Abou-Mohamed G, Papapetropoulos A, Catravas J D, Caldwell R W
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta 30912, USA.
Eur J Pharmacol. 1998 Jan 12;341(2-3):265-72. doi: 10.1016/s0014-2999(97)01416-7.
There is compelling evidence to indicate an anti-inflammatory action of Zn2+. Most inflammatory diseases are associated with an increase of the inducible form of nitric oxide (NO) synthase. Additionally, inflammatory mediators such as histamine or bradykinin stimulate the constitutive NO synthase. Thus, the present study was undertaken to investigate whether Zn2+ inhibits production of inducible NO synthase and/or constitutive NO synthase activity to produce NO. Lipopolysaccharide, 5 mg/kg i.v., administered to Zn2+-deficient (ZD) rats, rats supplemented with Zn2+ sulfate (ZG), 10 mg/kg s.c., or controls resulted in a significant reduction of their serum Zn2+. The levels of N(G)-nitro-L-arginine methylester (L-NAME)-sensitive cyclic GMP (cGMP) in aortas isolated from ZD or ZG were significantly lower than those obtained from control animals. Zinc (100-150 microM) produced a dose-dependent inhibition of lipopolysaccharide or interleukin-1beta-induced NO formation in isolated rat aortic smooth muscle cells. Compared to cyclohexamide or actinomycin-D, the time course of inhibition of NO formation by 150 microM Zn2+ did not suggest an effect of Zn2+ on inducible NO synthase protein synthesis. Moreover, Zn2+ (150 microM) significantly reduced the rate of conversion of [3H]arginine to [3H]citrulline in lung homogenates from lipopolysaccharide-treated rats. Incubation of rat aortic smooth muscle cells and bovine pulmonary artery endothelial cell co-cultures with Zn2+ (150 microM) caused a significant reduction in basal and bradykinin- or A-23187-induced formation of cGMP. Thus, our results indicate that Zn2+ is capable of inhibiting lipopolysaccharide- or interleukin-1beta-induced NO formation as well as NO formation by constitutive NO synthase basally or in response to bradykinin or A-23187, and may explain the reported anti-inflammatory activity of Zn2+.
有确凿证据表明锌离子（Zn2+）具有抗炎作用。大多数炎症性疾病都与诱导型一氧化氮（NO）合酶的增加有关。此外，组胺或缓激肽等炎症介质会刺激组成型NO合酶。因此，本研究旨在探讨Zn2+是否会抑制诱导型NO合酶的产生和/或组成型NO合酶产生NO的活性。给缺锌（ZD）大鼠静脉注射5mg/kg脂多糖，给补充硫酸锌（ZG）的大鼠皮下注射10mg/kg，或给对照组大鼠注射脂多糖后，它们的血清锌离子显著降低。从ZD或ZG大鼠分离的主动脉中，N（G）-硝基-L-精氨酸甲酯（L-NAME）敏感的环磷酸鸟苷（cGMP）水平显著低于对照组动物。锌（100-150μM）对脂多糖或白细胞介素-1β诱导的分离大鼠主动脉平滑肌细胞中NO的形成产生剂量依赖性抑制作用。与环己酰亚胺或放线菌素-D相比，150μM Zn2+对NO形成的抑制时间进程并不表明Zn2+对诱导型NO合酶蛋白合成有影响。此外，Zn2+（150μM）显著降低了脂多糖处理大鼠肺匀浆中[3H]精氨酸向[3H]瓜氨酸的转化速率。用Zn2+（150μM）孵育大鼠主动脉平滑肌细胞和牛肺动脉内皮细胞共培养物，可显著降低基础状态下以及缓激肽或A-23187诱导的cGMP形成。因此，我们的结果表明，Zn2+能够抑制脂多糖或白细胞介素-1β诱导的NO形成，以及基础状态下或对缓激肽或A-23187应答时组成型NO合酶产生的NO形成，这可能解释了报道的Zn2+的抗炎活性。
