RELEASE OF NOREPINEPHRINE AND DOPAMINE--HYDROXYLASE BY NERVE STIMULATION. II. EFFECTS OF PAPAVERINE

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

Papaverine, at a concentration which inhibits spleen phosphodiesterase activity (PDE), produces a marked increase in the nerve stimulation-mediated overflow of norepinephrine (NE), ³H-NE, total ³H and dopamine--hydroxylase (DBH) activity from the isolated, perfused cat spleen which had been prelabeled with ³H-NE. Spontaneous outflow of total ³H recovered as ³H-3,4-dihydroxyphenylethyleneglycol is also increased by papaverine. A positive, highly significant correlation between spontaneous release of total ³H and nerve stimulation-mediated release of both total ³H and DBH was observed. The increase in the nerve stimulation-mediated overflow of NE and DBH obtained with 0.1 mM papaverine was several-fold larger than that observed in the presence of the PDE inhibitors, 1-methyl-3-isobutylxanthine (MIX) or 4(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (BMI) (Ro 20-1724). In addition, neither MIX nor BMI enhanced the spontaneous outflow of ³H-deaminated metabolites. Pretreatment with MIX (0.5 mM) or BMI (0.5 mM) did not prevent papaverine effects either on the outflow of ³H-3, 4-dihydroxyphenylethyleneglycol or on the nerve stimulation-mediated outflow of NE and DBH activity. These results indicate that accumulation of 3', 5'-cyclic adenosine monophosphate subsequent to inhibition of PDE activity by papaverine probably accounts for only part of the enhanced release of NE and DBH by nerve stimulation. Since the enhanced spontaneous release of ³H and the enhanced release of neurotransmitter associated with nerve stimulation are highly correlated, the results suggest that a direct effect of papaverine on the synaptic vesicles and its effect on the nerve stimulation-mediated release of NE and DBH could be related.