d'Emmanuele di Villa Bianca R, Lippolis L, Autore G, Popolo A, Marzocco S, Sorrentino L, Pinto A, Sorrentino R
Dipartimento di Farmacologia Sperimentale, Università degli Studi di Napoli Federico II, Via D. Montesano, 49 80131 Napoli, Italy.
Br J Pharmacol. 2003 Sep;140(1):91-6. doi: 10.1038/sj.bjp.0705406. Epub 2003 Aug 4.
(1) Septic shock represents an important risk factor for patients critically ill. This pathology has been largely demonstrated to be a result of a myriad of events. Glucocorticoids represent the main pharmacological therapy used in this pathology. (2) Previously we showed that ATP-sensitive potassium (KATP) channels are involved in delayed vascular hyporeactivity in rats (24 h after Escherichia coli lipopolysaccharide (LPS) injection). In LPS-treated rats, we observed a significant hyporeactivity to phenylephrine (PE) that was reverted by glybenclamide (GLB), and a significant increase in cromakalim (CRK)-induced hypotension. (3) We evaluated the effect of dexamethasone (DEX 8 mg kg-1 i.p.) whether on hyporeactivity to PE or on hyperreactivity to CRK administration, in vivo, in a model of LPS (8 x 106 U kg-1 i.p.)-induced endotoxemia in urethane-anaesthetised rats. (4) DEX treatment significantly reduced, in a time-dependent manner, the increased hypotensive effect induced by CRK in LPS-treated rats. This effect was significantly (P<0.05) reverted by the glucocorticoid receptor antagonist RU38486 (6.6 mg kg-1 i.p.). (5) GLB-induced hypertension (40 mg kg-1 i.p.), in LPS-treated rats, was significantly inhibited by DEX if administered at the same time of LPS. (6) Simultaneous administration of DEX and LPS to rats completely abolished the hyporeactivity to PE observed after 24 h from LPS injection. (7) In conclusion, our results suggest that the beneficial effect of DEX in endotoxemia could be ascribed, at least in part, to its ability to interfere with KATP channel activation induced by LPS. This interaction may explain the improvement of vascular reactivity to PE, mediated by DEX, in LPS-treated rats, highlighting a new pharmacological activity to the well-known anti-inflammatory properties of glucocorticoids.
(1) 脓毒性休克是重症患者的一个重要危险因素。这种病理状态已被充分证明是多种事件导致的结果。糖皮质激素是用于治疗这种病理状态的主要药物疗法。(2) 此前我们发现，ATP敏感性钾（KATP）通道参与大鼠（注射大肠杆菌脂多糖（LPS）24小时后）延迟性血管反应性降低。在LPS处理的大鼠中，我们观察到对去氧肾上腺素（PE）的显著反应性降低，而格列本脲（GLB）可使其恢复，并且克罗卡林（CRK）诱导的低血压显著增加。(3) 我们在LPS（8×10⁶ U kg⁻¹腹腔注射）诱导的内毒素血症模型中，对乌拉坦麻醉的大鼠进行体内实验，评估地塞米松（DEX 8 mg kg⁻¹腹腔注射）对PE反应性降低或对CRK给药反应性增强的影响。(4) DEX治疗以时间依赖性方式显著降低了LPS处理大鼠中CRK诱导的增强的降压作用。糖皮质激素受体拮抗剂RU38486（6.6 mg kg⁻¹腹腔注射）可显著（P<0.05）逆转这种作用。(5) 在LPS处理的大鼠中，如果在注射LPS的同时给予DEX，GLB诱导的高血压（40 mg kg⁻¹腹腔注射）会受到显著抑制。(6) 同时给大鼠注射DEX和LPS完全消除了注射LPS 24小时后观察到的对PE的反应性降低。(7) 总之，我们的结果表明，DEX在内毒素血症中的有益作用至少部分可归因于其干扰LPS诱导的KATP通道激活的能力。这种相互作用可能解释了DEX介导的LPS处理大鼠对PE血管反应性的改善，突出了糖皮质激素已知抗炎特性的一种新的药理活性。
