Effects of 8-oxoberberine on sodium current in rat ventricular and human atrial myocytes

8-Oxoberberine (JKL1073A), a derivative of berberine, has been reported to exert positive inotropic action and antiarrhythmic activity, much like a class III antiarrhythmic agent. In addition to prolongation of cardiac action potential duration, JKL1073A also decreases the maximal rate of action potential upstroke. To characterize the mode of inhibition of action potential upstroke, the effects of JKL1073A on the sodium inward current (I(Na)) of rat and human cardiac myocytes were examined by voltage clamp in a whole cell configuration. In rat ventricular myocytes, JKL1073A and quinidine inhibited I(Na) with an average 50% inhibitory concentration (IC50) of 3.3 ± 0.2 μM (n = 9) and 2.1 ± 0.1 μM (n = 6), respectively. Voltage dependent steady state inactivation curves of I(Na) were shifted slightly by 10 μM JKL1073A but more significantly by 3 μM quinidine to negative potential. Though steady state inactivation of I(Na) was not significantly changed by 3 μM JKL1073A, the time constant of I(Na) recovery from inactivation state was partially prolonged from 51.7 ± 18.5 ms to 74.1 ± 23.8 ms. Quinidine (3 μM) prolonged the time course of I(Na), recovery from inactivation with an associated increase of slow recovery component. Inhibition of I(Na) by JKL1073A and quinidine was increased when cells were stimulated at higher frequency. The maxmial I(Na) obtained in cells held at -140 mV was significantly decreased by 10 μM quinidine to 45.3 ± 2.5% of control but only partially suppressed by 10 μM JKL1073A to 85.9 ± 8.6% of control. In human atrial myocytes, JKL1073A and quinidine suppressed I(Na) with an average IC50 of 2.4 ± 0.6 μM and 1.4 ± 0.3 μM, respectively. Both JKL1073A and quinidine increased the time constant of I(Na) recovery from activation. In conclusion, JKL1073A at concentrations of 3 μM and 10 μM may inhibit I(Na) mainly by binding to open and inactivated channels. Quinidine 3 μM may inhibit I(Na) by binding to resting, open and inactivated channels. Inhibition of I(Na) by JKL1073A may explain the inhibition of the action potential upstroke and contribute partially to its antiarrhythmic activity.