Rodrigues Stephen F, de Oliveira Maria A, dos Santos Rosangela A, Soares Antonio G, de Cássia Tostes Rita, Carvalho Maria Helena C, Fortes Zuleica B
Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
Eur J Pharmacol. 2008 Jul 28;589(1-3):206-14. doi: 10.1016/j.ejphar.2008.05.003. Epub 2008 May 15.
In addition to reducing blood pressure, hydralazine can reduce the production of inflammatory cytokines and reduce the expression of leukocyte adhesion molecules. Differences in leukocyte behavior and leukocyte adhesion molecule expression in spontaneously hypertensive rats (SHR) compared to normotensive rats have been reported. However, whether hydralazine can reduce leukocyte migration in vivo in hypertension and in normotension remains unknown. To address this question, male SHR and Wistar rats were treated for 15 days with hydralazine at a dose of ~3.5 mg/kg or ~14 mg/kg in their drinking water. The numbers of rollers and adherent and migrated cells were determined by direct vital microscopy, and blood pressure was assessed by tail plethysmography. In addition, following treatment with the higher dose, immunohistochemistry was used to measure the expression of intercellular adhesion molecule-1 (ICAM-1), P-selectin, and platelet-endothelial cell adhesion molecule-1 (PECAM-1) in endothelial cells, while flow cytometry was used to evaluate the expression of leukocyte CD18 and L-selectin. Hydralazine reduced leukocyte adherence and migration in SHR either at the higher, that reduced blood pressure levels, or lower dose, which did not reduce it. Reduced ICAM-1 expression might be involved in the reduced migration observed in SHR. In Wistar rats, only at the higher dose hydralazine reduced blood pressure levels and leukocyte migration. Reduced P-selectin expression might be involved. We therefore conclude that hydralazine reduces leukocyte migration by different mechanisms in SHR and Wistar rats, specifically by reducing ICAM-1 expression in the former and P-selectin expression in the latter.
除了降低血压外，肼屈嗪还可减少炎性细胞因子的产生，并降低白细胞黏附分子的表达。与正常血压大鼠相比，自发性高血压大鼠（SHR）的白细胞行为和白细胞黏附分子表达存在差异。然而，肼屈嗪是否能在高血压和正常血压状态下减少体内白细胞迁移仍不清楚。为解决这个问题，雄性SHR和Wistar大鼠通过饮用含剂量约为3.5mg/kg或约14mg/kg肼屈嗪的水进行15天治疗。通过直接活体显微镜确定滚动细胞、黏附细胞和迁移细胞的数量，并通过尾容积描记法评估血压。此外，在给予较高剂量治疗后，采用免疫组织化学法测量内皮细胞中细胞间黏附分子-1（ICAM-1）、P-选择素和血小板-内皮细胞黏附分子-1（PECAM-1）的表达，同时采用流式细胞术评估白细胞CD18和L-选择素的表达。在较高剂量（可降低血压水平）或较低剂量（不能降低血压水平）时，肼屈嗪均可减少SHR中的白细胞黏附和迁移。ICAM-1表达降低可能与SHR中观察到的迁移减少有关。在Wistar大鼠中，仅在较高剂量时肼屈嗪可降低血压水平和白细胞迁移。P-选择素表达降低可能与之有关。因此，我们得出结论，肼屈嗪通过不同机制减少SHR和Wistar大鼠中的白细胞迁移，具体而言，在前者中通过降低ICAM-1表达，在后者中通过降低P-选择素表达。
