EFFECT OF FALSE TRANSMITTERS ON NOREPINEPHRINE SYNTHESIS

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

The rate of synthesis of labeled norepinephrine in the rat heart from tyrosine-C¹⁴ and dopa-H³ was determined after administration of -methyldopa, metaraminol or octopamine. Thirty minutes after metaraminol or -methyldopa and 10 minutes after octopamine, there was a decrease in norepinephrine formation from both tyrosine-C¹⁴ and dopa-H³ although these compounds did not significantly inhibit tyrosine hydroxylase or dopamine--hydroxylase in vitro. The levels of norepinephrine in the heart were decreased. There was a decrease in conversion of tyrosine-C¹⁴ and of dopa-H³ to labeled norepinephrine. The decrease in the C¹⁴/H³ ratio indicates that the decreased conversion of tyrosine to norepinephrine was a consequence of decreased hydroxylation of tyroeine to dopa as weli as interference with dopa conversion to norepinephrine. Twenty-four hours after metaraminol or -methyldopa and two hours after octopamine, the norepinephrine content of the heart was decreased, but synthesis of norepinephrine from both tyrosine-C¹⁴ and dopa-H³ was still depressed. The ratio of carbon-14 to tritium in the norepinephrine had returned to control levels, suggesting that tyrosine conversion to dopa was normal and that the block was in conversion of dopa to norepinephrine. Six hours after octopamine, the synthesis rate of norepinephrine from tyrosine-C¹⁴ was increased, and conversion of dopa-H3 to norepinephrine was normal. The results are consistent with the view that only intraneuronal unbound norepinephrine is important in the feedback control of norepinephrine and that, under certain conditions, steps other than tyrosine hy- droxylation may be rate-limiting in norepinephrine synthesis.