Mechanism of cocaine potentiation of responses to amines

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Abstract
1 Effects of cocaine on the magnitude of responses to several biologically active amines and on their rates of inactivation were studied in strips of rabbit thoracic aorta in vitro. 2 Although cocaine both potentiated responses to noradrenaline, adrenaline and phenylephrine and slowed their inactivation, the correlation between these two parameters under various experimental conditions was poor, and in all cases the delay in intrinsic inactivation was inadequate to account for the observed potentiation. 3 Potentiation of responses to noradrenaline by cocaine was little decreased in strips stored at 6° C for up to 10 days, although the response to low doses of tyramine was abolished much earlier. Similarly, cocaine clearly potentiated responses to noradrenaline for at least 28 hr at 37° C, at which time responses to noradrenaline alone were markedly decreased. 4 Cocaine potentiated responses to phenylephrine as well after 60 as after 10 min exposure to the amine in strips in which all intra-neuronal disposition of this amine had been eliminated by treatment with reserpine and iproniazid. 5 Cocaine effectively potentiated responses to histamine, but had only a slight and variable effect on those to 5-hydroxytryptamine (5-HT). It did not alter the tissue inactivation of histamine, but did significantly slow the inactivation of 5-HT. 6 Procaine slowed amine inactivation in the same way and to the same extent as did cocaine, but did not potentiate responses or affect the potentiation produced by cocaine added in its presence. 7 Cocaine potentiated responses to methoxamine to approximately the same degree as it did those to noradrenaline, although studies by the oil immersion technique clearly demonstrated that the aortic strips were entirely incapable of inactivating methoxamine. 8 The observations reported and discussed are incompatible with the hypothesis that cocaine potentiates responses to sympathomimetic amines because it prevents their inactivation by nerve uptake and storage and thus diverts larger amounts of agonist to tissue receptors. It is concluded that potentiation and inhibition of amine inactivation reflect two largely independent actions of cocaine in this vascular smooth muscle preparation, and probably in other organs, and that potentiation is a generally unreliable criterion of the blockade of processes inactivating sympathomimetic amines or of the importance of these processes in terminating the action of the amines.