Nebe Barbara, Holzhausen Christian, Rychly Joachim, Urbaszek Wilhelm
Department of Internal Medicine, University of Rostock, Ernst-Heydemann-Strasse 6, 18055 Rostock, Germany.
Cardiovasc Drugs Ther. 2002 May;16(3):183-93. doi: 10.1023/a:1020688019792.
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.
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.
Mibefradil but not amlodipine and verapamil attenuated leukocyte adhesion in vitro. Regarding the mechanisms we found that mibefradil reduced the surface expression of beta2 integrins and L-selectin. The immobilization of the beta2 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.
Our data suggest that mibefradil or chemically related substances are promising to serve as potent drugs to prevent excessive adhesion of leukocytes.
增强对血管内皮的黏附以及过度迁移至血管外部位可导致严重的组织损伤和破坏。因此，干扰白细胞黏附于血管内皮的分子机制是阻断诸如慢性炎症和动脉粥样硬化等疾病的重要目标。
我们使用分离的人外周血白细胞，研究了钙拮抗剂米贝拉地尔（T型通道阻滞剂）、氨氯地平和维拉帕米（均为L型通道阻滞剂）对与白细胞黏附相关机制的影响。
米贝拉地尔而非氨氯地平和维拉帕米在体外减弱了白细胞黏附。关于其机制，我们发现米贝拉地尔降低了β2整合素和L-选择素的表面表达。受体交联诱导的β2整合素亚基与细胞骨架的固定化受到损害。米贝拉地尔能够显著抑制甲酰甲硫氨酰亮氨酰苯丙氨酸（fMLP）诱导的钙升高，这表明米贝拉地尔通过阻断细胞内钙升高来干扰整合素信号传导。SK&F 96365，一种容量性钙内流阻滞剂，对细胞黏附没有影响，并且在影响整合素介导的机制方面比米贝拉地尔效果更差。
我们的数据表明，米贝拉地尔或化学相关物质有望作为预防白细胞过度黏附的有效药物。
