Impaired mechanisms of leukocyte adhesion in vitro by the calcium channel antagonist mibefradil

被引：17

作者：

Nebe B. ^{[1
]}

Holzhausen C. ^{[1
]}

Rychly J. ^{[1
,2
]}

Urbaszek W. ^{[1
]}

机构：

[1] Department of Internal Medicine, University of Rostock, 18055 Rostock

[2] Universität Rostock, Klinik für Innere Medizin, 18055 Rostock

来源：

Cardiovascular Drugs and Therapy | 2002年 / 16卷 / 3期

关键词：

Adhesion; Calcium antagonist; Cytoskeleton; Integrin; Leukocytes;

D O I：

10.1023/A:1020688019792

中图分类号：

学科分类号：

摘要：

Purpose. Enhanced adhesion to the vascular endothelium and excessive trafficking to extravascular locations can lead to serious tissue injury and destruction. Therefore, interfering with molecular mechanisms of leukocyte adhesion to the vascular endothelium is an important goal to block diseases like chronic inflammations and atherosclerosis. Methods. We studied the influence of the calcium antagonists mibefradil (T-type channel blocker), amlodipine and verapamil (both L-type channel blockers) on mechanisms related to leukocyte adhesion using isolated peripheral human blood leukocytes. Results. Mibefradil but not amlodipine and verapamil attenuated leukocyte adhesion in vitro. Regarding the mechanisms we found that mibefradil reduced the surface expression of β2 integrins and L-selectin. The immobilization of the β2 integrin subunit to the cytoskeleton that was inducible by receptor cross linking was impaired. Mibefradil was able to significantly inhibit the formyl-methionyl-leucyl-phenylalanine (fMLP) induced calcium rise, which suggests that mibefradil interfered with integrin signaling through blocking the intracellular calcium rise. SK&F 96365, a blocker of the capacitative calcium entry had no effect on cell adhesion and was less effective to influence integrin mediated mechanisms than mibefradil. Conclusion. Our data suggest that mibefradil or chemically related substances are promising to serve as potent drugs to prevent excessive adhesion of leukocytes.

引用

页码：183 / 193

页数：10

共 57 条

[1]

Girard J.P., Springer T.A., High endothelial venules (HEVs): Specialized endothelium for lymphocyte migration, Immunol Today, 16, pp. 449-457, (1995)

[2]

Harlan J.M., Leukocyte-endothelial interactions, Blood, 65, pp. 513-525, (1985)

[3]

Imhof B.A., Dunon D., Leukocyte migration and adhesion, Adv Immunol, 58, pp. 345-416, (1995)

[4]

Albelda S.M., Smith C.W., Ward P.A., Adhesion molecules and inflammatory injury, Faseb J, 8, pp. 504-512, (1994)

[5]

Lefer A.M., Weyrich A.S., Buerke M., Role of selectins, a new family of adhesion molecules, in ischaemia-reperfusion injury, Cardiovasc Res, 28, pp. 289-294, (1994)

[6]

Schachter M., Calcium antagonists and atherosclerosis, Int J Cardiol, 62, SUPPL. 2, (1997)

[7]

Dunon D., Piali L., Imhof B.A., To stick or not to stick: The new leukocyte homing paradigm, Curr Opin Cell Biol, 8, pp. 714-723, (1996)

[8]

Carlos T.M., Harlan J.M., Leukocyte-endothelial adhesion molecules, Blood, 84, pp. 2068-2101, (1994)

[9]

Miller J., Knorr R., Ferrone M., Houdei R., Carron C.P., Dustin M.L., Intercellular adhesion molecule-1 dimerization and its consequences for adhesion mediated by lymphocyte function associated-1, J Exp Med, 182, pp. 1231-1241, (1995)

[10]

Meerschaert J., Furie M.B., The adhesion molecules used by monocytes for migration across endothelium include CD11a/CD18, CD11b/CD18, and VLA-4 on monocytes and ICAM-1, VCAM-1, and other ligands on endothelium, J Immunol, 154, pp. 4099-4112, (1995)

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