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1.
Int J Mol Med ; 44(5): 1932-1942, 2019 Nov.
Article in English | MEDLINE | ID: mdl-31545484

ABSTRACT

Isosteviol sodium (STVNa), which is a derivate of the natural sweet­tasting glycoside stevioside, has recently been developed and it has been determined that this compound exhibits neuro­ and cardio­protective properties. In the current study, whether STVNa interferes with the development of cardiac hypertrophy, which is induced by isoprenaline (Iso), was investigated in an experimental rat model. Rats were treated with a vehicle (0.9% NaCl; control), isoprenaline (Iso; 5 mg/kg) or Iso (5 mg/kg) with STVNa (4 mg/kg; Iso + STVNa). Cardiomyocytes were isolated using enzymatic dissociation and were treated with 5 µM Iso for 24 h and co­treated with 5 µM STVNa. Brain natriuretic peptide (BNP) mRNA expression was determined using PCR analysis. Cell surface area, intracellular reactive oxygen species (ROS), mitochondrial transmembrane potential (ΔΨm), cytoplasmic Ca2+ and Ca2+ and contractile function were examined using a laser scanning confocal microscope. The current study demonstrated that STVNa inhibited Iso­induced cardiac hypertrophy by inhibiting cardiomyocyte size. STVNa significantly reduced cell surface area and decreased BNP mRNA expression in ventricular cardiomyocyte Iso­induced hypertrophy. STVNa was also revealed to restore ΔΨm and reduce ROS generation and intracellular Ca2+ concentration when compared with the Iso­treated group. Additionally, STVNa preserved Ca2+ transients in hypertrophic cardiomyocytes. In conclusion, the present study demonstrated that STVNa protects against Iso­induced myocardial hypertrophy by reducing oxidative stress, restoring ΔΨm and maintaining Ca2+ homeostasis.


Subject(s)
Cardiomegaly/chemically induced , Cardiomegaly/prevention & control , Diterpenes, Kaurane/pharmacology , Isoproterenol/pharmacology , Myocytes, Cardiac/drug effects , Animals , Apoptosis/drug effects , Calcium/metabolism , Cardiomegaly/metabolism , Male , Membrane Potential, Mitochondrial/drug effects , Myocytes, Cardiac/metabolism , Natriuretic Peptide, Brain/metabolism , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Reactive Oxygen Species/metabolism , Signal Transduction/drug effects
2.
Biochim Biophys Acta Biomembr ; 1859(10): 1872-1879, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28428073

ABSTRACT

Cardiac hypertrophy is a thickening of the heart muscle that is associated with cardiovascular diseases such as hypertension and myocardial infarction. It occurs initially as an adaptive process against increased workloads and often leads to sudden arrhythmic deaths. Studies suggest that the lethal arrhythmia is attributed to hypertrophy-induced destabilization of cardiac electrical activity, especially the prolongation of the action potential. The reduced activity of Ito is demonstrated to be responsible for the ionic mechanism of prolonged action potential duration and arrhythmogeneity. Isosteviol (STV), a derivative of stevioside, plays a protective role in a variety of stress-induced cardiac diseases. Here we report effects of STV on rat ISO-induced hypertrophic cardiomyocytes. STV alleviated ISO-induced hypertrophy of cardiomyocytes by decreasing cell area of hypertrophied cardiomyocytes. STV application prevented the prolongation of action potential which was prominent in hypertrophied cells. The decrease and increase of current densities for Ito and ICaL observed in hypertrophied myocytes were both prevented by STV application. In addition, the results of qRT-PCR suggested that the changes of electrophysiological activity of Ito and ICaL are correlated to the alterations of the mRNA transcription level.


Subject(s)
Action Potentials/drug effects , Calcium Channels, L-Type/metabolism , Cardiomegaly/drug therapy , Diterpenes, Kaurane/pharmacology , Myocytes, Cardiac/drug effects , Potassium Channels/metabolism , Animals , Arrhythmias, Cardiac/drug therapy , Arrhythmias, Cardiac/metabolism , Cardiomegaly/metabolism , Glucosides/pharmacology , Myocardium/metabolism , Myocytes, Cardiac/metabolism , Potassium/metabolism , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley
3.
Biochim Biophys Acta ; 1858(11): 2745-2752, 2016 11.
Article in English | MEDLINE | ID: mdl-27480802

ABSTRACT

This study investigated the effect of the ß2 receptor agonist terbutaline on the single channel activity of BKCa channel. The effects of racemate and two isomers of terbutaline were all assessed. ß2 adrenoceptors were stably overexpressed on HEK293 cells by lentiviral transduction method and chicken BKCa channels were transiently expressed on normal HEK293 cell line or HEK293 cells overexpressing ß2 receptors. Data showed that terbutaline significantly increased the single channel open probability of BKCa channel within 10min. The channel activating effects of terbutaline are stereoselective and mainly stay with the R-enantiomers. The opening probability of BKCa channel at 10min after drug application normalized to that just before drug application (Po10/Po0s) for R- and S-terbutaline were 7.85±3.20 and 1.06±0.45 respectively at 1µM concentration, corresponding to 28.37±9.96 and 2.68±1.09 at the higher concentration of 10µM. ICI 118551 blocked the effect of R- but not S-terbutaline (10µM), whereas atropine blocked the channel activating effects of S-terbutaline of higher concentration. In addition, the muscarinic receptor agonist carbachol increased the BKCa channel activity in an atropine-sensitive manner as an positive control experiment, which indicate the involvement of M receptor in the channel activating effect of S-terbutaline.


Subject(s)
Adrenergic beta-2 Receptor Agonists/pharmacology , Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/metabolism , Receptors, Adrenergic, beta-2/metabolism , Receptors, Muscarinic/metabolism , Terbutaline/pharmacology , Animals , Atropine/pharmacology , Carbachol/pharmacology , Chickens , Gene Expression , Genetic Vectors/chemistry , HEK293 Cells , Humans , Ion Channel Gating/drug effects , Large-Conductance Calcium-Activated Potassium Channel alpha Subunits/genetics , Lentivirus/genetics , Lentivirus/metabolism , Membrane Potentials/drug effects , Membrane Potentials/physiology , Muscarinic Agonists/pharmacology , Muscarinic Antagonists/pharmacology , Propanolamines/pharmacology , Receptors, Adrenergic, beta-2/genetics , Receptors, Muscarinic/genetics , Stereoisomerism , Transgenes
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