Abstract
After a brief period of low frequency nerve stimulation, a proportional release of norepinephrine (NE), dopamine-β-hydroxylase activity (DBH) , total 3H and 3H-NE was obtained from the isolated perfused cat spleen over a wide range of transmitter release. Approximately 30% of the increase in the overflow of total 3H was recovered as 3H-metabolites, largely as 3H-dihyclroxyphenlylethyleneglycol (3H-DOPEG). Cocaine (0.03-3µM) enhanced the outflow of NE and 3H-NE and increased pressure responses; however, it failed to increase the overflow of total 3H and produced a decrease in the overflow of DBH and 3H-DOPEG When the formation of 3H-DOPEG was markedly inhibited there was a reduction in the formation of 3H-O-methylated deaminated metabolites. These results Support the view that 3H-DOPEG is formed presynaptically after recapture of the NE released by nerve stimulation and that part of the glycol can be further O-methylated by extraneuronal enzymes. The present results also suggest that, although neuronal uptake is an effective mechanism to decrease the concentration of NE in the synaptic space. it does not appear to he highly coupled with subsequent storage of the recaptured amine. Phenoxyhenzamine and phentolamine produced concentration-dependent inhibition of pressure responses and enhanced the nerve stimulation-mediated overflow of NE,3H-NE, total 3H and DBH activity. Higher concentrations of phenoxybenzamine (0.3 µM) markedly inhibited the formation of 3H-DOPEG and a still higher concentration (3 µM) completely prevented the metabolism of 3H-NE released by nerve stimulation. Phenoxyhenzamine was at least 10 times more potent and also more effective than phentolamine in enhancing the outflow of NE and DBH by nerve stimulation. Both phenoxybenzamine and phentolamine were more effective in inhibiting alpha postsynaptic than alpha presynaptic receptors, as judged by their potencies in blocking pressure responses and in enhancing nerve stimulation release of NE and DBH, suggesting that either differences in pre-and postsynaptic alpha receptors may exist or there may be a greater preponderance of spare receptors at the presynaptic sites.
Footnotes
- Received December 24, 1973.
- Accepted May 1, 1974.
- © 1974 by The Williams & Wilkins Co.
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