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

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 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. KEY FINDINGS: 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): ß-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). SIGNIFICANCE: 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.

Confirmation of a proarrhythmic risk underlying the clinical use of common Chinese herbal intravenous injections.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese herbal intravenous injections (CHI) which are extracted from herb(s) are used clinically in China as putative therapies for a variety of diseases. AIM OF THE STUDY: The mechanism(s) which underline findings of severe adverse drug reactions (ADR) noted in more than a thousand published articles on CHIs, are still poorly understood. With 109 CHIs currently in clinical use, we investigated the proarrhythmic effects of three specific CHIs, Shuanghuanglian (SHL), Qingkailing (QKL) and Yinzhihuang (YZH), using in vivo and in vitro ion channel models. MATERIALS AND METHODS: In vivo and in vitro guinea pig electrocardiogram, intracellular action potential and patch clamp recording techniques were carried out. RESULTS: Both SHL and QKL (both in one, five and ten times clinically relevant doses (CRD) for in vivo and clinically relevant concentrations (CRC) for in vitro) prolonged P-R intervals in a dose or concentration-dependent manner and SHL also prolonged QTc. YZH (ten and 20 times CRD and CRC) prolonged P-R intervals without changing QTc. Intracellular action potential recordings from guinea pig papillary muscle indicated SHL and QKL abolished the firing of action potentials at ten and 30 times CRC respectively. SHL significantly suppressed L-type Ca(2+) current from left ventricular myocytes of guinea pig, hNav1.5 current and hERG current with 50% inhibiting concentrations (IC(50)) of 6.0, 3.0 and 10.7 times CRC, respectively. Also, QKL significantly suppressed L-type Ca(2+) and hNav1.5 currents with IC(50)s of 10.7 and 13.8 times CRC. YZH significantly suppressed L-type Ca(2+), hNav1.5 and hERG currents with IC(50)s of 12.1, 32.9 and 141.7 times CRC, respectively. CONCLUSIONS: The three CHIs studied caused bradyarrhythmia mainly by inhibiting Na(+) current and L-type Ca(2+) current.