OXYGEN-SUPPLY DEPENDENCE OF UREA PRODUCTION IN THE ISOLATED-PERFUSED RAT-LIVER

To determine whether hepatic urea production is limited at low hepatic O-2 delivery (DO2) by O-2 itself or by the availability of substrate for urea synthesis, we isolated livers from normal rats and perfused t hem with Krebs-Henseleit bicarbonate (KHB) buffer, KHB + 5 mM NH4Cl, o r KHB + 5 mM glutamine (Gin) as an NH3 donor. The pump flow was lowere d in stages, and we determined at each flow rate inflow and outflow O- 2 content and urea levels in the outflow perfusate. Urea production in Gln-perfused livers remained constant at high Do, and declined in dir ect proportion to DO2 below a critical oxygen delivery (DO(2)crit, the point below which the hepatic O-2 consumption [(V) over dot O-2] beco mes limited by the hepatic DO2). The DO(2)crit calculated from the ure a release-DO2 relationship (147 +/- 32 mu l/min/ dry g) was similar to the DO(2)crit calculated from the (V) over dot O-2-DO2 relationship ( 158 +/- 26 mu l/min/dry g). When Gln concentration and flow rate were maintained constant while decreasing PO2 in the inflow perfusate (as w ell as hepatic DO2), urea production declined below the DO(2)crit. Fur thermore, when Gln concentration in the perfusate was gradually reduce d while keeping hepatic DO2 constant, urea production decreased propor tionally with Gln concentrations in the perfusate. Consequently, urea production is dependent on Gln and O-2 availability and becomes limite d at the same DO(2)crit determined by the (V) over dot O-2-DO2 relatio nship.