title: Release of norepinephrine and dopamine-beta-hydroxylase by nerve stimulation. V. Enhanced release associated with a granular effect of a benzoquinolizine derivative with reserpine-like properties.
abstract: A reserpine-like agent, 2-hydroxy-2-ethyl-3-isobutyl-9,10-dimethoxy-1,2,3,4,6,7,-hexa-hydro-11b-H-benzo[a]quinolizine (BQZ), at concentrations that do not inhibit phosphodiesterase activity, produces a marked increase in the outflow of 3-H-dihydroxyphenyl-ethyleneglycol from the isolated, perfused cat slpeen prelabeled with 3-H-norepinephrine (3-H-NE). The increased intraneuronal levels of catechols probably account for the inhibition of the conversion of 1-minus14C-L-tyrosine to 1-minus14C-L-dopa which is observed in the presence of the drug. In addition, in the presence of 0.9 muM BQZ, there is a 2.5- to 3-fold increase in the nerve stimulation-mediated overflow  of NE, 3-H-NE, total 3-H and dopamine-beta-hydroxylase activity. A highly significant positive correlation was observed between the increase in the spontaneous release of 3-H and the enhanced exocytotic release of transmitter by nerve stimulation. These results suggest that either a primary alteration of the storage granule membrane or the subsequent enhanced intraneuronal levels of NE or NE metabolites may be responsible for the enhanced exocytotic release by nerve stimulation. In the presence of 0.9 muM BQZ, addition of 3 muM cocaine produces an increase in the nerve stimulation-mediated overflow of NE and an inhibition of the formation of 3-H-dihydroxyphenylethyleneglycol. In addition, there is a 20 to 30% decrease in the overflow of 3-H and dopamine-beta-hydroxylase activity and a marked delay in the outflow of the enzyme elicited by nerve stimulation. These results suggested that, in the presence of BQZ, a large fraction of the NE released during nerve stimulation is recaptured into the nerve terminals where it is subsequently metabolized to 3-H-dihydroxyphenylethyleneglycol. The enhanced exocytotic release of NE, the extensive presynaptic metabolism of the recaptured transmitter subsequent to release by nerve stimulation, and inhibition of norepinephrine synthesis all appear to contribute to the accelerated depletion of tissue NE which is observed when the splenic nerves are stimulated in the presence of 0.9 muM BQZ. These results provide an explanation for the accelerated depletion of tissue NE in animals treated with reserpine-like compounds when the sympathetic innervation is intact.
mesh_terms: D012369:2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy- / Q000494:pharmacology*; D000818:Animals; D001338:Autonomic Fibers, Postganglionic / Q000502:physiology; D002415:Cats; D003594:Cytoplasmic Granules / Q000187:drug effects*; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism*; D004558:Electric Stimulation; D005260:Female; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D009647:Normetanephrine / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011807:Quinolizines / Q000494:pharmacology*; D012110:Reserpine; D013154:Spleen / Q000166:cytology / Q000201:enzymology / Q000294:innervation / Q000378:metabolism* / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D011807:Quinolizines; D009647:Normetanephrine; D012369:2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-hexahydro-3-isobutyl-9,10-dimethoxy-; D012110:Reserpine; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D010727:Phosphoric Diester Hydrolases; D009638:Norepinephrine