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The role of Uptake 2 in the extraneuronal metabolism of catecholamines in the isolated rat heart
Author(s) -
LIGHTMAN S. L.,
IVERSEN L. L.
Publication year - 1969
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1969.tb08502.x
Subject(s) - normetanephrine , phenoxybenzamine , chemistry , metabolism , perfusion , monoamine oxidase , metaraminol , endocrinology , medicine , metabolite , biochemistry , enzyme , biology , urine , receptor , blood pressure
1 . (±)‐ 3 H‐NA and labelled metabolites of NA were estimated in rat hearts after perfusion with various concentrations of NA in the range 0·01–50·0 μg/ml. Labelled metabolites of NA accounted for only a small proportion of the total uptake of radioactivity at low perfusion concentrations, but accounted for 50% of the total uptake at 1 μg NA/ml., thereafter declining to progressively smaller proportions at higher perfusion concentrations. 2 . If the formation of labelled metabolites of 3 H‐NA was blocked by a combination of monoamine oxidase and catechol‐O‐methyl transferase inhibitors, the accumulation of unchanged 3 H‐NA was doubled when hearts were perfused with 1 μg NA/ml. 3 . In hearts perfused with 0·5 μg NA/ml., an accumulation of unchanged 3 H‐NA was demonstrated in the presence of a combination of metabolic inhibitors and metaraminol. This appeared to be due to Uptake 2 , since the accumulation of NA under these conditions could be prevented by a low concentration of normetanephrine. 4 . Phenoxybenzamine prevented extraneuronal uptake (Uptake 2 ) and metabolism of 3 H‐NA with an estimated ID50 of 2·5 μ m . The inhibition of Uptake 2 by phenoxybenzamine (2·0 μ m ) was diminished at very high NA concentrations, suggesting that the drug may act competitively with NA. 5 . It was concluded that Uptake 2 operates at all catecholamine concentrations in the rat heart, but that in the lower range (less than 2·5 μg/ml. for NA and less than 0·75 μg/ml. for adrenaline) any catecholamine taken up by this process is rapidly metabolized. Thus the accumulation of unchanged amine is seen only at high perfusion concentrations. 6 . The relevance of these results to an understanding of the possible physiological and pharmacological importance of Uptake 2 is discussed.