Molecular Pharmacology, Vol 11, 211-222, Copyright © 1975 by the American Society for Pharmacology and Experimental Therapeutics

Dihydroxytryptamines: Effects on Noradrenergic Function in Mouse Heart in Vivo

¹ National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, Bethesda, Maryland 20014

A variety of tryptamines, including the four isomeric hydroxytryptamines and four isomeric dihydroxytryptamines, inhibit uptake of [³H]norepinephrine into mouse heart in vivo and elicit release of [³H]norepinephrine from cardiac storage sites. -Methyl congeners are more potent releasing agents, except in monoamine oxidase-inhibited mice, where in most cases the parent amines become almost as efficacious. Only 5.7-dihydroxytryptamine and, to a lesser extent, 6,7-dihydroxytryptamine have longterm cytotoxic effects on noradrenergic terminals in heart, as evident in a marked reduction in uptake of [³H]norepinephrine for 5-20 days after exposure to the amines and, for the 5,7-hydroxy-analog, in degenerative changes in the ultrastructure of atrial nerves. Cocaine prevents both [³H]norepinephrine release and the long-term effects of 5,7-dihydroxytryptamine. -Methyl-5,7dihydroxytryptamine does not elicit any long-term effects, nor does the parent amine in animals in which monoamine oxidase has been inhibited. Dihydroxytryptamines undergo autoxidation much more slowly than cytotoxic phenethylamines, such as 6-hydroxy-dopamine, which are autoxidized rapidly. The mechanism involved in the cytotoxic effects of 5,7-dihydroxytryptamine in heart tissue thus contrasts in many aspects with that involved in the action of 6-hydroxy-dopamine.

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ACKNOWLEDGMENT The authors wish to acknowledge the capable assistance of Mrs. M. Cahill.