On the mechanism of selective action of probucol on the inwardly rectifying potassium current in GH3 lactotrophs

Hung Ting Chiang, Sheng-Nan Wu

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The ionic mechanism of action of probucol, a known lipid-lowering agent, was examined in rat pituitary GH3 cells. Whole-cell voltage-clamp was used to measure hyperpolarization-activated K+ currents in GH3 cells bathed in a high-K+, Ca2+-free solution to determine the effect of probucol on the erg-like inwardly rectifying K+ current (IK(IR)). Probucol reversibly suppressed the amplitude of IK(IR) in a concentration-dependent manner. The IC50 value of probucol-induced inhibition of IK(IR) was 1 μM. Probucol shifted the steady-state inactivation curve of IK(IR) to less negative potentials and also prolonged the recovery of IK(IR) inactivation. The K+ inward current in response to hyperpolarizing voltage pulses was also inhibited by haloperidol (10 μM) and bepridil (10 μM) but not by reduced glutathione (10 mM) or superoxide dismutase (500 U/ml). Pretreatment with t-butyl hydroperoxide (1 mM) or thimerosal (1 mM) did not prevent the probucol-mediated inhibition of IK(IR). Probucol (10 μM) caused a slight reduction in the amplitude of voltage-dependent L-type Ca2+ current, but did not affect Ca2+-activated and voltage-dependent K+ currents. In the current-clamp configuration, probucol (10 μM) increased the firing frequency of action potentials. The present study provides substantial evidence that in addition to the presence of antioxidant activity, probucol is a selective blocker of IK(IR), and implies that probucol-mediated blockade of this current may affect membrane excitability and hormonal secretion in GH3 cells.

Original languageEnglish
Pages (from-to)1-11
Number of pages11
JournalDrug Development Research
Volume54
Issue number1
DOIs
Publication statusPublished - 2001 Jan 1

Fingerprint

Lactotrophs
Probucol
Potassium
Bepridil
Thimerosal
tert-Butylhydroperoxide
Haloperidol
Action Potentials
Inhibitory Concentration 50
Superoxide Dismutase
Glutathione
Antioxidants

All Science Journal Classification (ASJC) codes

  • Drug Discovery

Cite this

@article{b5da178430c64c7e88954b297ef07227,
title = "On the mechanism of selective action of probucol on the inwardly rectifying potassium current in GH3 lactotrophs",
abstract = "The ionic mechanism of action of probucol, a known lipid-lowering agent, was examined in rat pituitary GH3 cells. Whole-cell voltage-clamp was used to measure hyperpolarization-activated K+ currents in GH3 cells bathed in a high-K+, Ca2+-free solution to determine the effect of probucol on the erg-like inwardly rectifying K+ current (IK(IR)). Probucol reversibly suppressed the amplitude of IK(IR) in a concentration-dependent manner. The IC50 value of probucol-induced inhibition of IK(IR) was 1 μM. Probucol shifted the steady-state inactivation curve of IK(IR) to less negative potentials and also prolonged the recovery of IK(IR) inactivation. The K+ inward current in response to hyperpolarizing voltage pulses was also inhibited by haloperidol (10 μM) and bepridil (10 μM) but not by reduced glutathione (10 mM) or superoxide dismutase (500 U/ml). Pretreatment with t-butyl hydroperoxide (1 mM) or thimerosal (1 mM) did not prevent the probucol-mediated inhibition of IK(IR). Probucol (10 μM) caused a slight reduction in the amplitude of voltage-dependent L-type Ca2+ current, but did not affect Ca2+-activated and voltage-dependent K+ currents. In the current-clamp configuration, probucol (10 μM) increased the firing frequency of action potentials. The present study provides substantial evidence that in addition to the presence of antioxidant activity, probucol is a selective blocker of IK(IR), and implies that probucol-mediated blockade of this current may affect membrane excitability and hormonal secretion in GH3 cells.",
author = "Chiang, {Hung Ting} and Sheng-Nan Wu",
year = "2001",
month = "1",
day = "1",
doi = "10.1002/ddr.1198",
language = "English",
volume = "54",
pages = "1--11",
journal = "Drug Development Research",
issn = "0272-4391",
publisher = "John Wiley and Sons Inc.",
number = "1",

}

On the mechanism of selective action of probucol on the inwardly rectifying potassium current in GH3 lactotrophs. / Chiang, Hung Ting; Wu, Sheng-Nan.

