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Frequency-dependence of the metabolism of 3H-noradrenaline released from rabbit isolated aorta: effects of a combination of cocaine and corticosterone or hydrocortisone.

The effect of cocaine (neuronal uptake inhibitor) in combination with either hydrocortisone or corticosterone (extraneuronal uptake inhibitors) on the metabolism of 3H-noradrenaline (3H-NA) released spontaneously or by electrical-field stimulation was studied on the isolated rabbit aorta preloaded with 3H-NA. In the spontaneous outflow 3H-O-methylated and deaminated metabolites (3H-OMDA) accounted for 41% of the total radioactivity whereas 3H-NA represented only 22%. Cocaine (3 × 10-5M) + hydrocortisone (10-4 M) neither changed the spontaneous outflow of total tritium nor the distribution of the 3H-outflow on 3H-NA and its 3H-metabolites. However, cocaine (3 × 100-5M) + corticosterone (4 × 10-5M) enhanced the passive 3H-outflow, increased the percentage recovered as 3H-3,4-dihydroxyphenylglycol (3H-DOPEG), and reduced the percentage of 3H-OMDA + 3H-NMN. The effect of field-stimulation was investigated during and ofter stimulation at two frequencies: 3 and 10 Hz. The stimulation-induced 3H-overflow consisted mainly of unmetabolized 3H-NA and 3H-OMDA in the sample collected during stimulation. The ratio between 3H-NA and 3H-OMDA was strongly dependent on the frequency of stimulation, Thus it was 1:2 at 3 Hz, but 3:1 at 10 Hz. These ratios were about the same during the poststimulation period. On the other hand, whereas the formation of 3H-DOPEG from 3H-NA released during stimulation at both frequencies was small, it increased rapidly in the poststimulation sample. At 3 Hz, inhibition of neuronal and extraneuronal uptake by cocaine + steroids did not change the stimulation-induced 3H-overflow, but the distribution on 3H-NA and 3H-metabolites was markedly altered. Thus the percentage of 3H-N A was doubled, 3H-OMDA was halved, and 3H-DOPEG was almost abolished. At 10 Hz, however, cocaine + corticosterone decreased the stimulation-induced 3H-overflow, but did not change the proportions of 3H-NA and 3H-OMDA. Only the formation of 3H-DOPEG was markedly reduced. It is concluded that the distribution of stimulation-induced 3H-overflow on 3H-NA and its 3H-metabolites and the effect of neuronal and extraneuronal uptake inhibition on this is strongly influenced by the frequency of stimulation. Furthermore, inhibition of both neuronal and extraneuronal uptake does not fully prevent metabolism of 3H-NA released by electrical-field stimulation.