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

The effects of the β-adrenoceptor antagonist carvedilol on delayed rectifier K⁺ current (I_{K (DR)}) were examined in NG108-15 neuronal cells. Carvedilol (1-100μM) reversibly blocked I_{K (DR)} with an IC₅₀ value of 5 μM. 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 μM), or carbonyl cyanide m-chlorophenyl hydrazone (10 μM). The presence of carvedilol enhanced both the rate and extent of I_{K (DR)} inactivation. Recovery from block by carvedilol (3 μM) could be fitted by a single exponential with a value of 1.64s. 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.