In: Drug Development Research, Vol. 54, No. 1, 01.01.2001, p. 1-11.

Research output: Contribution to journalArticle

TY - JOUR

T1 - On the mechanism of selective action of probucol on the inwardly rectifying potassium current in GH3 lactotrophs

AU - Chiang, Hung Ting

AU - Wu, Sheng-Nan

PY - 2001/1/1

Y1 - 2001/1/1

N2 - The ionic mechanism of action of probucol, a known lipid-lowering agent, was examined in rat pituitary GH3 cells. Whole-cell voltage-clamp was used to measure hyperpolarization-activated K+ currents in GH3 cells bathed in a high-K+, Ca2+-free solution to determine the effect of probucol on the erg-like inwardly rectifying K+ current (IK(IR)). Probucol reversibly suppressed the amplitude of IK(IR) in a concentration-dependent manner. The IC50 value of probucol-induced inhibition of IK(IR) was 1 μM. Probucol shifted the steady-state inactivation curve of IK(IR) to less negative potentials and also prolonged the recovery of IK(IR) inactivation. The K+ inward current in response to hyperpolarizing voltage pulses was also inhibited by haloperidol (10 μM) and bepridil (10 μM) but not by reduced glutathione (10 mM) or superoxide dismutase (500 U/ml). Pretreatment with t-butyl hydroperoxide (1 mM) or thimerosal (1 mM) did not prevent the probucol-mediated inhibition of IK(IR). Probucol (10 μM) caused a slight reduction in the amplitude of voltage-dependent L-type Ca2+ current, but did not affect Ca2+-activated and voltage-dependent K+ currents. In the current-clamp configuration, probucol (10 μM) increased the firing frequency of action potentials. The present study provides substantial evidence that in addition to the presence of antioxidant activity, probucol is a selective blocker of IK(IR), and implies that probucol-mediated blockade of this current may affect membrane excitability and hormonal secretion in GH3 cells.

AB - The ionic mechanism of action of probucol, a known lipid-lowering agent, was examined in rat pituitary GH3 cells. Whole-cell voltage-clamp was used to measure hyperpolarization-activated K+ currents in GH3 cells bathed in a high-K+, Ca2+-free solution to determine the effect of probucol on the erg-like inwardly rectifying K+ current (IK(IR)). Probucol reversibly suppressed the amplitude of IK(IR) in a concentration-dependent manner. The IC50 value of probucol-induced inhibition of IK(IR) was 1 μM. Probucol shifted the steady-state inactivation curve of IK(IR) to less negative potentials and also prolonged the recovery of IK(IR) inactivation. The K+ inward current in response to hyperpolarizing voltage pulses was also inhibited by haloperidol (10 μM) and bepridil (10 μM) but not by reduced glutathione (10 mM) or superoxide dismutase (500 U/ml). Pretreatment with t-butyl hydroperoxide (1 mM) or thimerosal (1 mM) did not prevent the probucol-mediated inhibition of IK(IR). Probucol (10 μM) caused a slight reduction in the amplitude of voltage-dependent L-type Ca2+ current, but did not affect Ca2+-activated and voltage-dependent K+ currents. In the current-clamp configuration, probucol (10 μM) increased the firing frequency of action potentials. The present study provides substantial evidence that in addition to the presence of antioxidant activity, probucol is a selective blocker of IK(IR), and implies that probucol-mediated blockade of this current may affect membrane excitability and hormonal secretion in GH3 cells.

UR - http://www.scopus.com/inward/record.url?scp=0035199591&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035199591&partnerID=8YFLogxK

U2 - 10.1002/ddr.1198

DO - 10.1002/ddr.1198

M3 - Article

AN - SCOPUS:0035199591

VL - 54

SP - 1

EP - 11

JO - Drug Development Research

JF - Drug Development Research

SN - 0272-4391

IS - 1

ER -