Effects of a haloalkylamine on responses to and disposition of sympathomimetic amines

Abstract

1. The mechanisms by which a haloalkylamine (GD-131) alters the inactivation of and potentiates responses to certain sympathomimetic amines, and the relationship of these actions to the similar effects of cocaine were investigated in rabbit aortic strips. The technique of oil immersion was used to assess rates of amine inactivation.

2. Exposures to GD-131, which produced no detectable α-adrenergic blockade, markedly slowed the inactivation of noradrenaline. It was concluded that it is unnecessary to postulate a role of adrenergic receptors in the inactivation of catecholamines to account for the reported effects of haloalkylamines on amine output during adrenergic nerve stimulation.

3. The reduction in the rate of noradrenaline inactivation produced by moderate exposure to GD-131 was approximately equivalent to that due to inhibition of both monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). Addition of GD-131 did not further slow inactivation in preparations in which MAO and COMT had been inhibited, but the effects of both GD-131 and of enzyme inhibition on noradrenaline disposition were additive with that of cocaine.

4. Cocaine consistently inhibited and GD-131 markedly potentiated responses to tyramine. The augmentation of responses by GD-131 was much greater than could be accounted for by the slight release of endogenous catecholamine by this agent. Thus the principal effect of the haloalkylamine appears not to involve inhibition of nerve cell membrane transport of amine.

5. Maximal exposure to GD-131 short of that which produced α-adrenergic blockade sometimes slowed the inactivation of noradrenaline as much as did inhibition of both MAO and COMT plus the maximal effect of cocaine.

6. These results seem best explained by postulating that GD-131 and other haloalkylamines inhibit the passage of sympathomimetic amines through biological membranes. Passage to sites of enzymatic inactivation, predominantly in non-neuronal tissue, is most readily inhibited. The “cocaine-sensitive mechanism,” transport to sites of binding and storage, can also be inhibited, but is considerably less sensitive.

7. GD-131 potentiated responses to noradrenaline more than did the maximally effective concentration of cocaine. Cocaine produced very little additional potentiation when added in the presence of GD-131, whereas the latter had a reduced, but still significant effect in the presence of cocaine. Most of the effect of cocaine and at least half of that of GD-131 was due to a common action on effector cells, which is unrelated to any alteration of amine disposition. The balance of the potentiation by GD-131 may be due to inhibition of access of amine to sites of enzymatic inactivation, perhaps involving a reduction in the volume of distribution in intracellular water, and a very small part of the potentiation by cocaine may be secondary to inhibition of transport of amine to sites of binding and storage.

8. On the basis of the present observations, it is postulated that a major part of the noradrenaline released by adrenergic nerve activity is involved in the activation of tissue receptors and has its action terminated by movement away from the region of the receptors. A small portion of the mediator is removed by the circulation, some is taken up by adrenergic nerves, but the major part enters non-nervous cells and is distributed in intracellular water. The capacity of this intracellular compartment appears to be limited and enzymatic inactivation is essential to maintain its function. O-methylation is the dominant primary enzymatic process in the inactivation of physiological amounts of noradrenaline, but MAO appears to function “in series” as an effective alternate pathway of disposition.

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