Guanethidine-induced destruction of peripheral sympathetic neurons occurs by an immune-mediated mechanism.

Guanethidine, a guanidinium adrenergic neuron blocking agent, when administered chronically at high doses to newborn or adult rats, causes destruction of peripheral sympathetic neurons. Neuronal destruction is preceded by small cell infiltration of the sympathetic ganglia and is suggestive of an immunologically mediated mechanism. Immune reconstitution experiments were carried out to demonstrate that guanethidine-induced neuronal destruction occurs by an immunologically mediated mechanism. To determine the dose of irradiation necessary to protect against neuronal cell death induced by guanethidine, 3-week-old Lewis rats were treated with either 600, 750, or 900 rads of y-irradiation 6 hr prior to the initiation of guanethidine treatment. Rats received 50 mg/kg of guanethidine sulfate for 5 days, were killed 2 days later, and the superior cervical ganglia were dissected for assay of tyrosine hydroxylase activity and for light microscopic evaluation. Irradiation protected against guanethidine-induced destruction in a dose-related manner, with virtually complete protection afforded by doses of 900 rads. Adoptive transfer recipients were irradiated with 850 rads immediately prior to cell transfer. Adoptive transfer experiments involved four groups of animals: group A (guanethidine only); group B (irradiated only); group C (irradiated + guanethidine); and group D (irradiated + guanethidine + syngeneic spleen and bone marrow cells). By light microscopic examination, sympathetic ganglia from animals in groups B and C were normal, whereas ganglia from animals in group A showed the usual marked small cell infiltration and neuronal destruction. Animals in group D, in contrast to group C, showed clear small cell infiltration of the ganglia and neuronal destruction. In addition, tyrosine hydroxylase activity was significantly reduced in group D compared to groups B and C. By ultrastructural analysis, the cellular infiltrate within the ganglia of guanethidine-treated rats consists of small lymphocytes, activated lymphocytes, macrophages, and polymorphonuclear leukocytes. T lymphocytes, responsible largely for cell-mediated immune responses, were identified immunohistochemically within ganglia of treated animals. These results indicate that the small cell infiltration and neuronal destruction due to guanethidine treatment involve an immune-mediated component. Guanethidine is a guanidinium adrenergic neuron destruction of sympathetic neurons seems to be due to blocking agent used clinically as an antihypertensive the selective accumulation of guanethidine within this agent. The chronic administration of high doses of guacell type. Guanethidine does not accumulate in other cell nethidine to either newborn or adult rats, but not to types (i.e., sensory neurons) nor does it cause their deother species, causes destruction of peripheral sympastruction (Burnstock et al., 1971; Eranko and Eranko, thetic neurons (i.e., sympathectomy). The specificity for 1971; Jensen-Holm and Juul, 1971). Several mechanisms have been proposed to account ’ Part of the results were presented in abstract form at the annual for the cytotoxic effects of guanethidine, including the meeting of the Society for Neuroscience, October 1981. This work was inhibition of oxidative phosphorylation (Heath et al., supported by National Institutes of Health Grants HL-20604 and AM1972; Johnson and Aloe, 1974), the inhibition of the 19645 and Cardiovascular Training Grant 5-T32-HL-07275. P. T. M. is retrograde transport of nerve growth factor (NGF) an American Heart Association, Missouri, Affiliate Fellow. E. M. J. is (Johnson, 1978), and the inhibition of polyamine biosynan Established Investigator of the American Heart Association. thesis (Johnson and Taylor, 1980). However, none of * To whom correspondence should be addressed. these explanations seems to be responsible for the neu-