THE REGULATION OF NOREPINEPHRINE SYNTHESIS. EFFECT OF PUROMYCIN ON THE ACCELERATED SYNTHESIS OF NOREPINEPHRINE ASSOCIATED WITH NERVE STIMULATION

¹ Department of Pharmacology, Harvard Medical School; Neuropharmacology Laboratory, Massachusetts Mental Health Center, Boston, Massachusetts

Electrical stimulation of the hypogastric nerve of the guinea-pig vas deferens preparation (5-V intensity; 25 pulses/sec; 5-msec pulse duration; 5sec/min for 60 min) results in increased synthesis of H³-norepinephrine from H³-tyrosine during nerve stimulation. When the program of stimulation is prolonged to 30 sec/min, a significant further increase in norepinephrine synthesis is obtained. Continuous stimulation is a less potent stimulus to norepinephrine synthesis. Contractile responses are greatest with 5 sec/min stimulation and least with continuous stimulation. Synthesis of norepinephrine also is increased in the hour following the 30 sec/min stimulation program, but not after the 5 sec/min or the continuous stimulation programs. Norepinephrine, 6 x 10^-6 M, in the medium during stimulation does not inhibit the increased norepinephrine synthesis demonstrable in the poststimulation period. Puromycin, 1.8 X 10^-4 M, both partially inhibits norepinephrine synthesis from tyrosine in the unstimulated preparation and abolishes the increased norepinephrine synthesis of the poststimulation period. The enhanced norepinephrine synthesis during stimulation is not prevented by puromycin. Pretreatment of animals with cortisol does not affect the increased rate of norepinephrine synthesis associated with nerve stimulation. The results indicate that there are at least two distinct mechanisms for the regulation of norepinephrine synthesis by nerve stimulation: 1) enhanced norepinephrine synthesis during nerve stimulation which presumably results from diminution of end-product feedback inhibition; 2) increased norepi-nephrine synthesis which is demonstrable after nerve stimulation and which may involve either induced synthesis or reduced degradation of tyrosine hydroxylase and perhaps other biosynthetic enzymes.