Simulation of outward transport of neuronal 3H-noradrenaline with the help of a two-compartment model

Summary In order to simulate the outward transport of ³H-noradrenaline induced by veratridine from adrenergic varicosities, a mathematical two-compartment model was developed in which the two compartments (representing axoplasm and storage vesicles) are arranged in series. Simulated results were compared with experimental results obtained with 100 mol/l veratridine + 1 mmol/l ouabain and rat vasa deferentia kept in calcium-free solution (Bönisch and Trendelenburg 1987). As in experiments, the time course of efflux of ³H-noradrenaline had a pronounced and early peak under RPU-conditions, a minor peak under PU-conditions, and solely a plateau under U-conditions (where R stands for pretreatment with reserpine, P for pretreatment with pargyline, and U for inhibition of COMT by U-0521). From the width of the peak of release, it was deduced that — under RPU-conditions — about 40% of neuronal ³H-noradrenaline are distributed into the axoplasm, about 60% into the storage vesicle. However, this estimate represents an average value; the results are compatible with the view that the ratio axoplasmic/vesicular ³H-noradrenaline is quite variable from rat to rat. Under U-conditions, calculations confirm that reserpinelike compounds induce an efflux of tritium that consists predominantly of deaminated ³H-metabolites. The stimulation of outward transport, on the other hand, causes an efflux of tritium that consists predominantly of ³H-noradrenaline; indeed, the efflux of deaminated ³H-metabolites declines (as it did in experiments). Simulations showed further that the highest rates of outward transport of ³H-noradrenaline were achieved when there was a simultaneous induction of outward transport of ³H-noradrenaline and a reserpine-like effect (as it is known to occur when tissues are exposed to veratridine; Bönisch and Trendelenburg 1987). While there was satisfactory agreement between simulated and experimental results under various conditions, there were also two discrepancies that may be caused by a) inhomogeneous labelling of the storage vesicles in individual varicosities (RPU < PU < U) and b) saturation of outward transport of ³H-noradrenaline when a reserpine-like compound greatly increases the axoplasmic level of total noradrenaline (under U-conditions).Abbreviations COMT catechol-O-methyl transferase - DOMA dihydroxymandelic acid - DOPEG dihydroxyphenylglycol - FRL fractional rate of loss - MAO monoamine oxidaseSupported by the Deutsche Forschunesgemeinschaft (SFB 176)Send offprint requests to E. Schömig