Gadolinium chloride-induced improvement of postischemic hepatic perfusion after warm ischemia is associated with reduced hepatic endothelin secretion

Abstract

Selective Kupffer cell blockade by gadolinium chloride (GdCl(3)) pretreatment of liver donors previously proved to be effective in reducing ischemia/reperfusion injury in rat liver transplants. Physiological mechanisms of this effect have not been specified so far. Vasoactive peptides are involved in liver blood flow regulation. We tested the hypothesis, that hepatic hemodynamic effects of GdCl(3) pretreatment are mediated by intrahepatic endothelin-1 (ET) secretion in a standardized porcine model of warm liver ischemia and reperfusion. Standardized warm hepatic ischemia (45 min) was induced after laparotomy in intubation narcoses (ITN) by Pringle-maneuver in pigs (n = 12). Animals were either pretreated with GdCl(3) (20 mg/kg i.v.) or sodium chloride 0.9% (control group) in a randomized manner 24 h before investigation. Relaparotomy was performed at day 7. Before, during ischemia and until 6 h after liver reperfusion, transhepatic blood flow (portal venous + hepatic artery flow) was defined by ultrasonic flow probes and hepatic parenchymous microcirculation evaluated by implanted thermodiffusion electrodes. ET plasma concentrations were analyzed (commercial RIA) at all time points in the hepatic veins after selective canulation. GdCl(3) pretreatment of animals markedly improved hepatic macro- and microperfusion before and particularly after warm ischemia. Mean ET plasma concentrations in the hepatic vein were significantly lower before, 6 h and 7 days after ischemia, compared with controls. Kupffer cell destruction by GdCl(3) pretreatment improves hepatic micro- and macroperfusion after warm ischemia, thus indicating reduced ischemia/reperfusion injury. Documented reduction of postischemic liver blood flow impairment after GdCl(3) pretreatment could be mediated by a decreased hepatic ET secretion, as hemodynamic effects were associated with significantly reduced ET plasma levels in hepatic veins.