Effect of the endothelin receptor antagonist bosentan on postischemic liver microcirculation.
One mechanism evoked by ischemia is endothelin mediated vasoconstriction of the hepatic vascular bed. Postischemic sinusoidal constriction leads to microcirculatory disturbances and reduced blood flow, thereby causing local hypoxia and liver damage. The aim of the study was to avoid the constrictive response of sinusoids by blocking endothelin receptors.


METHODS
In an in vivo ischemia-reperfusion-model (21 Wistar rats, 250-300 g) with portal decompression by a splenocaval shunt, hepatic ischemia was induced for 30 min by cross clamping of the hepatoduodenal ligament. The effect of the endothelin receptor antagonist bosentan (10 mg/kg bw i.v.) injected before ischemia was assessed by in vivo microscopy. Microhemodynamic studies, including the sinusoidal perfusion rate, diameters of hepatic sinusoids and postsinusoidal venules, leukocyte endothelium interactions and leukocyte velocity were performed.


RESULTS
After ischemia sinusoidal diameters and diameters of postsinusoidal venules were significantly reduced to 76 +/- 7% and 86 +/- 10%, respectively, in the non-treatment group, but dilated to 109 +/- 6% and 118 +/- 8% in the group treated with endothelin receptor antagonist (p < 0.001). Increased percentage of postischemic permanent adherent leukocytes could be diminished in sinusoids and more markedly in venules by therapy (p < 0.001). Leukocyte velocity was decreased to 69 +/- 9% in the treatment group ( p < 0.001). Perfusion rate could be improved to 90 +/- 2% compared to 83 +/- 5% in the untreated group (p < 0.01). Systemic arterial blood pressure was not affected by administration of the receptor antagonist.


CONCLUSIONS
These data indicate that the endothelin receptor antagonist treatment results in prevention of postischemic sinusoidal constriction. Perfusion rate could be improved due to dilation of sinusoids and diminished leukocyte adhesion, but leukocyte velocity was reduced by 31%.
Spiegel
H U
HU
Department of General Surgery-Surgical Research, Westfaelische Wilhelms-Universitaet, Muenster, Germany.
Scommotau
S
S
Uhlmann
D
D
Giersch
B
B
D000818:Animals; D000077300:Bosentan; D065128:Endothelin Receptor Antagonists; D005260:Female; D007275:Injections, Intravenous; D007511:Ischemia / Q000473:pathology / Q000503:physiopathology*; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008833:Microcirculation / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000502:physiology; D013449:Sulfonamides / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000077300:Bosentan