Hepatic albumin and urea synthesis: The mathematical modelling of the dynamics of [14C]carbonate-derived guanidine-labelled arginine in the isolated perfused rat liver

Abstract

A mathematical model was constructed to define the dynamics of incorporation of radioactivity into urea carbon and the guanidine carbon of arginine in plasma albumin after the rapid intraportal-venous administration of Na214CO3 in the isolated perfused rat liver. 2. The model was formulated in terms of compartmental analysis and additional experiments were designed to provide further information on subsystem dynamics and to discriminate between alternative model structures. 3. Evidence for the rapid-time-constant of labelling of intracellular arginine was provided by precursor-product analysis of precursor [14C]carboante and product [14C]urea in the perfusate. 4. Compartmental analysis of the dynamics of newly synthesized urea was based on the fate of exogenous [13C]urea, endogenous [14C]urea and the accumulation of [12C]urea in perfusate water, confirming the early completion of urea carbon labelling, the absence of continuing synthesis of labelled urea, and the presence of a small intrahepatic urea-delay pool. 5. Analysis of the perfusate dynamics of endogenously synthesized and exogenously administered [6-14C]arginine indicated that although the capacity for extrahepatic formation of [14C]-urea exists, little or no arginine formed within the intrahepatic urea cycle was transported out of the liver. However, the presence of a rapidly turning-over intrahepatic arginine pool was confirmed. 6. On the basis of these subsystem analyses it was possible to offer feasible estimations for the parameters of the mathematical model. However, it was not possible to stimulate the form and magnitude of the dynamics of newly synthesized labelled urea and albumin which were simultaneously observed after administration of [14C]carbonate on the basis of a preliminary model which postulated that both products were derived from a single hepatic pool of [16-14C]arginine. On the other hand these observed dynamics could be satisfied to a two-compartment arginine model, which also provided an explanation for discrepancies observed between albumin synthesis measured radioisotopically and immunologically. This was based on a relative overestimation of [14C]urea specific radioactivity resulting from the rapid dynamics of [14C]carbonate and the [14C]urea subsystem relative to the labelled albumin subsystem. The effects of arginine compartmentalization could be minimized in the model by minor slowing of the rate of [14C]carbonate turnover or by constant infusion of [14C]carbonate, both of which permitted valid determination of albumin-synthesis rates.

The Role of Iron in the Regulation of Hepatic Transferrin Synthesis

“…(Tavill et al, 1973(Tavill et al, , 1975 The rat liver was perfused through the portal vein with a medium consisting of rat erythrocytes, obtained by thrice washing fresh rat blood to remove plasma and buEy coat, resuspended in fieshly drawn rabbit plasma to a PCV of 0.28-0.3. Both control and ID rats from which a small blood sample had been taken fiom a tail vein were transfked twice via the dorsal penile vein at a 2 day interval and the animals killed 24 or 48 h later.…”

The synthesis and secretion of albumin

“…In growing animals, for example, the rates of synthesis and catabolism are not in a steady state and this may affect the accuracy of the values shown in Part A of Table 4. Furthermore, recent work (e.g., Airhart et al, 1974;Tavill et al, 1975) has cast some doubt on the assumption of homogeneous amino acid pools in the liver. This assumption has been made in the direct determination of the rate of synthesis of albumin (Part B of Table 4).…”

Compartmental systems. An appealing class for kinetic modeling and identification of metabolic processes

“…This allows the risks associated with physiological simplification to be reduced. Subsystem analysis has been variously employed in solving validation problems, for instance in quantitating albumin metabolism 41 and in the study of the wholeorganism glucose control system via the glucose clamp technique, 42 which is able to produce a subsystem decoupling.…”