Article date: June 1996
By: Jo‐Feng Chi, Shu‐Hsun Chu, Chih‐Shone Lee, Nai‐Kaun Chou, Ming‐Jai Su, in Volume 118, Issue 3, pages 503-512
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.
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.
DOI: 10.1111/j.1476-5381.1996.tb15431.x
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