A novel secretagogue increases cardiac contractility by enhancement of L-type Ca2+ current

ArticleinBiochemical pharmacology 80(7):1000-6 · October 2010with6 Reads
DOI: 10.1016/j.bcp.2010.06.006 · Source: PubMed
N'1-(3,3,6,8-tetramethyl-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yliden)-2-cyanoethanohydrazide (TTYC) increases secretion of glucagon-like peptide-1 and intracellular Ca(2+) concentration in GLUTag cells. The purpose of the present study was to examine if TTYC exerts positive inotropic effects on isolated rabbit ventricular myocytes and in vivo heart in anesthetized rats, and if so to further define the potential mechanism of action. Contractility was assessed in vitro using changes in fractional shortening (FS) of myocyte sarcomere length and in vivo using changes in the velocity of left ventricular pressure. Changes in L-type Ca(2+) current of ventricular myocytes were evaluated using whole-cell voltage-clamp techniques. TTYC increased FS of myocyte sarcomere length in a concentration-dependent manner. The positive inotropic effect was not abrogated by beta-adrenergic blockade (propranolol) or protein kinase A inhibition. TTYC enhanced peak L-type Ca(2+) current in a voltage-dependent manner (current amplitudes increased by 4.0-fold at -10 mV and 1.5-fold at +10 mV). Voltage-dependence of steady-state activation of L-type Ca(2+) current was shifted by 15 mV in the negative direction. Inactivation time course of the L-type Ca(2+) currents at voltages of -10 to 20 mV was significantly slowed by 0.3 microM TTYC. In vivo studies demonstrated that TTYC increased cardiac contractility in a dose-dependent manner. In conclusion, TTYC is a novel L-type Ca(2+) current activator with positive cardiac inotropic effects. Negative shifting of the voltage-dependence of L-type Ca(2+) current activation and reduced inactivation are two mechanisms responsible for the enhanced L-type Ca(2+) current that contribute to the positive inotropic effects.
    • "To examine the effect of antioxidant and adrenergic inhibition in stress-induced cardiac mechanical derangement, isolated cardiomyocytes from control unstressed rats were exposed to the stress inducer phenylephrine (20 µM) [23] to mimic a stress environment in the absence or presence of the antioxidant NAC (500 µM) [24] the mixed α-/β-adrenergic antagonist carvedilol (100 nM) [25], or the β-adrenergic antagonist propanolol (1 µM) [26]. Phenylephrine incubation significantly interrupted intracellular Ca 2+ homeostasis as evidenced by decreased ΔFFI and peak FFI as well as prolonged intracellular Ca 2+ decay (single exponential) associated with unchanged baseline FFI levels, reminiscent of the intracellular Ca 2+ defect observed in socially stressed rat cardiomyocytes. "
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    • "The respective values obtained here are within the range reported for these compounds using electrophysiological methods and primary cardiomyocytes or human ES cellderived cardiomyocytes (Supporting InformationTable S2 and Denning and Anderson, 2008). However, the IC 50 values obtained by patch clamp in cells transfected with the hERG channel appear to be lower (Su et al., 2010; Gintant, 2011). In addition to cell type differences and levels of ERG channel expression (or hERG channel in the case of heterologous expression in CHO cells), the differences could be explained by the workflow of the two approaches. "
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