The endothelin/nitric oxide balance determines small-for-size liver injury after reduced-size rat liver transplantation

Abstract

Small-for-size (SFS) liver graft injury is probably related to microcirculatory disorders due to an imbalance of vasoconstricting, e.g. endothelin (ET)-1, and vasorelaxing mediators, e.g. nitric oxide (NO). We studied the role of ET-1/NO balance and the effect of an endothelin A receptor (ETAR) antagonist on SFS injury after liver resection and reduced-size liver transplantation (RSLT). One hundred twenty-six Lewis rats were divided into five groups: (I) 70% liver resection, (II) 70% liver resection treated with the ETAR antagonist LU 135252 (1 mg/kg b.w. i.v.), (III) RSLT (30% residual liver volume), (IV) RSLT treated with the ETAR antagonist, (V) sham operation. Liver microcirculation was measured by intravital microscopy. ET-1, ETAR, endothelial NO-synthase (eNOS), activation of Kupffer cells (KCs) and parenchymal injury were studied by immunohistology. Survival and liver function were followed up to 14 days. RSLT led to increased ET-1, ETAR and decreased eNOS protein expression, accompanied by activation of KC, reduced perfusion rate, vasoconstriction and elevated sinusoidal blood flow, as well as hepatocellular damage, impaired liver function and impaired survival. ETAR blockade (groups II + IV) improved the ET-1/NO balance, attenuated microcirculatory disorders and improved hepatocellular apoptosis and liver function. Microcirculatory disorders related to an ET-1/NO imbalance may contribute to SFS liver injury. Maintenance of ET-1/NO balance by blocking ETAR reduces SFS injury by protecting liver microcirculation, thus reducing hepatocellular damage.