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(Circulation Research. 1995;76:16-20.)
© 1995 American Heart Association, Inc.

Articles

K⁺ Channel Blockers Inhibit Tissue Factor Expression by Human Monocytic Cells

David J. Crutchley, Lobella B. Conanan, Benito G. Que

From the Miami Heart Research Institute, Miami Beach, Fla.

Correspondence to David J. Crutchley, PhD, Miami Heart Research Institute, 4701 Meridian Ave, Miami Beach, FL 33140.

Abstract Human monocytes express the important procoagulant protein, tissue factor (TF), after stimulation by a variety of agents, including bacterial lipopolysaccharide (LPS). Monocyte TF expression may contribute to intravascular coagulation in a number of disease states. The present studies show that monocytic cell TF expression can be inhibited by several agents known to block cellular K⁺ channels. Exposure of human peripheral blood to 100 ng/mL LPS for 2 hours led to pronounced TF procoagulant activity associated with the mononuclear cell fraction. This was inhibited by 4-aminopyridine (2 mmol/L), tetraethylammonium chloride (10 mmol/L), and apamin (1 µmol/L). In contrast, charybdotoxin (100 nmol/L) was inactive. More detailed studies were carried out in cultured human monocytic tumor THP-1 cells. These cells exhibited low but detectable levels of TF mRNA, measured by reverse transcription and polymerase chain reaction; cell surface procoagulant activity, measured by a plasma clotting assay; and cell homogenate TF antigen, measured by immunoassay. Exposure of THP-1 cells to 1 µg/mL LPS led to threefold to fivefold increases in all three parameters. Basal and LPS-induced levels of all three parameters were reduced in a dose-dependent manner by 4-aminopyridine (I₅₀, 1 mmol/L) and tetraethylammonium chloride (I₅₀, 20 mmol/L) but not by apamin or charybdotoxin. Expression of TF activity was also inhibited by glibenclamide, an inhibitor of ATP-dependent K⁺ channels (I₅₀, 25 µmol/L). These results suggest that facilitation of TF synthesis may be an important role for K⁺ channels in monocytes.

Key Words: thromboplastin • blood coagulation • ion channels

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