The novel compound liguzinediol exerts positive inotropic effects in isolated rat heart via sarcoplasmic reticulum Ca2+ ATPase-dependent mechanism.

The present work investigated the underlying mechanism for the positive inotropic effect of liguzinediol (LZDO) in isolated rat hearts. Isolated rat heart perfusion, intracellular action potential recording, patch clamp and Ca2+ imaging were used to measure the isolated rat heart contractility, action potential duration, L-type Ca2+ current and sarcoplasmic reticulum (SR) Ca2+ transient in rat cardiomyocyte, respectively. LZDO (1, 10, and 100μM) significantly enhanced the inotropy of isolated rat hearts, but not heart rates. Nimodipine (1μM, an L-type Ca2+ channel antagonist), ruthenium red (5μM, a ryanodine receptor inhibitor) and thapsigargin (2μM, an irreversible SR Ca2+ ATPase inhibitor) completely blocked the positive inotropic effect of LZDO. LZDO significantly enhanced the intracellular Ca2+ transient in rat cardiomyocyte. However, LZDO (100μM) did not increase L-type Ca2+ channel current. Moreover, LZDO (100μM) restored the depletion effect of caffeine on Ca2+ transient. The following compounds also failed to block the positive inotropic effect of LZDO (100μM): β-AR antagonist (propranolol 1μM), phosphodiesterase (PDE) inhibitor (IBMX 5μM), Na+-K+ ATPase inhibitor (ouabain 1μM), α(1)-AR antagonist (prazosin 1μM), dopamine D1 receptor antagonist (SCH23390 1μM) and Na+-Ca2+ exchange inhibitor (KB-R7943 1μM). The positive inotropic effect of LZDO in isolated rat hearts was mediated through an elevation of SR Ca2+ transient, which may act on SR Ca2+ ATPase. LZDO has a unique biological mechanism that may prove effective in treating heart failure in clinic.