Cellular influx and efflux in the heart.

It is with the development of new physical and analytical technology during the past 2 decades that we now can begin to make measurements of substrate uptake by cells in their in vivo state. In accordance with modern efforts to emphasize noninvasive approaches to the patient, attempts to interpret images obtained by external detection in terms of cellular metabolic rates are becoming widespread. Both gamma imaging and positron imaging have good possibilities in this regard. However, both are hampered because of two problems: difficulties in temporal resolution and differences in spatial resolution. Gamma imaging, by virtue of allowing multiple isotope dilution curves to be obtained simultaneously, has an advantage over positron imaging in that sets of tracers with different molecular characteristics can be used together; one or more of these can serve as references for the substrate or hormone of interest. The references serve to document the arrival times of the tracers in the organ, and the separation (in time) of the tracers as they traverse the organ’s capillary bed is the key to the estimation of transport rates across the capillary and cell walls. Although positron tomography provides better spatial resolution and quantitation of the tracer content of regions when the content is not changing rapidly, the inability to have simultaneous reference tracers for timing will impede the application of the technique for estimating unidirectional fluxes. The multiple indicator dilution technique, with injection of tracers into the arterial inflow while taking samples from the venous outflow from the organ, can be applied in fashions that are only moderately invasive. This approach gives excellent temporal resolution down to fractions of a second, and allows the use of both beta-and gamma-emitting radioactive tracers as well as indicators whose concentrations can be measured by chemical or optical methods. At this stage of development of the art or science, it is the only technique allowing accurate analysis of rapid kinetic events. The sacrifice is in the spatial resolution: there is no information concerning differences in rates or concentrations at different points within the organ. Obviously the most refined techniques will be those providing high resolution in both space and time. The current developments are dedicated toward that still somewhat distant goal, but are focused on obtaining data on unidirectional fluxes in situations that are as close as one gets to the normal physiological state while still providing a firm, well-characterized set of data from which reliable estimates can be obtained. A major virtue of the multiple indicator dilution technique is that an estimate of a flux or a conductance can be made from data that are acquired over a relatively short period (seconds or minutes) so that multiple assessments can be made in similar or different physiological states over periods of a few minutes or hours. Thus when one seeks information on mechanism of transport, for example, by looking at the effect of changing the concentration of the nontracer mother substance on cellular uptake (as in figure 2 of ref 2), one can try to perform the essential sequence of separate sets of dilution curves in one isolated organ, animal, or perhaps even a patient. In this presentation the emphasis is on the interpretation of outflow dilution curves for sets of tracers. Information on spatial variation within the organ is not obtainable from the venous dilution curves. However, the regional blood flows in the heart show substantial variation, and M. Levin and J. B. Bassingthwaighte (manuscript submitted) have shown that it is important to try to account for such flow heterogeneities. Failure to do so leads to systematic errors in the estimates of the transport rates. In the studies to be reported here we had the advantage of also injecting tracer-labeled microspheres and so could determine the regional blood flows from local concentrations of microspheres in the tissue.