HEPATOPROTECTIVE EFFECT OF A NONSELECTIVE ENDOTHELIN RECEPTOR ANTAGONIST (TAK-044) IN THE TRANSPLANTED LIVER

This study was designed to investigate whether or not a novel nonselec tive endothelin A/B (ETA/ETB) receptor antagonist (TAK-044) provides h epatoprotection during porcine liver transplantation. The grafts were stored in chilled Euro-Collins solution and recirculated following ref lush with lactated Ringer's with (TAR group) or without (control group ) TAK-044 (10 mg/kg). Intracellular (cytoplasma, mitochondria, and nuc leus) calcium (Ca) concentrations were measured in the hepatic biopsy materials obtained serially at varying time point from donor laparotom y to recipient closure using an electron probe X-ray microanalyzer. Li ver function tests also were determined. The cold and warm ischemia ti mes of the grafts were comparable between the tyro groups. The peak en dothelin-1 (ET-1) concentration after recirculation was significantly higher in the TAR group than in the control group (129 +/- 30 pg/ml vs 26 +/- 6.5 pg/ml), However, release of liver enzymes, increases in to tal bile acid, and deterioration of indocyanine green retention rate w ere significantly suppressed ill the TAK group. In the control group, the intracellular Ca concentrations, especially in the mitochondrial f raction, were elevated markedly following recirculation of the hepatic arterial flow. In the TAK group, this effect was suppressed. Thus, th e supplementary use of the nonselective ETA/ETB receptor antagonist TA K-044 via a rinse route may alleviate an early postreperfusion microci rculatory disturbance of the liver grafts without adverse effects by t he increased ET-1 on the systemic circulation. (C) 1997 Academic Press .