Dobutamine improves liver function after hemorrhagic shock through induction of heme oxygenase-1.
BACKGROUND
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.


OBJECTIVE
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 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).


METHODS
Hepatocellular metabolism and liver blood flow were measured by plasma disappearance rate of indocyanine green (PDR(ICG)) as a sensitive marker of liver function.


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 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.
Raddatz
Alexander
A
Klinik für Anaesthesiologie und Intensivmedizin, Universität des Saarlandes, D-66421 Homburg/Saar, Germany.
Kubulus
Darius
D
Winning
Johannes
J
Bauer
Inge
I
Pradarutti
Sascha
S
Wolf
Beate
B
Kreuer
Sascha
S
Rensing
Hauke
H
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001784:Blood Gas Analysis; D004280:Dobutamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051547:Heme Oxygenase-1 / Q000097:blood*; D006439:Hemodynamics / Q000187:drug effects; D007583:Jejunum / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D008107:Liver Diseases / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D008297:Male; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D012771:Shock, Hemorrhagic / Q000097:blood / Q000503:physiopathology*; D015854:Up-Regulation / Q000502:physiology
D000318:Adrenergic beta-Agonists; D011412:Propanolamines; D004280:Dobutamine; D051547:Heme Oxygenase-1; C036604:esmolol