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

Abstract

AbstractThe effects of the β‐adrenoceptor antagonist carvedilol on delayed rectifier K+ current (IK (DR)) were examined in NG108‐15 neuronal cells. Carvedilol (1–100µM) reversibly blocked IK (DR) with an IC50 value of 5 µM. IK (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 IK (DR) could not be reversed by further application of t‐butyl hydroperoxide or diazoxide. The inhibition of IK (DR) by carvedilol could still be observed in cells preincubated with t‐butyl hydroperoxide (1 mM), ruthenium red (30 µM), or carbonyl cyanide m‐chlorophenyl hydrazone (10 µM). The presence of carvedilol enhanced both the rate and extent of IK (DR) inactivation. Recovery from block by carvedilol (3 µM) 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 IK (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. Res. 58:196–208, 2003. © 2003 Wiley‐Liss, Inc.