ABSTRACT
The present study was designed to determine the effects of Guanfu base A (GFA) on the late sodium current (INa.L), transient sodium current (INa.T), HERG current (IHERG), and Kv1.5 current (IKv1.5). The values of INa.L, INa.T, IHERG and IKv1.5 were recorded using the whole-cell patch clamp technique. Compared with other channels, GFA showed selective blocking activity in late sodium channel. It inhibited INa.L in a concentration-dependent manner with an IC50 of (1.57 ± 0.14) μmol · L(-1), which was significantly lower than its IC50 values of (21.17 ± 4.51) μmol · L(-1) for the INa.T. The inhibitory effect of GFA on INa,L was not affected by 200 μmol · L(-1) H2O2. It inhibited IHERG with an IC50 of (273 ± 34) μmol · L(-1) and has slight blocking effect on IKv1.5, decreasing IKv1.5 by only 20.6% at 200 μmol · L(-1). In summary, GFA inhibited INa.L selectively and remained similar inhibition in presence of reactive oxygen species. These findings may suggest a novel molecular mechanism for the potential clinical application of GFA in the treatment of cardiovascular disorders.
Subject(s)
Animals , Female , Humans , Male , Analysis of Variance , Anti-Arrhythmia Agents , Pharmacology , Dose-Response Relationship, Drug , Guinea Pigs , HEK293 Cells , Heart Ventricles , Heterocyclic Compounds, 4 or More Rings , Pharmacology , Inhibitory Concentration 50 , Membrane Potentials , Myocytes, Cardiac , Metabolism , Patch-Clamp Techniques , Sodium Channel Blockers , Pharmacology , Sodium ChannelsABSTRACT
@#This study aimed at evaluating the antioxidant effects of Guanfu base A(GFA)on acetylcholine(Ach)/CaCl2(CaCl2 10 mg/mL, Ach 66 μg/mL)-induced atrial fibrillation(AF)in rats. SD rats were rando-mized into normal group, model group, GFA treatment groups(6 mg/kg, 12 mg/kg), Amiodarone(Ami)treatment group(50 mg/kg)and Lovastatin(Lov)treatment group(10 mg/kg). The AF durations were measured by electrocardiogram(ECG). The effective refractory periods(AERP)were measured in the left atrial appendage. Oxidative stress-related gene and protein expression was evaluated by RT-PCR and Western blot. The activity of antioxidant enzymes was measured by enzymatic assay. Results indicated that, in comparison with that in the vehicle-treated AF rats, treatment with GFA(6 mg/kg, 12 mg/kg, po), significantly shortened the AF duration and prolonged the AERP in rats. In addition, treatment with GFA reduced the levels of plasma and myocardium malondialdehyde, increased the activity of plasma superoxide dismutase in a dose-dependent manner. Moreover, treatment with GFA mitigated AF-up-regulated p22phox, p47phox, gp91phox, and p67phox NADPH oxidase expression, and AF-increased ratios of membrane to cytosolic Rac-1 in the atrium. It also significantly prevented AF-down-regulated atrial connexin40 expression in rats. Data suggested that GFA(6 mg/kg, 12 mg/kg)has potent anti-oxidant activity and inhibits oxidative-stress-related AF in rats.