Khalfi F, Gressier B, Brunet C, Dine T, Luyckx M, Cazin M, Cazin J C
Laboratoire de Pharmacologie, Faculté des Sciences Pharmaceutiques et Biologiques, Lille, France.
Pharmacol Res. 1996 Feb;33(2):117-22. doi: 10.1006/phrs.1996.0017.
During inflammatory disorders, some proteases and very reactive oxygen metabolites are produced by activated phagocytic cells. These proteases and oxidants are involved in many diseases like tissue injury or atherosclerosis. It was shown in vitro that diltiazem, 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) or by formyl-methionyl-leucylphenylalanine (fMLP) with an IC50 of 144.5 microM, and 132.8 microM, respectively. Towards the oxidants, the 50% inhibitory concentrations (IC50) of diltiazem are 422 microM, 138 microM and 165 microM for superoxide anion, hypochlorous acid and hydroxyl radical production by PMA stimulated human neutrophils, respectively. In the case of fMLP stimulated human neutrophils, the IC50 for superoxide anion is 78 microM. When human neutrophils were stimulated by dioctanoylglycerol (DiC8) or by calcium ionophore (Ca.I), the IC50 for superoxide anion were 175.5 microM and 186 microM, respectively. When human neutrophils were stimulated by opsonized zymosan (OZ), diltiazem did not show an inhibition of superoxide production in a dose dependent manner. This drug did not act by scavenging elastase or oxidants as demonstrated by cell free models. A mechanism of elastase and oxygen metabolites inhibition by diltiazem has been considered specially toward the mobilization of cytosolic calcium and an inhibition of protein kinase C cannot be excluded. The results suggest that diltiazem might contribute to attenuate the development and the progression of atheroma where oxidants and elastase have been implicated.
在炎症性疾病期间，活化的吞噬细胞会产生一些蛋白酶和高活性氧代谢产物。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。体外实验表明，钙通道阻滞剂地尔硫䓬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）或甲酰甲硫氨酰 - 亮氨酰 - 苯丙氨酸（fMLP）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，IC50分别为144.5微摩尔和132.8微摩尔。对于氧化剂，地尔硫䓬对PMA刺激的人中性粒细胞产生超氧阴离子、次氯酸和羟基自由基的50%抑制浓度（IC50）分别为422微摩尔、138微摩尔和165微摩尔。在fMLP刺激的人中性粒细胞的情况下，超氧阴离子的IC50为78微摩尔。当人中性粒细胞受到二辛酰甘油（DiC8）或钙离子载体（Ca.I）刺激时，超氧阴离子的IC50分别为175.5微摩尔和186微摩尔。当人中性粒细胞受到调理酵母聚糖（OZ）刺激时，地尔硫䓬未呈现剂量依赖性抑制超氧产生。如无细胞模型所示，该药物并非通过清除弹性蛋白酶或氧化剂起作用。地尔硫䓬抑制弹性蛋白酶和氧代谢产物的机制已特别考虑到胞质钙的动员，并且不能排除对蛋白激酶C的抑制作用。结果表明，地尔硫䓬可能有助于减轻已涉及氧化剂和弹性蛋白酶的动脉粥样硬化的发展和进展。
