Involvement of endothelin/nitric oxide balance in hepatic ischemia/reperfusion injury.
BACKGROUND
Endothelin (ET) and nitric oxide (NO) act as opponents in the regulation of the hepatic microcirculation. During ischemia/reperfusion (I/R) ET levels are increased, whereas no rise in NO levels is observed. This imbalance may be responsible for microcirculatory disturbances. The aim of this study was to restore the delicate ET/NO balance to maintain the integrity of the hepatic microcirculation and to reduce I/R injury.


METHODS
Ischemia was induced by crossclamping of the hepatoduodenal ligament for 30 min with portal decompression using a splenocaval shunt (56 Wistar rats, 200-250 g). Sham operation, ischemia and treatment groups with the endothelin receptor antagonist (ERA) bosentan (1 mg/kg body weight i.v.) and the NO donor L-arginine (400 mg/kg body weight i.v.) were performed. For assessment of the microcirculation, sinusoidal perfusion rate, diameters of sinusoids and postsinusoidal venules, leukocyte endothelium interactions and velocity of free-flowing leukocytes were investigated by means of in vivo microscopy 30-90 min after reperfusion. Local hepatic tissue PO2 was measured prior to ischemia, 30 min and 60 min after reperfusion and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels were investigated 2 h and 6 h after reperfusion.


RESULTS
After ischemia, sinusoidal and venular diameters were reduced to 76% and 85%, respectively, of sham operation group values (P<0.05), but were maintained at baseline in ERA (98/102%) and NO (102/105%) groups (P<0.05). Increased postischemic leukocyte sticking in sinusoids (144%) and venules (435%) was reduced by therapy to 110/253% (ERA) and 111/ 324% (NO), respectively (P<0.05). Perfusion rate was increased to 93% and 94% compared with 82% in the ischemia group (P<0.05). Concomitant with the improved microcirculation in therapy groups, local hepatic tissue pO2 was improved 30 min after reperfusion in the ERA (11.0 mmHg) and the L-arginine group (11.5 mmHg) relative to the ischemic group (6.9 mmHg) (P<0.05). In addition, postischemic AST/ALT increase was reduced by therapy.


CONCLUSIONS
Our results indicate that maintenance of ET/NO balance by blocking ET receptors, as well as providing a NO donor, protects the liver microcirculation and reduces hepatic I/R injury.
Scommotau
S
S
University of Leipzig, Department of Ophthalmology, Germany. Uhld@server3.medizin.uni-leipzig.de
Uhlmann
D
D
Löffler
B M
BM
Breu
V
V
Spiegel
H U
HU
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism*; D005260:Female; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000098:blood supply*; D008833:Microcirculation / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D020030:Nitric Oxide Donors; D013449:Sulfonamides; D009569:Nitric Oxide; D001120:Arginine; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077300:Bosentan