Role of endothelins and nitric oxide in hepatic reperfusion injury in the rat.
We determined the functional role of nitric oxide (NO) and endothelins (ET), two potent vasoactive mediator systems in the liver, for the pathogenesis of sinusoidal perfusion failure and lethal hepatocyte injury after low-flow ischemia/reperfusion in the isolated perfused rat liver. NO synthase blockade with Nomega-nitro-L-arginine methyl ester (L-NAME) (10[-3] mol/L) before reperfusion prevented increased N02-/NO3- the final products of NO oxidation, which could be observed in the vehicle group. Epifluorescence microscopy revealed that the decrease in functional sinusoid density during reperfusion was much more profound compared with vehicle. This was associated with a lower surface PO2, a substantially higher number of nonviable hepatocytes, as assessed by in situ propidium iodide staining, and enhanced enzyme release into the perfusate compared with vehicle. In contrast, reperfusion in the presence of the endothelinA+B receptor antagonist bosentan (2 x 10(-4) mol/L) restored functional sinusoid density and surface PO2 to baseline values, resulted in a small reduction in the number of propidium iodide-positive hepatocytes, and caused similar increases in enzyme release as compared with vehicle. This indicates that hepatic generation of NO attenuates sinusoidal perfusion failure and improves liver tissue oxygenation, thus limiting hepatocyte injury during early reperfusion after hepatic low-flow ischemia. In contrast, endothelins counteract the microcirculatory effects of NO, i.e., mediate the no-reflow in hepatic sinusoids; however, the restoration of functional sinusoid density with bosentan resulted only in a small reduction in tissue damage, suggesting that additional components, which are independent of microcirculatory failure, contribute to hepatic reperfusion injury under these conditions.
Pannen
B H
BH
Department of Anesthesiology and Critical Care Medicine, University of Freiburg, Germany.
Al-Adili
F
F
Bauer
M
M
Clemens
M G
MG
Geiger
K K
KK
D000818:Animals; D000077300:Bosentan; D016232:Endothelins / Q000502:physiology*; D007657:Ketone Bodies / Q000378:metabolism; D008099:Liver / Q000098:blood supply*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000209:etiology*; D013449:Sulfonamides / Q000494:pharmacology
D016232:Endothelins; D007657:Ketone Bodies; D013449:Sulfonamides; D009569:Nitric Oxide; D000077300:Bosentan; D019331:NG-Nitroarginine Methyl Ester