RESUMEN
Abnormal enhanced transmural dispersion of repolarization (TDR) plays an important role in the maintaining of the severe ventricular arrhythmias such as torsades de pointes (TDP) which can be induced in long-QT (LQT) syndrome. Taking advantage of an in vitro rabbit model of LQT2, we detected the effects of KN-93, a CaM-dependent kinase (CaMK) II inhibitor on repolarization heterogeneity of ventricular myocardium. Using the monophasic action potential recording technique, the action potentials of epicardium and endocardium were recorded in rabbit cardiac wedge infused with hypokalemic, hypomagnesaemic Tyrode's solution. At a basic length (BCL) of 2000 ms, LQT2 model was successfully mimicked with the perfusion of 0.5 μmol/L E-4031, QT intervals and the interval from the peak of T wave to the end of T wave (Tp-e) were prolonged, and Tp-e/QT increased. Besides, TDR was increased and the occurrence rate of arrhythmias like EAD, R-on-T extrasystole, and TDP increased under the above condition. Pretreatment with KN-93 (0.5 μmol/L) could inhibit EAD, R-on-T extrasystole, and TDP induced by E-4031 without affecting QT interval, Tp-e, and Tp-e/QT. This study demonstrated KN-93, a CaMKII inhibitor, can inhibit EADs which are the triggers of TDP, resulting in the suppression of TDP induced by LQT2 without affecting TDR.
RESUMEN
Abnormal enhanced transmural dispersion of repolarization (TDR) plays an important role in the maintaining of the severe ventricular arrhythmias such as torsades de pointes (TDP) which can be induced in long-QT (LQT) syndrome. Taking advantage of an in vitro rabbit model of LQT2, we detected the effects of KN-93, a CaM-dependent kinase (CaMK) II inhibitor on repolarization heterogeneity of ventricular myocardium. Using the monophasic action potential recording technique, the action potentials of epicardium and endocardium were recorded in rabbit cardiac wedge infused with hypokalemic, hypomagnesaemic Tyrode's solution. At a basic length (BCL) of 2000 ms, LQT2 model was successfully mimicked with the perfusion of 0.5 μmol/L E-4031, QT intervals and the interval from the peak of T wave to the end of T wave (Tp-e) were prolonged, and Tp-e/QT increased. Besides, TDR was increased and the occurrence rate of arrhythmias like EAD, R-on-T extrasystole, and TDP increased under the above condition. Pretreatment with KN-93 (0.5 μmol/L) could inhibit EAD, R-on-T extrasystole, and TDP induced by E-4031 without affecting QT interval, Tp-e, and Tp-e/QT. This study demonstrated KN-93, a CaMKII inhibitor, can inhibit EADs which are the triggers of TDP, resulting in the suppression of TDP induced by LQT2 without affecting TDR.
Asunto(s)
Animales , Conejos , Potenciales de Acción , Antiarrítmicos , Farmacología , Arritmias Cardíacas , Bencilaminas , Farmacología , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Metabolismo , Electrocardiografía , Técnicas Electrofisiológicas Cardíacas , Endocardio , Corazón , Técnicas In Vitro , Síndrome de QT Prolongado , Pericardio , Piperidinas , Farmacología , Inhibidores de Proteínas Quinasas , Farmacología , Piridinas , Farmacología , Sulfonamidas , Farmacología , Torsades de PointesRESUMEN
<p><b>OBJECTIVE</b>To study the effect of matrine and oxymatrine on proliferation and the expression of Stat3, Stat5 mRNA in SMMC-7721 cell line.</p><p><b>METHOD</b>Treated with matrine and oxymatrine, the inhibitory effect on SMMC-7721 cell proliferation was detected by MTT, double fluorescence labeling was applied to measure the apotosis ratios of SMMC-7721cells, the expression of Stat3 and Stat5 mRNA in SMMC-7721 cell line were assessed with RT-PCR.</p><p><b>RESULT</b>Matrine and oxymatrine could inhibit the proliferation and induce the apoptosis of SMMC-7721 cells and it was time and dose dependent, the expression of Stat3 and Stat5 mRNA in SMMC-7721 cell with matrine and oxymatrine were significantly lower than those in control group (P<0.05 or P<0.01). Compared with the same dose of matrine and oxymatrine, matrine showed stronger effect on cell proliferation, apoptosis, and Stat3 and Stat5 mRNA (P<0.05 or P<0.01).</p><p><b>CONCLUSION</b>Matrine and oxymatrine inhibited the proliferation and induced the of SMMC-7721 cells significantly, the mechanism of which might be related to the down-regulation of stat3 and stat5 mRNA and inhibition of the signaling transduction pathway.</p>