Chemical sympathectomy by guanidinium adrenergic neuron blocking agents

Abstract

Chronic administration of high doses of the adrenergic neuron blocking agent, guanethidine, to neonatal or adult rats produces destruction of the sympathetic nervous system (sympathectomy). Although the mechanism of cytotoxicity is not established, it has been proposed to be due to inhibition of oxidative phosphorylation, an activity of guanethidine which has been demonstrated in vitro in isolated mitochondria. In this study, 40 guanidinium adrenergic neuron blocking agents were examined for cytotoxic effects on sympathetic neurons when administered chronically to neonatal rats. The ability of many of the compounds to concentrate in sympathetic neurons was determined, using, in most cases, an assay based on the development of a phenanthrenequinone derivative. The ability of several of the compounds to inhibit oxidative phosphorylation in isolated rat liver mitochondria was also determined. The results show that only a few compounds, very similar in structure to guanethidine, are cytotoxic in vivo. Only compounds very similar to guanethidine accumulate to high concentrations in the neuronal cell bodies, and this may explain the lack of toxicity of some compounds. However, compounds were found, particularly Pharmacia 881/7, which accumulate in the cell body but are not cytotoxic. In isolated mitochondria, Pharmacia 881/7 was ten times more potent than guanethidine as an inhibitor of oxidative phosphorylation. Some compounds which were cytotoxic in vivo produced little or no inhibition of oxidative phosphorylation. These data indicate that inhibition of oxidative phosphorylation is not the mechanism by which guanethidine destroys sympathetic neurons.