased the SERCA2a activity and combinational activities of Na⁺-Ca²⁺ exchanger (NCX) and plasma membrane Ca²⁺-ATPase (PMCA) (P<0.05); Deslanoside (10 μmol/L) only increased combinational activities of NCX and PMCA (P<0.05)，resulting in lowering percentage of contribution of SERCA2a in Ca²⁺ reuptake phase of Ca²⁺ transient (P<0.05). CONCLUSION Calyculin A increases the amplitude of Ca²⁺ transient by enhancing activity of SERCA2a and combinational activities of NCX and PMCA， resulting in the positive inotropy and favorable relaxation. PP can be a potential therapeutic target to develop pharmacological inotropic agents in treatment of heart failure.