THE RELATIONSHIPS BETWEEN ALPHA RECEPTOR BLOCK, INHIBITION OF NOREPINEPHRINE UPTAKE AND THE RELEASE AND METABOLISM OF ³H-NOREPINEPHRINE

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

The effects of alpha receptor block and inhibition of neuronal uptake on the release and metabolism of ³H-norepinephrine (³H-NE) were evaluated in the isolated, perfused cat spleen. Phenoxybenzamine and phentolamine are more potent as blockers of the alpha receptor than as inhibitors of the uptake of L-³H-NE. Cocaine and phenoxybenzamine are equipotent in inhibiting removal of ³H-NE ; phentolamine is approximately 100 times less potent. At least a 30-fold greater concentration of both phenoxybenzamine and cocaine is required to induce release of ³H-NE than is required to inhibit uptake of the catecholamines. The concentration of phentolamine which increases the spontaneous efflux of total ³H is identical to that required to inhibit neuronal uptake of NE. ³H-3,4-dihydroxyphenylethyleneglycol represents nearly 60% of the total spontaneous efflux of radioactivity from spleens previously labeled with L-³H-NE. ³H-3,4-dihydroxymandelic acid constitutes less than 4% of the total radioactivity. Selective inhibition of neuronal uptake of NE affects the metabolite pattern of spontaneously released ³H-NE only by producing a slight increase in the percentage of unchanged NE in the effluent. It therefore appears that most of the ³H-3,4-dihydroxyphenylethyleneglycol which is released spontaneously is formed from ³H-NE which leaks from the granules into the cytoplasm of the nerve ending and which is deaminated by intraneuronal monoamine oxidase. The O-methylated NE metabolites presumably arise from extraneuronal O-methylation of ³H-NE and the ³H-deaminated metabolites of NE, since there is a selective decrease in the proportion of these metabolites when concentrations of phenoxybenzamine or phentolamine known to inhibit extraneuronal uptake are perfused through the spleen.