Guanethidine-Induced Destruction of Sympathetic Neurons: An Autoimmune “Disease” Prevented by Nerve Growth Factor

Abstract

Guanethidine, the structure of which is shown in Fig. 1, is a guanidinium adrenergic-neuron-blocking agent. It is the prototype of this class of drugs that act to reduce the efficacy of sympathetic neurotransmission primarily by dissociating the action potential from the secretion of the neurotransmitter norepinephrine (NE). By virtue of its ability to block NE release, it lowers blood pressure, and has thus been used clinically as an antihypertensive agent since the 1960s. In 1971, it was demonstrated by Burnstock et al. (1971), Eränkö and Eränkö (1971), and Jensen-Holm and Juul (1971) that chronic treatment of rats with high doses of guanethidine (about 10 times that needed to produce adrenergic-neuron blockade) resulted in the destruction of sympathetic neurons in both neonatal and adult animals. The destruction was selective for sympathetic neurons; other neurons such as sensory or parasympathetic neurons were not affected. The basis for this selectivity arises from the ability of guanethidine to accumulate to high concentrations in sympathetic neurons via the catecholamine (CA)-uptake pump as the neuronal destruction is prevented by an inhibitor of this uptake mechanism, desmethylimipramine (Juul and Sand, 1973). It is excluded from neurons that lack this active-uptake mechanism because it is a highly charged guanidinium compound.