Endothelin-A receptor antagonist reduces microcirculatory disturbances and transplant dysfunction after partial liver transplantation



Endothelin-1 can induce microcirculatory disorders by mediating sinusoidal vasoconstriction, lowering the perfusion rate and promoting leukocyte adhesion, all of which may play a role in the pathogenesis of the damage sustained by partial liver transplants. In this pilot study, we investigated a selective endothelin-A receptor antagonist (Darusentan; Knoll GmbH, Ludwigshafen, Germany) for its potential influence on the microcirculation in the setting of partial liver transplantation. One hundred and forty isogeneic Lewis rats were divided into four groups: 1. partial liver transplantation (30% of the initial liver volume); 2. partial liver transplantation treated with Darusentan (1 mg/kg bodyweight intravenously) immediately before reperfusion; 3. full-size liver transplantation; and 4. sham operation. Subsequently, the liver microcirculation was evaluated by intravital microscopy, and survival, liver function, and morphology were followed up to the fourteenth day. Compared with full-size transplanted animals, rats subjected to partial liver transplantation without Darusentan (group I) displayed severe microcirculatory lesions characterized by a significantly decreased perfusion rate, increased leukocyte velocity, and increased leukocyte adhesion. Disintegration of endothelium and increased recruitment of Kupffer cells were frequent morphologic findings. The Darusentan-treated group II showed improved parameters of microcirculatory function and morphology as well as improved liver function. Microcirculatory disturbances play a key role in the pathogenesis of partial liver transplant dysfunction. Treatment with selective endothelin-A receptor antagonists represent a new therapeutic approach to improve the function of partial liver transplants by reducing microcirculatory lesions and their sequelae affecting sinusoidal endothelium and hepatocytes.