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Dobutamine Improves Liver Function after Hemorrhagic Shock through Induction of Heme Oxygenase-1

Department of Anesthesiology and Critical Care Medicine, University of the Saarland, Homburg, Germany

Correspondence and requests for reprints should be addressed to Hauke Rensing, M.D., Klinik für Anaesthesiologie und Intensivmedizin, Universität des Saarlandes, D-66421 Homburg/Saar, Germany. E-mail: aihren{at}uniklinik-saarland.de

Rationale: Induction of heme oxygenase-1 (HO-1) protects the liver against reperfusion injury after hemorrhagic shock. 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's (Vehicle/Shock), 10 µg/kg/min of the ₁-adrenoceptor agonist dobutamine (Dob/Shock), or 10 µg/kg/min dobutamine and 500 µg/kg/min of the 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 µmol/kg tin-mesoporphyrin-IX (Dob/SnMP/Shock) or animals received 100 mg/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 (PDR_ICG) as a sensitive marker of liver function.

Main Results: 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.

Conclusions: These results suggest a 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.

Key Words: dobutamine • heme oxygenase-1 • hemorrhagic shock • liver • preconditioning

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