Submitted on August 8, 2005
Accepted on April 20, 2006
Dobutamine Improves Liver Function after Hemorrhagic Shock through Induction of Heme Oxygenase-1
Alexander Raddatz1, Darius Kubulus1, Johannes Winning1, Inge Bauer1, Sascha Pradarutti1, Beate Wolf1, Sascha Kreuer1, and Hauke Rensing1*
1 Department of Anesthesiology and Critical Care Medicine, University of the Saarland, Homburg, Germany
* To whom correspondence should be addressed. E-mail: aihren{at}uniklinik-saarland.de.
Rationale: Induction of heme oxygenase-1 (HO-1) protects the liver against reperfusion injury after hemorrhagic shock (H/R). Previous data suggest, that the 
1-adrenoceptor-agonist dobutamine induces HO-1 in hepatocytes.
Objectives: To investigate the functional significance of dobutamine pretreatment for liver function after hemorrhagic shock in vivo.
Methods: Anesthetized rats received either Ringer ("Vehicle/Shock"), 10µg/kg/min of the 1-adrenoceptor-agonist dobutamine ("Dob/Shock"), or 10µg/kg/min dobutamine and 500µg/kg/min of the 1-adrenoceptor-antagonist esmolol ("Dob/Esmolol/Shock") for 6 hours. Hemorrhagic shock was induced thereafter (MAP 35mmHg for 90min). Animals were resuscitated with shed blood and Ringer. In addition, the HO-pathway was blocked after dobutamine pretreatment with 10µmol/kg tin-mesoporphyrin-IX ("Dob/SnMP/Shock") or animals received 100mg/kg of the carbon monoxide donor dichloromethane ("DCM/Shock").
Measurements: Hepatocellular metabolism and liver blood flow were measured by plasma disappearance rate of indocyanine green (PDRICG) as a sensitive marker of liver function.
Main results: Pretreatment with dobutamine induced HO-1 in pericentral hepatocytes and improved PDRICG (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 PDRICG (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 PDRICG (DCM/Shock: 18.0±3.19%/min, p= 0.022) compared to Vehicle/Shock.
Conclusions: These results suggest a 1-adrenoceptor-dependent hepatic upregulation 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 due to upregulation of HO-1. Therefore, pretreatment with dobutamine might be a potential means of pharmacological preconditioning before ischemia/reperfusion of the liver.
Key words: hemorrhagic shock, heme oxygenase-1, dobutamine, preconditioning, liver
