Abstract

Cocaine inhibited the uptake of H³-norepinephrine by the isolated atria of the guinea pig, but immediate uptake of H³-norepinephrine (i.e., at 1 min in our experiments) was not affected. Likewise, uptake and retention of H³-norepinephrine were normal at 1 min in atria from reserpine-pretreated animals. It seems that tissue has the ability to take up large amounts of norepinephrine into nonspecific binding sites for a short period (i.e., 1 min in our experiments). On these nonspecific binding sites cocaine or reserpine pretreatment seems to have no effect. The present study also reveals the presence of an extraneuronal store for H³-norepinephrine, on which cocaine had no effect. This store was partially released by dimethylphenylpiperazinium (DMPP) and tyramine but not by nicotine. Thus actions of DMPP on guinea-pig atria are similar to that of tyramine. Cocaine shifted the dose-response curve of l-norepinephrine and l-epinephrine to the left by factors of 12.4 and 6.5 respectively, which appear to be proportional to their respective rate of uptake. The response to isoproterenol, which is hardly retained by the heart, was not potentiated by cocaine. Thus these results provide additional evidence that cocaine causes supersensitivity to a directly-acting amine by inhibiting its uptake into norepinephrine stores and that the magnitude of its sensitization is proportional to the rate of uptake of the amine.