Pannen B H, Köhler N, Hole B, Bauer M, Clemens M G, Geiger K K
Department of Anesthesiology and Critical Care Medicine, University of Freiburg, D-79106 Freiburg, Germany.
J Clin Invest. 1998 Sep 15;102(6):1220-8. doi: 10.1172/JCI3428.
Maintenance of hepatic microcirculatory flow after ischemia of the liver is essential to prevent hepatic dysfunction. Thus, we determined the differential role of carbon monoxide (CO) and nitric oxide (NO) in the intrinsic control of sinusoidal perfusion, mitochondrial redox state, and bile production in the isolated perfused rat liver after hemorrhagic shock. Administration of tin protoporphyrin-IX (50 microM), a specific inhibitor of the CO generating enzyme heme oxygenase, caused a decrease in sinusoidal flow that was more pronounced after shock compared with sham shock, as determined by in situ epifluorescence microscopy. This was associated with a shift in hepatocellular redox potential to a more reduced state (increased fluorescence intensity of reduced pyridine nucleotides in hepatocytes, decreased acetoacetate/beta-hydroxybutyrate ratio in the perfusate) and a profound reduction in bile flow. In sharp contrast, the preferential inhibitor of the inducible isoform of NO synthase S-methylisothiourea sulfate (100 microM) did not affect sinusoidal flow, hepatic redox state, or function. This indicates that 1.) endogenously generated CO preserves sinusoidal perfusion after hemorrhagic shock, 2.) protection of the hepatic microcirculation by CO may serve to limit shock-induced liver dysfunction, and 3.) in contrast to CO, inducible NO synthase-derived NO is of only minor importance for the intrinsic control of hepatic perfusion and function under these conditions.
肝脏缺血后维持肝微循环血流对于预防肝功能障碍至关重要。因此，我们确定了一氧化碳（CO）和一氧化氮（NO）在失血性休克后离体灌注大鼠肝脏中窦状隙灌注的内在调控、线粒体氧化还原状态及胆汁生成方面的不同作用。通过原位落射荧光显微镜观察发现，给予锡原卟啉-IX（50微摩尔），一种CO生成酶血红素加氧酶的特异性抑制剂，会导致窦状隙血流减少，与假休克相比，休克后这种减少更为明显。这伴随着肝细胞氧化还原电位向更还原状态的转变（肝细胞中还原型吡啶核苷酸荧光强度增加，灌注液中乙酰乙酸/β-羟丁酸比值降低）以及胆汁流量的显著减少。与之形成鲜明对比的是，诱导型一氧化氮合酶的优先抑制剂硫酸S-甲基异硫脲（100微摩尔）对窦状隙血流、肝脏氧化还原状态或功能没有影响。这表明：1. 内源性生成的CO在失血性休克后维持窦状隙灌注；2. CO对肝微循环的保护作用可能有助于限制休克诱导的肝功能障碍；3. 与CO相反，在这些条件下，诱导型一氧化氮合酶衍生的NO对肝脏灌注和功能的内在调控仅具有次要重要性。
