V-A and A-V modes in whole body and regional kinetics: domain of validity from a physiological model

In turnover studies, both at whole body and regional level, sources of tracer and tracee are in general nonidentical thus resulting in nonuniformity of specific activity (SA). Guidelines are available in literature to deal with the heterogeneous SA problem, and either the V-A or A-V modes, based on the arterial and mixed venous blood SA, respectively, have been recommended for different substrates. In particular, the A-V mode is considered the method of choice for studying lactate, amino acids, free fatty acid, etc. Guidelines are based on specific models chosen to describe kinetic and circulatory events of the substance under study but are often conflicting. A unitary physiological framework to understand assumptions of various models is also lacking. In this paper, we first review these models to assess their domain of validity. In particular, we point out major drawbacks that relate to the tissue compartment being treated as a lumped well-mixed pool with a single SA value. We then attempt to handle the nonuniform tissue SA by employing a more physiological model. The tissue system is thought to be made up of elementary units connected in parallel and categorized according to their functional ability to affect incoming SA. Potential changes of SA within individual units are examined. Thus each tissue unit may provide a different contribution to the overall change in SA, as measured in mixed venous blood. A spatial profile of SA is also identified both along the direction of blood flow and transversely toward the inner cellular space. This distributed model allows assessment of the domain of validity of V-A and A-V modes. We show that, in general, the V-A mode underestimates the production rate both at whole body and regional level, whereas the A-V mode can either under- or overestimate it.