Inhibition of intermediate-conductance Ca2+-activated K + channel and cytoprotective properties of 4-piperidinomethyl-2- isopropyl-5-methylphenol

Ai Yu Shen, Jen Hsiang Tsai, Hsiu Chen Teng, Mei Han Huang, Sheng-Nan Wu

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

The ionic mechanisms and cytoprotective activities of 4-piperidinomethyl-2- isopropyl-5-methylphenol (THPI), an analogue of thymol, were investigated in HL-60 granulocytes and in human erythrocytes, respectively. THPI inhibited K+ outward current (IK) in a concentration-dependent manner in HL-60 leukocytes, with an IC50 value of 4 μM. Neither iberiotoxin (200 nM) nor paxilline (1 μM) suppressed the amplitude of IK, whereas clotrimazole (5 μM) significantly inhibited it. In the inside-out configuration of single channel recordings, application of THPI (5 μM) into the bath medium did not alter the single-channel conductance of intermediate-conductance Ca2+-activated K+ (IK Ca) channels (i.e KCa3.1 channels), but it suppressed the channel activity significantly. THPI-induced inhibition of IKCa channels was reversed by a further application of 1-ethyl-2-benzimidazolinone (10 μM). THPI-induced reduction in IKCa-channel activity in these cells was primarily due to a decrease in mean open time. These results provide direct evidence that THPI is capable of suppressing the activity of IK Ca channels in HL-60 cells. The antioxidant action of THPI also revealed a beneficial cytoprotective effect against mitomycin C-mediated haemolytic effect in human erythrocytes. The results of this study suggest that blockade of IKCa channels and the membrane-protecting activity of THPI would combine to have beneficial effects in lessening the severity of haemolytic crisis and reducing anaemia in sickle cell disease.

Original languageEnglish
Pages (from-to)679-685
Number of pages7
JournalJournal of Pharmacy and Pharmacology
Volume59
Issue number5
DOIs
Publication statusPublished - 2007 May 1

Fingerprint

Calcium-Activated Potassium Channels
Erythrocytes
Clotrimazole
Thymol
HL-60 Cells
Sickle Cell Anemia
Mitomycin
Baths
Ion Channels
Granulocytes
Inhibitory Concentration 50
Anemia
Leukocytes
Antioxidants
4-piperidinomethyl-2-isopropyl-5-methylphenol
iberiotoxin
paxilline
1-ethyl-2-benzimidazolinone

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

@article{0b14dbcda933474683f9b587652c31c4,
title = "Inhibition of intermediate-conductance Ca2+-activated K + channel and cytoprotective properties of 4-piperidinomethyl-2- isopropyl-5-methylphenol",
abstract = "The ionic mechanisms and cytoprotective activities of 4-piperidinomethyl-2- isopropyl-5-methylphenol (THPI), an analogue of thymol, were investigated in HL-60 granulocytes and in human erythrocytes, respectively. THPI inhibited K+ outward current (IK) in a concentration-dependent manner in HL-60 leukocytes, with an IC50 value of 4 μM. Neither iberiotoxin (200 nM) nor paxilline (1 μM) suppressed the amplitude of IK, whereas clotrimazole (5 μM) significantly inhibited it. In the inside-out configuration of single channel recordings, application of THPI (5 μM) into the bath medium did not alter the single-channel conductance of intermediate-conductance Ca2+-activated K+ (IK Ca) channels (i.e KCa3.1 channels), but it suppressed the channel activity significantly. THPI-induced inhibition of IKCa channels was reversed by a further application of 1-ethyl-2-benzimidazolinone (10 μM). THPI-induced reduction in IKCa-channel activity in these cells was primarily due to a decrease in mean open time. These results provide direct evidence that THPI is capable of suppressing the activity of IK Ca channels in HL-60 cells. The antioxidant action of THPI also revealed a beneficial cytoprotective effect against mitomycin C-mediated haemolytic effect in human erythrocytes. The results of this study suggest that blockade of IKCa channels and the membrane-protecting activity of THPI would combine to have beneficial effects in lessening the severity of haemolytic crisis and reducing anaemia in sickle cell disease.",
author = "Shen, {Ai Yu} and Tsai, {Jen Hsiang} and Teng, {Hsiu Chen} and Huang, {Mei Han} and Sheng-Nan Wu",
year = "2007",
month = "5",
day = "1",
doi = "10.1211/jpp.59.5.0008",
language = "English",
volume = "59",
pages = "679--685",
journal = "Journal of Pharmacy and Pharmacology",
issn = "0022-3573",
publisher = "Pharmaceutical Press",
number = "5",

}

Inhibition of intermediate-conductance Ca2+-activated K + channel and cytoprotective properties of 4-piperidinomethyl-2- isopropyl-5-methylphenol. / Shen, Ai Yu; Tsai, Jen Hsiang; Teng, Hsiu Chen; Huang, Mei Han; Wu, Sheng-Nan.

