THE EFFECT OF RESERPINE UPON THE SYNTHESIS OF NOREPINEPHRINE IN THE ISOLATED RABBIT HEART

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

In perfused hearts from reserpine-prctreated rabbits, the amounts of H³-norepinephrine and H³-3,4-dihydroxyphenyhethylamine (H³-dopamine) formed from H³-tyrosine were markedly lower than those formed in hearts of control animals. The effect was apparent as early as 15 min after the injection of reserpine and was dose-related. The effect of reserpine on the content of H³-amines preceded the depletion of endogenous norepinephrine content. R Reserpine produced the same effect whlen H³-dopa was perfused through the heart. When isolated atria from reserpine-pretreated rabbits were incubated with H³-dopamine, the amount of norepinephrine formed was much lower thlan that found when control atria were similarly incubated, and the metabolites of newly formed norepinephrine were not increased. The total formation of norepinephrine (norepinephrine plus norepinephrine metabolites) was inhibited in a dose-dependent manner. The metabolites of dopamine tended to increase in atrma Pretreated with reserpine. Isolated atria incubated with H³-norepinephrine metabolized the amine to 3,4-dihydroxyphenylglycol, 3-methoxy-4-hydroxyphenylglycol, 3,4-dihydroxymandehic acid and vanilmandelic acid. The predominant metabolite was dihdroxyphenylglycol. All of the metabolites of norepinephrine were increased in atria from reserpine-pretreated animals. These studies indicate that reserpine inhibits the synthesis of norepinephrine by inhibiting the uptake of its precursor, dopaminc, into the storage vesicle which contains the enzyme, dopamine--hydroxylase. This action of reserpine also leads to reduced quantities of newly formed dopamine, since dopamine, which is not taken up and stored, is more rapidly metabolized, primarily by monoamine oxidase.