The action of extracellular NAD+ in the liver of healthy and tumor-bearing rats: Model analysis of the tumor-induced modified response

The chronic inflammatory state induced by cancer is expected to affect the actions of extracellular NAD+ in the liver because these are largely mediated by eicosanoids. Under this assumption the present work was planned to investigate the influence of the Walker-256 tumor on the action of extracellular NAD+ on metabolism and hemodynamics in the perfused rat liver. The experiments were done with livers from healthy and tumor-bearing rats with measurements of gluconeogenesis from lactate, pyruvate production, oxygen consumption and portal pressure. A model describing the biphasic effects of NAD+ was proposed as an auxiliary worktool for interpretation. The Walker-256 tumor modified the responses of metabolism to extracellular NAD+ by delaying the peak of maximal responses and by prolonging the inhibitory effects. The transient increase in portal perfusion pressure caused by NAD+ was enhanced and delayed. The model was constructed assuming the mediation of a down-regulator (inhibition), an up-regulator (stimulation) and receptor dessensitization. Analysis suggested that the productions of both the down- and up-regulators were substantially increased and delayed in time in the tumor-bearing condition. Since the regulators are probably eicosanoids, this analysis is consistent with the increased capacity of producing these agents in the chronic inflammatory state induced by cancer.