No abstract

The effects of beauverficin, a cyclodepsipeptide compound, on ion currents in a mouse neuroblastoma and rat glioma hybrid cell line, NG108-15, were investigated with the aid of the whole-cell voltage-clamp technique. Beauvericin (0.3-100 microM) reversibly produced an inhibition of L-type voltage-dependent Ca2+ current (I(Ca,L)) in a concentration-dependent manner. Beauvericin caused no change in the overall shape of the current-voltage relationship of I(Ca,L). The IC(50) value of beauvericin-induced inhibition of I(Ca,L) was 4 microM. Neither gabapentin (30 microM) nor omega-conotoxin GVIA (3 microM) had effects on I(Ca,L). Beauvericin (30 microM) shifted the steady-state inactivation curve of I(Ca,L) to more negative membrane potentials by approximately -15 mV. The inhibitory effects of beauvericin on I(Ca,L) exhibited tonic and use-dependent characteristics. Beauvericin also suppressed I(Ca,L) evoked by repetitive action potential waveforms effectively. However, beauvericin (30 microM) had no effect on delayed rectifier K+ current in NG105-18 cells. Under current-clamp configuration, beauvericin reduced the firing frequency of action potentials. Therefore, this study indicates that beauvericin is a relatively specific inhibitor of L-type Ca2+ current in NG108-15 cells.

The effects of S-petasin, a sesquiterpene isolated from Petasites formosanus Kitamura, on ion currents in a mouse neuroblastoma and a rat glioma hybrid cell line, NG108-15, were examined with the aid of the whole-cell voltage-clamp technique. S-Petasin (1 - 300 microM) caused a decrease in the amplitude of L-type Ca2+ current (I(Ca,L)) in a concentration-dependent manner, however, it did not change the overall shape of the current-voltage relationship of I(Ca,L). The IC50 value for S-petasin-induced inhibition of I(Ca,L) was 11 microM. S-Petasin (10 microM) shifted the steady-state inactivation of I(Ca,L) to a more negative membrane potential by approximately -10 mV. S-petasin could prolong the recovery of I(Ca,L) inactivation. The inhibitory effect of S-petasin on I(Ca,L) was found to exhibit tonic and use-dependent characteristics. S-Petasin could inhibit I(Ca,L) evoked by action potential waveforms effectively. S-Petasin also suppressed low voltage-activated I(Ca,L) in NG108-15 cells. S-Petasin at a concentration of 100 microM had little effect on voltage-dependent Na+ current; however, it did produce an inhibitory effect on delayed rectifier K+ current in a time-dependent manner. These results demonstrate that S-petasin can interact directly with L-type Ca2+ channels in NG108-15 cells. These effects could contribute to the regulation of neuronal activity if similar results were found in neurons in vivo.

Arecaidine propargyl ester (APE) was developed as a potential candidate compound for the treatment of Alzheimer's disease. APE has been shown to have cardiovascular effects. APE produces negative chronotropic and inotropic effects in isolated atria. However, the ionic mechanisms underlying the cardiovascular effects of APE in guinea-pig atria are unclear. The aims of this study were: (1) to examine the shortening effect of APE on action potential duration (APD) and to compare the difference in potency between APE and muscarine in isolated single guinea-pig atrial myocytes by using the current clamp method, (2) to examine by using patch clamp techniques the ionic mechanisms underlying the cardiac effects of APE, and (3) to determine whether the cardiac effects caused by APE affect the usefulness of APE as a potential candidate for the treatment of Alzheimer's disease. The APE significantly reduced the APD in guinea-pig atria and produced no direct effect on ventricular myocytes. APE is approximately 20 times as potent as muscarine in shortening the APD. Attenuation of the APD was consistently accompanied by a hyperpolarization of the resting membrane potential in a concentration-dependent manner. The APE activated muscarinic K+ channels and increased potassium conductance in guinea-pig atrial myocytes. In the cell-attached configuration, the APE contained in the pipette increased the channel-opening probability and decreased the closed-state time interval. The proposal that APE can be used as a potential remedy for the treatment of Alzheimer's disease should be taken into consideration the undesirable cardiovascular side effects that APE causes at lower concentrations.