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Journal of Pharmacology And Experimental Therapeutics, Vol. 158, Issue 3, 378-385, 1967
Copyright © 1967 by American Society for Pharmacology and Experimental Therapeutics

EFFECT OF DRUGS ON THE ACCUMULATION AND METABOLISM OF EXTRANEURONAL NOREPINEPHRINE IN THE RAT HEART

Arnold J. Eisenfeld 1, Lewis Landsberg 1, and Julius Axelrod 1

1 Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland

The accumulation and metabolism of extraneuronal H3- norepinephrine in the isolated, perfused rat heart were studied. Uptake into sympathetic neurons was prevented by the presence of cocaine in the perfusion medium. It has previously been shown that alpha-adrenergic blocking agents markedly decrease this extraneuronal accumulation and metabolism of norepinephrine. The adrenergic blocking agents did not inhibit either catechol-O-methyl transferase or monoamine oxidase activity in heart homogenates. It was proposed that the adrenergic blocking agents were preventing entry of norepinephrine into extraneuronal cells, thereby reducing access of the substrate to intracellular enzymes. After 10 min of perfusion the concentration of norepinephrine in the heart is lower than that in the medium, so that this process may represent facilitated diffusion. In the present study, the ability of phenylethylamine derivatives to block the extraneuronal accumulation and metabolism paralleled their potency for blockade of uptake of norepinephrine when perfused at a high concentration without cocaine (uptake 2). There was a dissociation between the abilities of phenylethylamines to block the extra-and intraneuronal uptake of norepinephrine. Inhibitors of catechol-O-methyl transferase prevented the extraneuronal formation of O-methylated derivatives and also elevated the concentration of norepinephrine, while monoamine oxidase inhibitors reduced formation of deaminated metabolites but did not increase the norepinephrine concentration. The most effective inhibitors of the extraneuronal accumulation and metabolism of norepinephrine are the alpha-adrenergic blocking agents. Quinidine, lidocaine, guanethidine, tripelennamine and desmethylimipramine were also found to inhibit the extraneuronal accumulation and metabolism. Accumulation and O-methylation of H3-isoproterenol in the heart were also reduced by adrenergic blocking agents; phenoxybenzamine was more effective than dichloro-isoproterenol.

Submitted on April 17, 1967
Accepted on July 26, 1967




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J. Axelrod
Noradrenaline: Fate and Control of Its Biosynthesis
Science, August 13, 1971; 173(3997): 598 - 606.
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Copyright © 1967 by the American Society for Pharmacology and Experimental Therapeutics.