Mechanism of carvedilol‐induced block of delayed rectifier K⁺ current in the NG108‐15 neuronal cell line

Abstract

The effects of the b-adrenoceptor antagonist carvedilol on delayed rectifier K + current (I K (DR) ) were examined in NG108-15 neuronal cells. Carvedilol (1-100mM) reversibly blocked I K (DR) with an IC 50 value of 5 mM. I K (DR) in response to depolarizing pulses was sensitive to inhibition by quinidine or dendrotoxin, but not by iberiotoxin, 5-hydroxydecanoate sodium, or linopiridine. The carvedilol-induced inhibition of I K (DR) could not be reversed by further application of t-butyl hydroperoxide or diazoxide. The inhibition of I K (DR) by carvedilol could still be observed in cells preincubated with t-butyl hydroperoxide (1 mM), ruthenium red (30 mM), or carbonyl cyanide m-chlorophenyl hydrazone (10 mM). The presence of carvedilol enhanced both the rate and extent of I K (DR) inactivation. Recovery from block by carvedilol (3 mM) could be fitted by a single exponential with a value of 1.64 s. Crossover of tail currents in the presence of carvedilol was also observed. Cell-attached single-channel recordings revealed that carvedilol suppressed channel activity without altering single-channel amplitude. With the aid of the binding scheme, a quantitative description of the carvedilol actions on I K (DR) was also developed that clearly showed that in addition to being an antioxidative agent, carvedilol can block delayed rectifying K + channel of neurons in an open-and state-dependent manner. Drug Dev.

Bisoprolol, Known to Be a Selective β1-Receptor Antagonist, Differentially but Directly Suppresses IK(M) and IK(erg) in Pituitary Cells and Hippocampal Neurons

“…Previous studies have reported the importance of I K(erg) functionally expressed in pituitary cells including GH 3 cells [41,42]. Some of β-adrenoceptor blockers have been previously demonstrated to suppress HERG K + or other types of voltage-gated K + channels [13,14]. As such, we further studied the possible perturbation by BIS on this type of K + currents (i.e., I K(erg) ).…”

“…An earlier report showed the ability of carvedilol to suppress I K(DR) in NG108-15 neuronal cells [13]. We also explored whether or not the presence of BIS produced any effects on another types of K + currents (e.g., I K(DR) ) in these cells.…”

“…The present results are of particular importance, as they suggest that the inhibition of both I K(M) and I K(erg) caused by BIS is direct and appears to be unnecessarily linked to its binding to β-adrenergic receptor, although binding to β 1 -adrenergic receptor was previously reported to influence pituitary function [7,8,11,12,45]. However, distinguishable from the inhibitory effect of carvedilol, a non-selective blocker of β-adrenergic receptors, on the amplitude and inactivation kinetics I K(DR) [13], BIS at a concentration greater than 10 µM slightly suppressed I K(DR) amplitude with no discernible change in the inactivation time course of the current.…”

“…Carvedilol or other blockers of β-adrenergic receptors were indeed previously shown to suppress the amplitude of delayed-rectifier K + currents ( I K(DR) ) and of HERG-mediated K + currents [13,14]. There is also evidence showing that BIS appears to modulate a variety of ion currents.…”