Skimming Jeffrey W, Nasiroglu Omer, Huang Chun-Jen, Wood Charles E, Stevens Bruce R, Haque Ikram U L, Scumpia Philip O, Sarcia Paul J
Department of Child Health, University of Missouri, Columbia, MO 65212, USA.
Am J Physiol Lung Cell Mol Physiol. 2003 Aug;285(2):L484-91. doi: 10.1152/ajplung.00433.2002. Epub 2003 Apr 25.
The in vivo mechanisms by which glucocorticoids inhibit nitric oxide expression await detailed investigation. In cell culture experiments, glucocorticoids have been shown to inhibit inducible nitric oxide synthase (iNOS) formation and activity. Glucocorticoids can inhibit iNOS activity in cultured cells by blocking arginine transport and inhibiting tetrahydrobiopterin biosynthesis. We recently reported that changes in intrapulmonary formation of nitric oxide in endotoxemic rats correspond with changes in transcription of the predominant arginine transporter cationic amino acid transporter (CAT)-2. Realizing that hemorrhagic shock induces nitric oxide overproduction in intact animals, we sought to explore whether glucocorticoids attenuate hemorrhagic shock-induced increases in intrapulmonary nitric oxide formation and whether they might do so by inhibiting the formation of tetrahydrobiopterin, iNOS protein, and CAT-2. We randomly assigned 10 male Sprague-Dawley rats to receive dexamethasone or normal saline. Bleeding the animals to a mean systemic blood pressure of between 40 and 45 mmHg created the hemorrhagic shock. Dexamethasone abrogated the increase in exhaled nitric oxide concentrations caused by hemorrhagic shock. At the end of the experiment, plasma nitrate/nitrite values were lower in the dexamethasone group than in the control group. The iNOS protein concentrations were also lower in the dexamethasone group than in the control group. Dexamethasone decreased the intrapulmonary iNOS mRNA concentrations yet increased both guanosine triphosphate cyclohydrolase I mRNA and CAT-2 mRNA. Our results support the idea that dexamethasone inhibits nitric oxide formation in a manner that is independent of tetrahydrobiopterin and arginine transport yet dependent on downregulation of iNOS mRNA expression.
糖皮质激素抑制一氧化氮表达的体内机制有待详细研究。在细胞培养实验中，已表明糖皮质激素可抑制诱导型一氧化氮合酶（iNOS）的形成和活性。糖皮质激素可通过阻断精氨酸转运和抑制四氢生物蝶呤生物合成来抑制培养细胞中的iNOS活性。我们最近报道，内毒素血症大鼠肺内一氧化氮形成的变化与主要精氨酸转运体阳离子氨基酸转运体（CAT）-2转录的变化相对应。鉴于失血性休克会在完整动物中诱导一氧化氮过量产生，我们试图探究糖皮质激素是否能减轻失血性休克诱导的肺内一氧化氮形成增加，以及它们是否可能通过抑制四氢生物蝶呤、iNOS蛋白和CAT-2的形成来做到这一点。我们将10只雄性Sprague-Dawley大鼠随机分为两组，分别给予地塞米松或生理盐水。将动物放血至平均体循环血压在40至45 mmHg之间，造成失血性休克。地塞米松消除了失血性休克引起的呼出一氧化氮浓度增加。实验结束时，地塞米松组的血浆硝酸盐/亚硝酸盐值低于对照组。地塞米松组的iNOS蛋白浓度也低于对照组。地塞米松降低了肺内iNOS mRNA浓度，但增加了鸟苷三磷酸环化水解酶I mRNA和CAT-2 mRNA。我们的结果支持这样一种观点，即地塞米松以一种独立于四氢生物蝶呤和精氨酸转运但依赖于iNOS mRNA表达下调的方式抑制一氧化氮的形成。