In: Journal of Pharmacy and Pharmacology, Vol. 59, No. 5, 01.05.2007, p. 679-685.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibition of intermediate-conductance Ca2+-activated K + channel and cytoprotective properties of 4-piperidinomethyl-2- isopropyl-5-methylphenol

AU - Shen, Ai Yu

AU - Tsai, Jen Hsiang

AU - Teng, Hsiu Chen

AU - Huang, Mei Han

AU - Wu, Sheng-Nan

PY - 2007/5/1

Y1 - 2007/5/1

N2 - The ionic mechanisms and cytoprotective activities of 4-piperidinomethyl-2- isopropyl-5-methylphenol (THPI), an analogue of thymol, were investigated in HL-60 granulocytes and in human erythrocytes, respectively. THPI inhibited K+ outward current (IK) in a concentration-dependent manner in HL-60 leukocytes, with an IC50 value of 4 μM. Neither iberiotoxin (200 nM) nor paxilline (1 μM) suppressed the amplitude of IK, whereas clotrimazole (5 μM) significantly inhibited it. In the inside-out configuration of single channel recordings, application of THPI (5 μM) into the bath medium did not alter the single-channel conductance of intermediate-conductance Ca2+-activated K+ (IK Ca) channels (i.e KCa3.1 channels), but it suppressed the channel activity significantly. THPI-induced inhibition of IKCa channels was reversed by a further application of 1-ethyl-2-benzimidazolinone (10 μM). THPI-induced reduction in IKCa-channel activity in these cells was primarily due to a decrease in mean open time. These results provide direct evidence that THPI is capable of suppressing the activity of IK Ca channels in HL-60 cells. The antioxidant action of THPI also revealed a beneficial cytoprotective effect against mitomycin C-mediated haemolytic effect in human erythrocytes. The results of this study suggest that blockade of IKCa channels and the membrane-protecting activity of THPI would combine to have beneficial effects in lessening the severity of haemolytic crisis and reducing anaemia in sickle cell disease.

AB - The ionic mechanisms and cytoprotective activities of 4-piperidinomethyl-2- isopropyl-5-methylphenol (THPI), an analogue of thymol, were investigated in HL-60 granulocytes and in human erythrocytes, respectively. THPI inhibited K+ outward current (IK) in a concentration-dependent manner in HL-60 leukocytes, with an IC50 value of 4 μM. Neither iberiotoxin (200 nM) nor paxilline (1 μM) suppressed the amplitude of IK, whereas clotrimazole (5 μM) significantly inhibited it. In the inside-out configuration of single channel recordings, application of THPI (5 μM) into the bath medium did not alter the single-channel conductance of intermediate-conductance Ca2+-activated K+ (IK Ca) channels (i.e KCa3.1 channels), but it suppressed the channel activity significantly. THPI-induced inhibition of IKCa channels was reversed by a further application of 1-ethyl-2-benzimidazolinone (10 μM). THPI-induced reduction in IKCa-channel activity in these cells was primarily due to a decrease in mean open time. These results provide direct evidence that THPI is capable of suppressing the activity of IK Ca channels in HL-60 cells. The antioxidant action of THPI also revealed a beneficial cytoprotective effect against mitomycin C-mediated haemolytic effect in human erythrocytes. The results of this study suggest that blockade of IKCa channels and the membrane-protecting activity of THPI would combine to have beneficial effects in lessening the severity of haemolytic crisis and reducing anaemia in sickle cell disease.

UR - http://www.scopus.com/inward/record.url?scp=34447329069&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34447329069&partnerID=8YFLogxK

U2 - 10.1211/jpp.59.5.0008

DO - 10.1211/jpp.59.5.0008

M3 - Article

C2 - 17524233

AN - SCOPUS:34447329069

VL - 59

SP - 679

EP - 685

JO - Journal of Pharmacy and Pharmacology

JF - Journal of Pharmacy and Pharmacology

SN - 0022-3573

IS - 5

ER -