New, simple models to evaluate zone-specific damage due to hypoxia in the perfused rat liver: time course and effect of nutritional state.

Models were developed to study zone-specific damage in periportal and pericentral regions of the liver lobule due to hypoxia produced in the perfused liver by ischemia, nitrogen or perfusion with low flow followed by reflow. Damage was assessed by lactate dehydrogenase release and trypan blue uptake in specific regions. Perfusion for up to 120 min under the conditions employed in all models failed to damage liver from well fed rats. In contrast, perfusion of livers from fasted rats for 30 min with N2-saturated buffer produced dye uptake of 37% and 66% in periportal and pericentral regions, respectively. Damage tended to be greater in this model when calcium was omitted from the perfusate (69% and 88% staining of periportal and pericentral regions, respectively). Release of lactate dehydrogenase correlated well with the percentage of cells stained with dye. In livers from fasted rats, 90 min of low flow (ca. 1 ml/g/min) followed by 30 min of reflow at normal flow rates (ca. 4 ml/g/min) produced damage exclusively to pericental regions of the liver lobule. On the average, about 40% of hepatocytes were stained with the dye under these conditions. Sixty minutes of ischemia followed by 13 min of reflow produced damage in 12% of periportal and 32% of pericentral regions of the liver lobule. When perfusion was in the retrograde direction (60 min low flow, 30 min reflow), periportal areas were damaged but pericentral regions were spared. Thus, models have been developed to study zone-specific damage due to hypoxia in the perfused liver. The data indicate that nutritional status is an important determinant of damage to hepatocytes due to hypoxia.