The bradycardic and mydriatic effects of chlordimeform and its demethylated analogs in the rat: antagonism by idazoxan but not by prazosin.
Pupillary and cardiac responses to i.v. injections of chlordimeform (CDM, 0.3-10 mg/kg), a formamidine insecticide, and its metabolites demethylchlordimeform (DCDM, 0.03-1 mg/kg) and didemethylchlordimeform (DDCDM, 0.1-3 mg/kg) were studied in rats anesthetized with pentobarbital. Both CDM and DCDM induced a dose-dependent mydriasis and bradycardia and DCDM was 10 times more potent than CDM in causing these effects. In contrast, DDCDM did not induce a mydriasis or bradycardia. The alpha 2-adrenoreceptor antagonist, idazoxan (0.2 mg/kg, i.v.) abolished or reduced CDM- and DCDM-induced mydriasis and bradycardia, whereas the alpha 1-adrenoreceptor antagonist, prazosin (1.5 mg/kg, i.v.) did not change these effects of CDM and DCDM. SKF 525-A (50 mg/kg, i.p.), an inhibitor of enzymatic demethylation, administered 10 min before the first dose of CDM, failed to reduce the effects of CDM. The results suggested: 1) the mydriatic and bradycardic effects of CDM and DCDM are mediated by alpha 2-adrenoreceptors, 2) the monodemethylation of CDM increases its alpha 2-adrenoreceptor agonistic activities, but the didemethylation of CDM abolishes these activities, and 3) CDM can exert alpha 2-adrenoreceptor agonistic activities without undergoing a demethylation process.
Hsu
W H
WH
Department of Veterinary Physiology and Pharmacology, Iowa State University, Ames 50011.
Smith
B E
BE
Hollingworth
R M
RM
D000578:Amidines / Q000494:pharmacology*; D000818:Animals; D002742:Chlorphenamidine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004146:Dioxanes / Q000494:pharmacology*; D004147:Dioxins / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects*; D019329:Idazoxan; D007306:Insecticides; D008297:Male; D008745:Methylation; D011224:Prazosin / Q000494:pharmacology*; D011335:Proadifen / Q000494:pharmacology; D011680:Pupil / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology; D013329:Structure-Activity Relationship
D000578:Amidines; D004146:Dioxanes; D004147:Dioxins; D007306:Insecticides; D011942:Receptors, Adrenergic, alpha; C011741:demethylchlordimeform; C042787:N,N-didemethylchlordimeform; D011335:Proadifen; D002742:Chlorphenamidine; D011224:Prazosin; D019329:Idazoxan