Oriji G K, Keiser H R
Hypertension-Endocrine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
Am J Hypertens. 1999 Nov;12(11 Pt 1):1091-7. doi: 10.1016/s0895-7061(99)00089-8.
Chronic treatment with cyclosporine A (CsA), an immunosuppressive agent, causes hypertension. The effect of CsA on vascular responses was determined in Sprague-Dawley rats and isolated rat aortic rings. Male rats weighing 250 to 300 g were given either CsA (25 mg/kg/day) in olive oil or vehicle by intraperitoneal injection for 7 days. Cyclosporine A administration produced a 42% increase (P<.001) in mean arterial pressure (MAP), which reached a plateau after 3 days. Conversely, the level of both nitrate/nitrite (NO2/NO3), metabolites of nitric oxide (NO), and 3', 5' cyclic guanosine monophosphate (cGMP), which mediates NO action, decreased by 50% (P<.001) and 35% (P<.001), respectively, in the urine. Thoracic aortic rings from rats treated with CsA, and precontracted with endothelin (10(-9) mol/L), showed a 35% increase (P<.001) in tension, whereas acetylcholine-induced (Ach; 10(-9) mol/L) endothelium-dependent relaxation was inhibited 65% (P<.001) compared with untreated rats. This response was similar to that of aortic rings, denuded of endothelium, from untreated rats in which Ach-induced relaxation was completely abolished (P<.001). Ach-induced formation of both NO2/NO3 and cGMP by both denuded and CsA-treated aortic rings was inhibited 95% (P<.001) and 65% P<.001), respectively, compared with intact aortic rings. The effects of CsA were reversed both in vivo and in vitro by pretreatment with L-arginine (L-Arg; 10 mg/kg/day intraperitoneally), the precursor of NO. There were no changes in MAP and tension in rats treated with L-Arg alone. In addition, in the aorta of rats that were treated intraperitoneally with CsA for 7 days, CsA significantly activated protein kinase C (PKC) translocation and decreased NO2/NO3 production. This suggest that PKC mediates, in part, CsA-induced hypertension. In summary, CsA activates PKC, which inhibits endothelial NO formation, with resulting increases in MAP and tension, and this inhibition can be overcome by L-Arg administration.
免疫抑制剂环孢素A（CsA）的长期治疗会导致高血压。在Sprague-Dawley大鼠和离体大鼠主动脉环中测定了CsA对血管反应的影响。给体重250至300克的雄性大鼠腹腔注射橄榄油中的CsA（25毫克/千克/天）或赋形剂，持续7天。给予环孢素A后平均动脉压（MAP）升高了42%（P<0.001），3天后达到平稳状态。相反，尿液中一氧化氮（NO）的代谢产物硝酸盐/亚硝酸盐（NO2/NO3）以及介导NO作用的3',5'环磷酸鸟苷（cGMP）水平分别降低了50%（P<0.001）和35%（P<0.001）。用CsA处理并用内皮素（10(-9)摩尔/升）预收缩的大鼠胸主动脉环，张力增加了35%（P<0.001），而与未处理的大鼠相比，乙酰胆碱（Ach；10(-9)摩尔/升）诱导的内皮依赖性舒张受到65%的抑制（P<0.001）。这种反应与未处理大鼠的去内皮主动脉环相似，在去内皮主动脉环中Ach诱导的舒张完全消失（P<0.001）。与完整主动脉环相比，去内皮和用CsA处理的主动脉环中Ach诱导的NO2/NO3和cGMP形成分别受到95%（P<0.001）和65%（P<0.001）的抑制。通过用L-精氨酸（L-Arg；10毫克/千克/天腹腔注射）预处理，CsA在体内和体外的作用均被逆转。单独用L-Arg处理的大鼠MAP和张力没有变化。此外，在腹腔注射CsA 7天的大鼠主动脉中，CsA显著激活蛋白激酶C（PKC）易位并降低NO2/NO3生成。这表明PKC部分介导了CsA诱导的高血压。总之，CsA激活PKC，抑制内皮NO形成，导致MAP和张力升高，而这种抑制可通过给予L-Arg来克服。
