Abstract

The actions and interactions of norepinephrine (NE), tyramine and cocaine were studied on strips of thoracic aorta from rabbits and on electrically driven left atria from guinea pigs. On preparations from normal animals cocaine at 10^-5 caused an increase in sensitivity to NE (much greater in atria) and a decrease in sensitivity to tyramine (much greater in aortic strips). Cocaine also potentiated the positive inotropic response of atria to "supramaximal voltage" stimulation (presumably stimulation of intramural sympathetic nerves). Cocaine alone produced a small to moderate positive inotropic response in most atria, but no response in aortic strips.

Atria and aortic strips from reserpine-treated animals showed only small increases in sensitivity to NE over that of normal preparations. Reserpinized atria did not respond to either tyramine or cocaine, and gave very little or no positive inotropic response to supramaximal voltage stimulation. Reserpinized strips were very insensitive to tyramine, giving contractions only at very high concentrations. Such contractions were not antagonized by cocaine, and are thought to result from a direct action of tyramine rather than an indirect action dependent on NE release. Cocaine potentiated the responses to NE on reserpinized preparations almost as much as on normal preparations. Tyramine at high concentrations potentiated responses to NE on reserpinized preparations to the same degree as did cocaine.

Incubation of reserpinized preparations with sufficient NE for short periods (NE "repletion") led to restoration of essentially normal sensitivity to tyramine. On continued exposure to tyramine, the restored sensitivity was lost, but could be restored again by reincubation with NE. Incubation of reserpinized atria with NE also restored sensitivity to cocaine to above the normal level, but failed completely to restore the sensitivity to supramaximal voltage stimulation. If either tyramine or cocaine was present in high concentrations during the period of incubation with NE, the restoration of sensitivity to either agent was blocked.

Normal and reserpinized left atria of cats behaved qualitatively like those of guinea pigs, except that cocaine alone had no positive inotropic action on cat atria, and in moderately high concentrations had a strong depressing action.

On left atria of cats, 6 to 10 days after bilateral stellate ganglionectomy, the sensitivity to NE was elevated above the normal level, and was increased relatively little or not at all by cocaine. Sensitivities to tyramine and to supramaximal voltage stimulation, though considerably decreased, were not completely lost—probably indicating that the ganglionectomy did not produce a total cardiac sympathectomy.

The present results have been discussed in conjunction with the recent findings of others. A hypothetical scheme has been developed for the relationship between effector cells and structures, possibly adrenergic nerve terminals, which remove NE either by storage (dominant normally) or enzymatic inactivation (dominant after reserpine). It is proposed that these latter structures contain at least two types of storage sites for NE, and that they possess on their exterior sites of a specific type with which NE molecules and tyramine molecules (for the most part) must first combine before being transferred into the interior. Cocaine molecules, by also combining with these "transfer sites," competitively block the uptake of both NE and tyramine, thus potentiating the response to the former and antagonizing the release of NE by the latter.