PT  - JOURNAL ARTICLE
AU  - L Cubeddu
AU  - N Weiner
TI  - Nerve stimulation-meditated overflow of norepinephrine and dopamine-beta-hydroxylase. III. Effects of norepinephrine depletion on the alpha presynaptic regulation of release.
DP  - 1975 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1--14
VI  - 192
IP  - 1
4099  - http://jpet.aspetjournals.org/content/192/1/1.short
4100  - http://jpet.aspetjournals.org/content/192/1/1.full
SO  - J Pharmacol Exp Ther1975 Jan 01; 192
AB  - A frequency-dependent increase in the overflow of norepinephrine (NE), 3-H-NE, total 3-H and dopamine-beta-hydroxylase (DBH) activity per nerve impulse was obtained after electrical stimulation of the isolated, perfused cat spleen. Over the range of frequencies studied, a proportional increase in the overflow of transmitter and DBH activity was observed, suggesting that an increase in the exocytotic release of NE is the primary mechanism by which the overflow of transmitter is enhanced with increasing frequencies of stimulation. The effects of 3 muM phenoxybenzamine (PBA) on the nerve stimulation-mediated overflow of NE, total 3-h, 3-h-ne and DBH activity were studied at two frequencies of stimulation, 1 and 5 Hz, in spleens from control and alpha-methyl-p-tyrosine-treated cats. Similarly, release of DBH activity was studied in spleens of reserpine-treated cats. In spleens from control cats, PBA produced a marked increase in the overflow of transmitter and DBH activity. This enhancement was more pronounced at 5 Hz than at 1 Hz. It was estimated that only 10 and 25% of the overflow of NE obtained in the presence of PBA at 1 and 5 Hz, respectively, could be accounted for by increased exocytosis. Depletion of tissue NE (80%) by pretreatment with alpha-methyl-p-tyrosine considerably reduced the effectiveness of PBA in enhancing the nerve stimulation-mediated overflow of NE, 3-H-NE, total 3-H and, particularly, of DBH activity. After reserpine treatment, the tissue NE content was reduced by more than 99%, yet the nerve stimulation-mediated release of DBH activity was similar to control spleens. PBA failed to enhance the nerve stimulation-mediated overflow of DBH activity after reserpine treatment. Thus it appears that the enhancement in the exocytotic release of transmitter by nerve stimulation observed in the presence of PBA is related to the concentration of NE in the synaptic space. Therefore, the present study is in favor of the notion that presynaptic alphareceptors may form part of a negative feedback control mechanism by which the transmitter may inhibit its own release.