Microcirculation Research Group, Department of Cardiovascular Sciences, University of Sheffield, Faculty of Medicine, Dentistry and Health, Beech Hill Road, Sheffield S10 2RX, UK.
Br J Anaesth. 2010 Feb;104(2):183-90. doi: 10.1093/bja/aep361.
Sepsis induces microvascular inflammation and production of the vasodilator nitric oxide (NO) via endothelial and inducible nitric oxide synthase (eNOS or NOS III and iNOS or NOS II). Statins are cholesterol-lowering drugs; however, they also attenuate inflammation. This study aimed to determine whether pravastatin protected against sepsis-induced hypotension, loss of vascular tone, and microvascular inflammation via NOS pathways.
Male Wistar rats (n=18) were anaesthetized and the mesentery prepared for fluorescent intravital microscopy. Animals received either lipopolysaccharide (LPS; n=6); LPS+pravastatin (18 and 3 h before LPS; n=6), or saline as a control, for 4 h.
Mean arterial pressure decreased in LPS-treated animals (P<0.05), but not in those also receiving pravastatin. Acetylcholine-induced relaxation of venules was abolished by LPS but improved by pravastatin. Pravastatin also reduced the increase in nitrite concentration and macromolecular leak from venules induced by LPS (P<0.05). The increased leucocyte adhesion seen in LPS-treated rats was also reduced in those also treated with pravastatin. Immunohistochemical analysis showed that pravastatin increased endothelial cell expression of NOS III during sepsis, but had no effect on LPS-induced up-regulation of NOS II.
Pravastatin improved NOS III-mediated vessel relaxation and exerted anti-inflammatory effects within the microcirculation after LPS administration in rats. Pravastatin therefore appears to have beneficial effects during sepsis, as a result of increased microvascular expression and function of NOS III.
脓毒症通过内皮细胞和诱导型一氧化氮合酶（eNOS 或 NOS III 和 iNOS 或 NOS II）诱导微血管炎症和血管舒张因子一氧化氮（NO）的产生。他汀类药物是降低胆固醇的药物；然而，它们也能减轻炎症。本研究旨在确定普伐他汀是否通过 NOS 途径预防脓毒症引起的低血压、血管张力丧失和微血管炎症。
雄性 Wistar 大鼠（n=18）麻醉并制备肠系膜用于荧光活体显微镜检查。动物接受脂多糖（LPS；n=6）；LPS+普伐他汀（LPS 前 18 和 3 小时；n=6），或生理盐水作为对照，共 4 小时。
LPS 处理的动物平均动脉压降低（P<0.05），但同时接受普伐他汀治疗的动物则不然。乙酰胆碱诱导的小静脉舒张在 LPS 作用下被消除，但在普伐他汀作用下得到改善。普伐他汀还降低了 LPS 诱导的小静脉中硝酸盐浓度和大分子渗漏的增加（P<0.05）。LPS 处理的大鼠中观察到的白细胞黏附也在同时接受普伐他汀治疗的大鼠中减少。免疫组织化学分析显示，普伐他汀在脓毒症期间增加了内皮细胞 NOS III 的表达，但对 LPS 诱导的 NOS II 上调没有影响。
普伐他汀改善了 NOS III 介导的血管舒张，并在 LPS 给药后大鼠的微循环中发挥抗炎作用。因此，普伐他汀似乎在脓毒症期间具有有益的作用，这是由于 NOS III 的微血管表达和功能增加所致。
