Raddatz Alexander, Kubulus Darius, Winning Johannes, Bauer Inge, Pradarutti Sascha, Wolf Beate, Kreuer Sascha, Rensing Hauke
Klinik für Anaesthesiologie und Intensivmedizin, Universität des Saarlandes, D-66421 Homburg/Saar, Germany.
Am J Respir Crit Care Med. 2006 Jul 15;174(2):198-207. doi: 10.1164/rccm.200508-1221OC. Epub 2006 Apr 20.
Induction of heme oxygenase-1 (HO-1) protects the liver against reperfusion injury after hemorrhagic shock. Previous data suggest that the beta(1)-adrenoceptor agonist dobutamine induces HO-1 in hepatocytes.
To investigate the functional significance of dobutamine pretreatment for liver function after hemorrhagic shock in vivo.
Anesthetized rats received either Ringer's (Vehicle/Shock), 10 microg/kg/min of the beta(1)-adrenoceptor agonist dobutamine (Dob/Shock), or 10 microg/kg/min dobutamine and 500 microg/kg/min of the beta(1)-adrenoceptor antagonist esmolol (Dob/Esmolol/Shock) for 6 h. Hemorrhagic shock was induced thereafter (mean arterial pressure, 35 mm Hg for 90 min). Animals were resuscitated with shed blood and Ringer's. In addition, the HO pathway was blocked after dobutamine pretreatment with 10 micromol/kg tin-mesoporphyrin-IX (Dob/SnMP/Shock) or animals received 100 mg/kg of the carbon monoxide donor dichloromethane (DCM/Shock).
Hepatocellular metabolism and liver blood flow were measured by plasma disappearance rate of indocyanine green (PDR(ICG)) as a sensitive marker of liver function.
Pretreatment with dobutamine induced HO-1 in pericentral hepatocytes and improved PDR(ICG) (Vehicle/Shock: 11.7 +/- 8.12%/min vs. Dob/Shock: 19.7 +/- 2.46%/min, p = 0.006). Blockade of the HO pathway after preconditioning and the combined pretreatment with dobutamine and esmolol decreased PDR(ICG) (Dob/SnMP/Shock: 12.6 +/- 4.24%/min, p = 0.011; Dob/Esmolol/Shock: 10.2 +/- 4.34%/min, p = 0.008). Pretreatment with a carbon monoxide donor improved PDR(ICG) (DCM/Shock: 18 +/- 3.19%/min, p = 0.022) compared with Vehicle/Shock.
These results suggest a beta(1)-adrenoceptor-dependent hepatic up-regulation of HO-1 and a better maintained hepatocellular function after hemorrhagic shock in animals pretreated with dobutamine. The improved hepatocellular function may be in part mediated by carbon monoxide because of up-regulation of HO-1. Pretreatment with dobutamine might be a potential means of pharmacologic preconditioning before ischemia-reperfusion of the liver.
诱导血红素加氧酶-1（HO-1）可保护肝脏免受失血性休克后的再灌注损伤。先前的数据表明，β1-肾上腺素能受体激动剂多巴酚丁胺可诱导肝细胞中的HO-1。
研究多巴酚丁胺预处理对失血性休克后体内肝功能的功能意义。
将麻醉的大鼠分为三组，分别接受林格氏液（载体/休克组）、10μg/kg/min的β1-肾上腺素能受体激动剂多巴酚丁胺（多巴酚丁胺/休克组）或10μg/kg/min多巴酚丁胺和500μg/kg/min的β1-肾上腺素能受体拮抗剂艾司洛尔（多巴酚丁胺/艾司洛尔/休克组），持续6小时。此后诱导失血性休克（平均动脉压35mmHg，持续90分钟）。动物用自体血和林格氏液进行复苏。此外，在用10μmol/kg锡-中卟啉-IX对多巴酚丁胺进行预处理后阻断HO途径（多巴酚丁胺/锡卟啉/休克组），或动物接受100mg/kg的一氧化碳供体二氯甲烷（二氯甲烷/休克组）。
通过吲哚菁绿的血浆消失率（PDR(ICG)）来测量肝细胞代谢和肝血流量，作为肝功能的敏感指标。
多巴酚丁胺预处理可诱导中央周围肝细胞中的HO-1，并改善PDR(ICG)（载体/休克组：11.7±8.12%/分钟 vs. 多巴酚丁胺/休克组：19.7±2.46%/分钟，p = 0.006）。预处理后阻断HO途径以及多巴酚丁胺和艾司洛尔联合预处理可降低PDR(ICG)（多巴酚丁胺/锡卟啉/休克组：12.6±4.24%/分钟，p = 0.011；多巴酚丁胺/艾司洛尔/休克组：10.2±4.34%/分钟，p = 0.008）。与载体/休克组相比，用一氧化碳供体预处理可改善PDR(ICG)（二氯甲烷/休克组：18±3.19%/分钟，p = 0.022）。
这些结果表明，在多巴酚丁胺预处理的动物中，HO-1的肝脏上调依赖于β1-肾上腺素能受体，且失血性休克后肝细胞功能得到更好的维持。肝细胞功能的改善可能部分由一氧化碳介导，这是由于HO-1的上调所致。多巴酚丁胺预处理可能是肝脏缺血再灌注前进行药理预处理的一种潜在手段。
