THE EFFECT OF DRUGS ON THE RELEASE OF EPINEPHRINE FROM ADRENOMEDULLARY PARTICLES IN VITRO

¹ Clinical Neuropharmacology Research Center, National Institute of Mental Health, Saint Elizabeths Hospital, Washington, D. C.

The spontaneous and drug-induced release of particle-bound epinephrine in 600-g supernates of rabbit adrenal glands has been studied under various conditions. An isotonic solution of potassium chloride containing 0.005 M phosphate, pH 6.5, and 0.006 Mg⁺⁺, at 25°, was found most suitable for the observation of releasing effects while 0.3 M sucrose, at 37°, was used to study the inhibition of release.

Reserpine and chlorpromazine caused practically complete release at 10^-4 M within 30 minutes at 25°. Prochlorperazine, thioridazine, trifluoperazine and triflupromazine, all potent phenothiazine tranquilizers, were approximately as active as chlorpromazine while promazine, promethazine and methylene blue, which are less active as tranquilizers, also seemed to be less active as agents of release. Syrosingopine was similar to reserpine in activity; imipramine also possessed some activity but apparently less than chlorpromazine.

Derivatives of chlorpromazine, promazine and imipramine, representing actual metabolites or analogues of metabolites, showed varying degrees of releasing activity.

Out of a large number of substances only 3 were found to have activity comparable to that of reserpine and the phenothiazines: p-chloromercuribenzoate, sodium deoxycholate and suramin sodium. It is suggested that in these cases releasing effects were the result of unspecific denaturation or lysis. Substances with little or no releasing activity at concentrations below 4 x 10^-4 M included sedatives and tranquilizers not belonging to the phenothiazine series, agents causing release in vivo, adrenergic, cholinergic and histaminic blocking agents, monoamine oxidase inhibitors, convulsants, hallucinogens, SH-inhibitors, uncoupling agents and drugs structurally related to reserpine or to phenothiazines.

Various combinations of releasing drugs with each other or with inactive compounds were tried but no instances of potentiation or inhibition were observed. In particular, it was not possible to duplicate, in vitro, the inhibition of the releasing effect of reserpine by monoamine oxidase inhibitors observed in vivo.

At concentrations of about 10^-5 M, reserpine as well as several phenothiazines were found to inhibit significantly the spontaneous release of particle-bound epinephrine.