The novel compound liguzinediol exerts positive inotropic effects in isolated rat heart via sarcoplasmic reticulum Ca 2 + ATPase-dependent mechanism

摘要

Aims: The present work investigated the underlying mechanism for the positive inotropic effect of liguzinediol (LZDO) in isolated rat hearts. Main methods: Isolated rat heart perfusion, intracellular action potential recording, patch clamp and Ca 2 + imaging were used to measure the isolated rat heart contractility, action potential duration, L-type Ca 2 + current and sarcoplasmic reticulum (SR) Ca 2 + transient in rat cardiomyocyte, respectively. Key findings: LZDO (1, 10, and 100 μM) significantly enhanced the inotropy of isolated rat hearts, but not heart rates. Nimodipine (1 μM, an L-type Ca 2 + channel antagonist), ruthenium red (5 μM, a ryanodine receptor inhibitor) and thapsigargin (2 μM, an irreversible SR Ca 2 + ATPase inhibitor) completely blocked the positive inotropic effect of LZDO. LZDO significantly enhanced the intracellular Ca 2 + transient in rat cardiomyocyte. However, LZDO (100 μM) did not increase L-type Ca 2 + channel current. Moreover, LZDO (100 μM) restored the depletion effect of caffeine on Ca 2 + transient. The following compounds also failed to block the positive inotropic effect of LZDO (100 μM): β-AR antagonist (propranolol 1 μM), phosphodiesterase (PDE) inhibitor (IBMX 5 μM), Na +-K + ATPase inhibitor (ouabain 1 μM), α 1-AR antagonist (prazosin 1 μM), dopamine D 1 receptor antagonist (SCH23390 1 μM) and Na +-Ca 2 + exchange inhibitor (KB-R7943 1 μM). Significance: The positive inotropic effect of LZDO in isolated rat hearts was mediated through an elevation of SR Ca 2 + transient, which may act on SR Ca 2 + ATPase. LZDO has a unique biological mechanism that may prove effective in treating heart failure in clinic.