The mechanism of the 3H-noradrenaline releasing effect of various substrates of uptake1: role of monoamine oxidase and of vesicularly stored 3H-noradrenaline.

The mechanism of action of indirectly acting sympathomimetic amines was studied in vasa deferentia of unpretreated rats (COMT inhibited), preloaded with 3H-noradrenaline. 1. Concentration-release curves were obtained for 12 unlabelled indirectly acting amines. From differences between these results and those in an accompanying report (involving tissues from rats pretreated with reserpine and pargyline), it is concluded that a "mobilisation" of vesicular 3H-noradrenaline is required for high and sustained rates of outward transport of 3H-noradrenaline from intact adrenergic varicosities. 2. Experiments with a reserpine-like compound (Ro 4-1284) supported the view that a "mobilisation" of vesicular 3H-noradrenaline is required for substantial release. 3. An atypical time course of release and abnormally high rates of release were observed in the presence of excessive concentrations of (+)-amphetamine. Such atypical effects are ascribed to the of basic amines to increase the intravesicular pH. 4. Analysis of the ratio NA/DOPEG (rate of efflux of 3H-noradrenaline/rate of efflux of 3H-DOPEG) indicated that the inward transport (by uptake) of substrates of MAO fails to achieve axoplasmic concentrations which saturate MAO. Inhibition (or saturation) of MAO is not a prerequisite for the initiation of outward transport. 5. A larger fraction of vesicular 3H-noradrenaline is accessible to equireleasing concentrations of (+)-amphetamine (an inhibitor of MAO) than of tyramine (a substrate of MAO). 6. From the present and the accompanying report it is concluded that "substantial and sustained indirect sympathomimetic effects" are to be expected for substrates of uptake which additionally mobilise vesicular noradrenaline. However, this "mobilisation" does not seem to involve a change in intravesicular pH, except at excessive concentrations.