Species and structural specificity of the lipopigment accumulation and neuronal destruction induced by N-(2-guanidinoethyl)-4-methyl-1,2,5,6-tetrahydropyridine (guanacline).
Guanacline, a guanidinium adrenergic neuron blocking agent similar to guanethidine, was studied clinically and experimentally during the late 1960s. Like guanethidine, it has been reported to produce sympathetic neuronal destruction in rats. Unlike guanethidine, it has been reported to produce irreversible sympathetic deficits in man and to produce fluorescent lipopigment in rat sympathetic neurons. Guanacline and its derivative in which the double bond of the tetrahydropyridine ring is reduced (saturated analog of guanacline, SAG) were prepared. Several species were treated chronically with varying doses of guanethidine, guanacline or SAG; the superior cervical ganglia were examined light microscopically for neuronal destruction and for osmiophilic fluorescent lipopigment accumulation. All 3 drugs produced rapid neuronal destruction in rats accompanied by massive small-cell infiltration. In striking contrast, treatment for many weeks with doses up to 100 mg/kg/day produced no small-cell infiltration or apparent neuronal destruction in mice or guinea pigs. The neuronal destruction produced by guanacline and SAG in the rat, like that caused by guanethidine, was prevented by immunosuppression or gamma-irradiation, indicating that all 3 agents produce neuronal destruction in rats by an immune-mediated mechanism. Thus, the ability of the drug to produce sympathectomy is species specific but not drug specific. The opposite was found with respect to fluorescent lipopigment accumulation. Guanacline, but not guanethidine or SAG, produced fluorescent lipopigment in all species examined. Therefore, the double bond of the tetrahydropyridine ring plays a critical role in the production of the fluorescent lipopigment.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D006224:Cricetinae; D005728:Ganglia, Sympathetic / Q000378:metabolism*; D006145:Guanethidine / Q000378:metabolism; D006146:Guanidines / Q000378:metabolism / Q000494:pharmacology*; D006168:Guinea Pigs; D007166:Immunosuppressive Agents; D051379:Mice; D010860:Pigments, Biological / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013563:Sympathectomy, Chemical; D013565:Sympatholytics / Q000494:pharmacology*
D006146:Guanidines; D007166:Immunosuppressive Agents; D010860:Pigments, Biological; D013565:Sympatholytics; C004943:guanacline; C050595:N-(2-guanidinoethyl)-4-methylpiperidine; D006145:Guanethidine