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Journal of Pharmacology And Experimental Therapeutics, Vol. 186, Issue 1, 75-85, 1973
Copyright © 1973 by American Society for Pharmacology and Experimental Therapeutics

FURTHER STUDIES ON THE INCREASED SYNTHESIS OF NOREPINEPHRINE DURING NERVE STIMULATION OF GUINEA-PIG VAS DEFERENS PREPARATION: EFFECT OF TYROSINE AND 6,7-DIMETHYLTETRAHYDROPTERIN

G. CLOUTIER 1 and N. WEINER 1

1 Department of Pharmacology, University of Colorado School of Medicine, Denver, Colorado

Norepinephrine synthesis from tyrosine, but not from dihydroxyphenylalanine, is increased approximately 60% during intermittent stimulation of the hypogastric nerve of the vas deferens preparation of the guinea pig. The effect is at least partially abolished by addition of norepinephrine to the medium. Norepinephrine accumulation is not significantly affected by intermittent nerve stimulation. Kinetic analysis indicates that the effect of nerve stimulation on norepinephrine synthesis from tyrosine in the intact tissue is not competitively antagonized by either 6,7-dimethyltetrahydropterin (DMPH4) or tyrosine. The Km for tyrosine and that for DMPH4 are unaffected by nerve stimulation, whereas the Vmax for DMPH4 is increased approximately 2-fold and that for tyrosine is increased to a similar degree in the stimulated preparation. In contrast, the inhibitory effect of norepinephrine on tyrosine hydroxylase activity in the intact preparation is competitively antagonized by DMPH4. These results suggest that the enhanced synthesis of norepinephrine from tyrosine associated with nerve stimulation is not due to a reduction in end-product feedback inhibition of tyrosine hydroxylase which is competitive with the pterin cofactor. Tyrosine hydroxylase may be activated during nerve stimulation either by an as yet unknown positive allosteric effector or by a diminution in the level of catecholamine or a negative allosteric effector which does not compete with the pteridine co-factor for an allosteric site on the enzyme. Recent studies of Gutman and Segal (Biochem. Pharmacol. 21: 2664-2666, 1972) suggest that Na+ or Ca++ may affect tyrosine hydroxylase activity. It is possible that an influx of these cations during nerve stimulation is responsible for the observed increase in catecholamine synthesis.

Submitted on November 6, 1972
Accepted on February 26, 1973




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