Regional heterogeneities in the production of uric acid from adenosine in the bivascularly perfused rat liver

The heterogeneity of the liver parenchyma in relation to uric acid producti on from adenosine was investigated using the bivascularly perfused rat live r in the anterograde and retrograde modes. Adenosine was infused in livers from fed rats during 20 min at four different concentrations (20, 50, 100 a nd 200 mu M) according to four experimental protocols as follows: (A) anter ograde perfusion, with adenosine infusion into the portal vein; (B) anterog rade perfusion, with adenosine in the hepatic artery, (C) retrograde perfus ion, with adenosine in the hepatic vein; (D) retrograde perfusion, with ade nosine in the hepatic artery. With protocols A, B, and D uric acid producti on from adenosine was always characterized by initial bursts followed by pr ogressive decreases toward smaller steady-states. With protocol C the initi al burst was present only when 200 mu M adenosine was infused. The initial bursts in uric acid production were accompanied by simultaneous increases i n the ratio of uric acid production/adenosine uptake rate. These initial bu rsts are thus representing increments in the production of uric acid that a re not corresponded by similar increments in the metabolic uptake rates of adenosine. Global analysis of uric acid production revealed that the final steady-state rates were approximately equal for all infusion rates with pro tocols A, B and C, but smaller with protocol D. This difference, however, c an be explained in terms of the differences in accessible cellular spaces, which are much smaller when protocol D is employed. When the analysis was p erformed in terms of the extra amounts of uric acid produced during the inf usion of adenosine, where the initial bursts are also taken into account, d ifferent dose-response curves were found for each experimental protocol. Th ese differences cannot be explained in terms of the accessible cell spaces and they are likely to reflect regional heterogeneities. From the various d ose-response curves and from the known characteristics of the microcirculat ion of the rat liver it can be concluded that the initial bursts in uric ac id production are generated in periportal hepatocytes. The reason for this heterogeneity could be related to the metabolic effects of adenosine, espec ially to oxygen uptake inhibition, which is likely to produce changes in th e ATP/AMP ratios.