Khalfi F, Gressier B, Dine T, Brunet C, Luyckx M, Ballester L, Cazin M, Cazin J C
Laboratoire de Pharmacologie, Pharmacocinétique et Pharmacie Clinique, Faculté des Sciences Pharmaceutiques et Biologiques, Lille, France.
Biol Pharm Bull. 1998 Feb;21(2):109-12. doi: 10.1248/bpb.21.109.
In response to activation of phagocytic cells and during inflammatory disorders, some proteases and very reactive oxygen species are produced. These proteases and oxidants are involved in many diseases like tissue injury or atherosclerosis. We have shown in vitro that verapamil, a calcium channel blocker, had antielastase and antioxidant properties. This drug inhibited the release of elastase by neutrophils in a dose-dependent manner when these cells were stimulated by phorbol-myristate-acetate (PMA), by N-formyl-methionyl-leucylphenylalanine (fMLP) and by the calcium ionophore A23187 (Ca.I). In addition, verapamil inhibited superoxide anion when human neutrophils were stimulated by PMA, fMLP, dioctanoylglycerol (DiC8), Ca.I or by opsonised zymosan (OZ). Verapamil did not act by scavenging elastase or oxidants as demonstrated in cell-free models which showed no direct antielastase or antioxidant effect involved by verapamil. Superoxide anion and elastase inhibition by verapamil has been considered to the mobilization of cytosolic calcium and inhibition of protein kinase C. The results suggest that verapamil might contribute help the development and progression of atheroma where oxidants and elastase are involved.
在吞噬细胞激活以及炎症性疾病过程中，会产生一些蛋白酶和极具活性的氧物质。这些蛋白酶和氧化剂参与许多疾病，如组织损伤或动脉粥样硬化。我们在体外已表明，钙通道阻滞剂维拉帕米具有抗弹性蛋白酶和抗氧化特性。当这些细胞受到佛波酯-肉豆蔻酸酯-乙酸酯（PMA）、N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸（fMLP）和钙离子载体A23187（Ca.I）刺激时，该药物以剂量依赖性方式抑制中性粒细胞释放弹性蛋白酶。此外，当人中性粒细胞受到PMA、fMLP、二辛酰甘油（DiC8）、Ca.I或调理酵母聚糖（OZ）刺激时，维拉帕米抑制超氧阴离子。如在无细胞模型中所证明的，维拉帕米并非通过清除弹性蛋白酶或氧化剂起作用，该模型显示维拉帕米不存在直接的抗弹性蛋白酶或抗氧化作用。维拉帕米对超氧阴离子和弹性蛋白酶的抑制作用被认为与胞质钙的动员和蛋白激酶C的抑制有关。结果表明，维拉帕米可能有助于涉及氧化剂和弹性蛋白酶的动脉粥样硬化的发生和发展。
