Protective role of endogenous carbon monoxide in hepatic microcirculatory dysfunction after hemorrhagic shock in rats.
Maintenance of hepatic microcirculatory flow after ischemia of the liver is essential to prevent hepatic dysfunction. Thus, we determined the differential role of carbon monoxide (CO) and nitric oxide (NO) in the intrinsic control of sinusoidal perfusion, mitochondrial redox state, and bile production in the isolated perfused rat liver after hemorrhagic shock. Administration of tin protoporphyrin-IX (50 microM), a specific inhibitor of the CO generating enzyme heme oxygenase, caused a decrease in sinusoidal flow that was more pronounced after shock compared with sham shock, as determined by in situ epifluorescence microscopy. This was associated with a shift in hepatocellular redox potential to a more reduced state (increased fluorescence intensity of reduced pyridine nucleotides in hepatocytes, decreased acetoacetate/beta-hydroxybutyrate ratio in the perfusate) and a profound reduction in bile flow. In sharp contrast, the preferential inhibitor of the inducible isoform of NO synthase S-methylisothiourea sulfate (100 microM) did not affect sinusoidal flow, hepatic redox state, or function. This indicates that 1.) endogenously generated CO preserves sinusoidal perfusion after hemorrhagic shock, 2.) protection of the hepatic microcirculation by CO may serve to limit shock-induced liver dysfunction, and 3.) in contrast to CO, inducible NO synthase-derived NO is of only minor importance for the intrinsic control of hepatic perfusion and function under these conditions.
Pannen
B H
BH
Department of Anesthesiology and Critical Care Medicine, University of Freiburg, D-79106 Freiburg, Germany. pannen@nz11.uni-freiburg.de
Köhler
N
N
Hole
B
B
Bauer
M
M
Clemens
M G
MG
Geiger
K K
KK
D000818:Animals; D001646:Bile / Q000378:metabolism; D002248:Carbon Monoxide / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007511:Ischemia / Q000209:etiology / Q000517:prevention & control*; D007550:Isothiuronium / Q000031:analogs & derivatives / Q000494:pharmacology; D008099:Liver / Q000098:blood supply* / Q000187:drug effects; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D008833:Microcirculation / Q000187:drug effects*; D008928:Mitochondria / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D010084:Oxidation-Reduction; D010477:Perfusion; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000150:complications*
D008665:Metalloporphyrins; D011524:Protoporphyrins; D007550:Isothiuronium; D009569:Nitric Oxide; D002248:Carbon Monoxide; C032628:tin protoporphyrin IX; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006419:Heme Oxygenase (Decyclizing); C027744:S-methylisothiopseudouronium