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Mechanism of carvedilol‐induced block of delayed rectifier K + current in the NG108‐15 neuronal cell line
Author(s) -
Liu ChunPeng,
Chiang HungTing,
Jan ChungRen,
Wu ShengNan
Publication year - 2003
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.10165
Subject(s) - carvedilol , chemistry , quinidine , potassium channel blocker , diazoxide , antagonist , patch clamp , depolarization , membrane potential , pharmacology , iberiotoxin , potassium channel , stereochemistry , biophysics , potassium , medicine , biochemistry , receptor , heart failure , organic chemistry , insulin , biology
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 IC 50 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 1.64 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. Res. 58:196–208, 2003. © 2003 Wiley‐Liss, Inc.