Release of tritiated noradrenaline from perfused rat hearts by sympathomimetic amines

The hypothesis that the limiting factor controlling the noradrenaline-releasing activity of a sympathomimetic amine is the ability of the nerve ending to take up the amine, i.e. the affinity of the amine for the postulated amine carrier in the sympathetic nerve ending, was tested on perfused rat hearts labelled with tritiated noradrenaline (NA). Experiments were done to determine whether cocaine and desmethylimipramine (DMI) would block the releasing action of sympathomimetic amines (SMA) and to determine whether the ranking order of the releasing activity of a series of SMA corresponds to the order of affinity for the amine carrier as reported by Iversen. The releasing activity of NA was found to be a saturable process, reaching a maximum rate estimated to be 2.6% of the amount present in the heart per minute. In addition, cocaine and DMI competitively blocked the releasing activity of infused NA, adrenaline, and dopamine, but this inhibition could be overcome by increasing the dose of the SMA. The ranking order of releasing activity of this series of amines was l-noradrenaline, dopamine, l-adrenaline, p-tyramine, d-noradrenaline, d-adrenaline, l-isoproterenol, phenylethylamine, d-isoproterenol, which was approximately the same as their order of affinity for the amine carrier. Our results indicate that uptake by a membrane carrier is probably the limiting factor in the releasing activity of SMA which are catechols and have a β-OH group. However, those amines studied which do not have these structural properties, i.e. dopamine, tyramine, and phenylethylamine, are further limited in their releasing activity, possibly owing to a less rapid exchange at the binding site on the storage granule.