Estimation of rate constants for serotonin uptake and compartmentation in normal human platelets

Abstract

Biochemical and pharmacological experiments led to a model describing a thrombin-releasable (vesicular) compartment and two non-thrombin-releasable compartments for 5-hydroxytryptamine (5-HT, serotonin) in normal human platelets (J. L. Costa, K. L. Kirk, D. L. Murphy, and H. Stark. Br. J. Pharmacol. 72: 449-459, 1981). With tritiated 5-HT as substrate, the amounts of total and nonreleasable intraplatelet tritiated material were measured. Moreover, in the last set of experiments, the amounts of extraplatelet tritiated material and extraplatelet tritiated 5-HT were also measured. With these data, identification of the kinetic constants for movement between the various compartments was possible. A recent extension of the similarity transformation approach to nonlinear compartmental models was used to carry out the a priori identifiability analysis. Then numerical identification was performed by implementing and achieving efficient methods from optimal control theory. Under our experimental conditions, the main results are as follows: 1) the vesicular compartment corresponds to the platelet storage 5-HT compartment, 2) instead of pools I and II proposed previously, only a single nonreleasable thrombin-resistant pool could be detected, and 3) the optimized model computed to suit the first set of experiments fits homologous intraplatelet results obtained under similar experimental conditions in the last set of experiments and also fits one of the two supplementary extraplatelet investigations.