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 (INa) of rat and human cardiac myocytes were examined by voltage clamp in a whole cell configuration. In rat ventricular myocytes, JKL1073A and quinidine inhibited INa with an average 50% inhibitory concentration (IC50) of 3.3 +/- 0.2 microM (n = 9) and 2.1 +/- 0.1 microM (n = 6), respectively. Voltage-dependent steady state inactivation curves of INa were shifted slightly by 10 microM JKL1073A but more significantly by 3 microM quinidine to negative potential. Though steady state inactivation of INa was not significantly changed by 3 microM JKL1073A, the time constant of INa recovery from inactivation state was partially prolonged from 51.7 +/- 18.5 ms to 74.1 +/- 23.8 ms. Quinidine (3 microM) prolonged the time course of INa recovery from inactivation with an associated increase of slow recovery component. Inhibition of INa by JKL1073A and quinidine was increased when cells were stimulated at higher frequency. The maximal INa obtained in cells held at -140 mV was significantly decreased by 10 microM quinidine to 45.3 +/- 2.5% of control but only partially suppressed by 10 microM JKL1073A to 85.9 +/- 8.6% of control. In human atrial myocytes, JKL1073A and quinidine suppressed INa with an average IC50 of 2.4 +/- 0.6 microM and 1.4 +/- 0.3 microM, respectively. Both JKL1073A and quinidine increased the time constant of INa recovery from inactivation. In conclusion, JKL1073A at concentrations of 3 microM and 10 microM may inhibit INa mainly by binding to open and inactivated channels. Quinidine 3 microM may inhibit INa by binding to resting, open and inactivated channels. Inhibition of INa by JKL1073A may explain the inhibition of the action potential upstroke and contribute partially to its antiarrhythmic activity.

1996-06-01·British Journal of Pharmacology

Mechanical and electrophysiological effects of 8‐oxoberberine (JKL1073A) on atrial tissue

Article

作者: Nai-Kaun Chou ; Jo-Feng Chi ; Shu-Hsun Chu ; Ming-Jai Su ; Chih-Shone Lee

The effects of 8‐oxoberberine (JKL1073A) on contractions and electrophysiological characteristics of atrial tissues were examined.In driven left atria of the rat JKL1073A (10–100 μm) increased twitch tension dose‐dependently. In spontaneously beating right atria, JKL1073A increased twitch tension but decreased beating rate slightly.The positive inotropic and the negative chronotropic effect of 30 μm JKL1073A was not affected by prazosin (1 μm), propranolol (1 μm) and 3‐isobutyl‐1‐methyl‐xanthine (10 μm) but significantly suppressed by 4‐aminopyridine (2 mM 4‐AP).Current‐clamp study revealed that JKL1073A prolonged rat atrial action potential duration (APD). This prolongation of APD by JKL1073A was decreased by pretreating the cells with 2 mM 4‐AP. Voltage‐clamp study showed that JKL1073A inhibited the integral of the transient outward current (Ito) dose‐dependently with a KD value of 3.66 ± 0.93 μm in rat atrial myocytes. The equilibrium dissociation constant (Kd) for JKL1073A bindings to open state Ito was 0.50 ± 0.08 μm. The suppression of Ito by 3 μm JKL1073A was accompanied by shortening of its inactivation time constant from 52.5 ± 0.9 ms to 16.8 ± 0.7 ms. V0.5 for the steady‐state inactivation curve of Ito was shifted from −25.7 ± 3.3 mV to −34.8 ± 3.2 mV.In human atrial cells, similar inhibition of Ito and prolongation of APD by JKL1073A was found. The KD value of JKL1073A for inhibition of the integral of Ito in human atrial cells is 4.03 ± 0.02 μm. The Kd for bindings to open state Ito is 0.5 μm.Currents through K1 channels of rat and human atrial myocytes were not inhibited by JKL1073A at concentrations up to 10 μm.These results indicate that JKL1073A exerts a positive inotropic effect by inhibition of Ito. JKL1073A inhibit Ito by binding to open state channels or shifting of the steady‐state inactivation curve of Ito.

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