Perianin A, Giroud J P, Hakim J
Département de Pharmacologie, CNRS URA 595, Hôpital Cochin-Port Royal, Paris, France.
Biochem Pharmacol. 1990 Nov 1;40(9):2039-45. doi: 10.1016/0006-2952(90)90234-c.
Diclofenac sodium, a non-steroidal anti-inflammatory drug, has been shown to impair the stimulation of human polymorphonuclear leukocytes (PMNs) by chemoattractants. To gain insight into the mechanism of action of this agent, we investigated the uptake of diclofenac by resting and activated PMNs and the effect of the drug on PMN locomotion. During incubation of resting PMNs at 37 degrees in the presence of 78 microM (25 micrograms/mL) diclofenac, drug uptake reached a plateau in less than 2 min. The resulting cellular to extracellular diclofenac concentration ratio (C/E) was 1.01 +/- 0.13 (mean +/- SD). Stimulation of PMNs at 37 degrees but not at 4 degrees with the chemoattractant formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol myristate acetate (PMA), induced a rise in diclofenac uptake, which was dependent on incubation time and diclofenac and stimulus concentrations. Maximal C/E was 1.83 +/- 0.18 and 4.40 +/- 0.60 (mean +/- SD) for PMNs stimulated with 10 microM fMLP and 0.16 microM PMA, respectively. The diclofenac associated with PMNs was predominantly present in the soluble fraction of disrupted cells. Interestingly, PMNs which were pretreated with diclofenac and stimulated with fMLP, exhibited impaired random and directional locomotion induced by activated serum, as compared to controls, i.e. PMNs treated with diclofenac alone or fMLP alone. Thus, stimulation of PMNs enhances diclofenac uptake and potentiates the drug impairment of chemotactic activity. These findings could explain, in part, the observed anti-inflammatory properties of this compound.
双氯芬酸钠是一种非甾体抗炎药，已被证明会损害趋化因子对人多形核白细胞（PMN）的刺激作用。为深入了解该药物的作用机制，我们研究了静息和活化的PMN对双氯芬酸钠的摄取情况以及该药物对PMN运动的影响。在37℃下，将静息的PMN与78微摩尔/升（25微克/毫升）双氯芬酸钠一起孵育时，药物摄取在不到2分钟内达到平台期。由此产生的细胞内与细胞外双氯芬酸钠浓度比（C/E）为1.01±0.13（平均值±标准差）。用趋化因子甲酰甲硫氨酰亮氨酰苯丙氨酸（fMLP）或佛波酯肉豆蔻酸酯乙酸酯（PMA）在37℃而非4℃刺激PMN，会导致双氯芬酸钠摄取增加，这取决于孵育时间、双氯芬酸钠和刺激物浓度。用10微摩尔/升fMLP和0.16微摩尔/升PMA刺激的PMN的最大C/E分别为1.83±0.18和4.40±0.60（平均值±标准差）。与PMN相关的双氯芬酸钠主要存在于破碎细胞的可溶部分。有趣的是，与对照组相比，即单独用双氯芬酸钠或单独用fMLP处理的PMN，预先用双氯芬酸钠处理并经fMLP刺激的PMN，由活化血清诱导的随机和定向运动受损。因此，对PMN的刺激会增强双氯芬酸钠的摄取，并增强该药物对趋化活性的损害作用。这些发现可以部分解释该化合物所观察到的抗炎特性。
