Inhibition of intermediate-conductance Ca2+-activated K+ channel and cytoprotective properties of 4-piperidinomethyl-2-isopropyl-5-methylphenol.
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 (I(K)) in a concentration-dependent manner in HL-60 leukocytes, with an IC50 value of 4 microM. Neither iberiotoxin (200 nM) nor paxilline (1 microM) suppressed the amplitude of I(K), whereas clotrimazole (5 microM) significantly inhibited it. In the inside-out configuration of single channel recordings, application of THPI (5 microM) into the bath medium did not alter the single-channel conductance of intermediate-conductance Ca2+-activated K+ (IK(Ca)) channels (i.e K(Ca)3.1 channels), but it suppressed the channel activity significantly. THPI-induced inhibition of IK(Ca) channels was reversed by a further application of 1-ethyl-2-benzimidazolinone (10 microM). THPI-induced reduction in IK(Ca)-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 IK(Ca) 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.
Shen
Ai-Yu
AY
Basic Medical Science Education Center, Fooyin University, Ta-Liao Hsiang, Kaohsiung Hsien, Taiwan.
Tsai
Jen-Hsiang
JH
Teng
Hsiu-Chen
HC
Huang
Mei-Han
MH
Wu
Sheng-Nan
SN
D000975:Antioxidants / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D004594:Electrophysiology; D004912:Erythrocytes / Q000187:drug effects; D006098:Granulocytes / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D016685:Mitomycin; D010636:Phenols / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*
C506851:4-piperidinomethyl-2-isopropyl-5-methylphenol; D000975:Antioxidants; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D010636:Phenols; D010880:Piperidines; D016685:Mitomycin