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

Chun Peng Liu, Hung Ting Chiang, Chung Ren Jan, Sheng-Nan Wu

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The 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 1.64s. 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 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.

Original languageEnglish
Pages (from-to)196-208
Number of pages13
JournalDrug Development Research
Volume58
Issue number2
DOIs
Publication statusPublished - 2003 Feb 1

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Cell Line
tert-Butylhydroperoxide
Carbonyl Cyanide m-Chlorophenyl Hydrazone
carvedilol
Diazoxide
Ruthenium Red
Quinidine
Adrenergic Receptors
Inhibitory Concentration 50
Neurons

All Science Journal Classification (ASJC) codes

  • Drug Discovery

Cite this

Liu, Chun Peng ; Chiang, Hung Ting ; Jan, Chung Ren ; Wu, Sheng-Nan. / Mechanism of carvedilol-induced block of delayed rectifier K+ current in the NG108-15 neuronal cell line. In: Drug Development Research. 2003 ; Vol. 58, No. 2. pp. 196-208.
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abstract = "The 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 1.64s. 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 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.",
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Mechanism of carvedilol-induced block of delayed rectifier K+ current in the NG108-15 neuronal cell line. / Liu, Chun Peng; Chiang, Hung Ting; Jan, Chung Ren; Wu, Sheng-Nan.

In: Drug Development Research, Vol. 58, No. 2, 01.02.2003, p. 196-208.

Research output: Contribution to journalArticle

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N2 - The 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 1.64s. 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 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.

AB - The 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 1.64s. 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 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.

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