SUPERSENSITIVITY BY COCAINE TO DEXTROROTATORY ISOMERS OF NOREPINEPHRINE AND EPINEPHRINE

¹ Department of Pharmacology, Harvard Medical School, Boston, Massachusetts

The sensitization by cocaine of the nictitating membrane of the spinal cat has been determined quantitatively. For three amines the rates of uptake into the norepinephrine stores are known to be : l-norepinephrine > l-epinephrine > d-norepinephrine. The sensitizing effect of cocaine was found to have the same sequence of order. These observations provide further evidence for the view that cocaine causes supersensitivity by preventing uptake into the norepinephrine stores.

After chronic denervation, which is known to prevent uptake, supersensitivity to the three amines was found to follow a similar pattern.

After chronic decentralization there was a moderate supersensitivity to all optical isomers of epinephrine and norepinephrine. This observation is consistent with the view that decentralization supersensitivity differs from the supersensitivity induced by cocaine.

The duration of the response of the nictitating membrane to the four amines was not strictly related to their rates of uptake. The duration increased in the following order: l-epinephrine < i-norepinephrine = d-epinephrine < d-norepinephrine.

The clearance by the liver of the four amines was studied by comparison of the response of the nictitating membrane to intravenous and to intraportal injections. Clearance by the liver decreased in the following order: l-epinephrine > l-norepinephrine > d-epinephrine > d-norepinephrine. Studies with enzyme inhibitors (pyrogallol and iproniazid) showed that both catechol O-methyl transferase and monoamine oxidase were involved. The relative rates of clearance are in agreement with the view that enzymatic metabolism is one of the factors determining the duration of the response of the nictitating membrane to the amines under study. The observations indicate that stereospecific processes play a role in the clearance of the amines by the liver, although in vitro experiments reported in the literature showed no stereospecificity of catechol O-methyl transferase. A stereospecific uptake mechanism may precede enzymatic metabolism.