Zimmerman J J, Zuk S M, Millard J R
Division of Critical Care Medicine, University of Wisconsin Children's Hospital, Madison 53792.
Biochem Pharmacol. 1989 Oct 15;38(20):3601-10. doi: 10.1016/0006-2952(89)90133-0.
Generation of toxic oxygen species by activated polymorphonuclear leukocytes (PMNs) may represent an important mechanism of ischemia-reperfusion injury. Concentration-response data concerning inhibition of superoxide anion (O2-) generation by NADPH oxidoreductase (NADPH OR) from isolated human PMN were generated for five calcium channel antagonists commonly utilized in ischemia-reperfusion investigational therapeutics. Regression analysis derived IC50 values for verapamil, nimodipine, nicardipine and lidoflazine were 45, 20, 12 and 7 microM respectively. Inhibition of the extent of reaction at 5 min paralleled inhibition of initial velocity. No inhibition by flunarizine was noted at concentrations less than or equal to 25 microM (where it did not alter reaction mixture composition). Only nicardipine demonstrated a significant concentration-response effect relative to prolonging lag time preceding O2- synthesis. Inhibition appeared at least partially reversible for all five agents. Neither PMN activation/desensitization, free-radical scavenging, nor PMN cytotoxicity appeared to be involved in the inhibition of PMN O2- synthesis by these agents. Ca2+ antagonist inhibition of PMN NADPH OR appears to involve more than simple inhibition of Ca2+ flux across the PMN plasma membrane. Direct inhibition of the intracellular events involved in the activation and/or activity of NADPH OR may be operative.
活化的多形核白细胞（PMN）产生活性氧可能是缺血再灌注损伤的一个重要机制。针对缺血再灌注研究治疗中常用的五种钙通道拮抗剂，生成了有关分离的人PMN中NADPH氧化还原酶（NADPH OR）对超氧阴离子（O2-）生成抑制作用的浓度-反应数据。维拉帕米、尼莫地平、尼卡地平利多氟嗪的回归分析得出的IC50值分别为45、20、12和7微摩尔。5分钟时反应程度的抑制与初始速度的抑制平行。在浓度小于或等于25微摩尔时（此时它不改变反应混合物组成），未观察到氟桂利嗪有抑制作用。只有尼卡地平在延长O2-合成前的延迟时间方面表现出显著的浓度-反应效应。所有五种药物的抑制作用似乎至少部分是可逆的。这些药物对PMN O2-合成的抑制似乎不涉及PMN活化/脱敏、自由基清除或PMN细胞毒性。Ca2+拮抗剂对PMN NADPH OR的抑制似乎不仅仅是简单地抑制Ca2+穿过PMN质膜的通量。对NADPH OR活化和/或活性所涉及的细胞内事件的直接抑制可能起作用。
