Antagonism of bromobenzene-induced hepatotoxicity by the alpha-adrenoreceptor blocking agents phentolamine and idazoxan: role of hypothermia.
A recent study from our laboratory revealed that cotreating mice with the alpha-adrenoreceptor antagonists phentolamine and idazoxan markedly diminished bromobenzene-induced hepatotoxicity. Subsequent studies also revealed that such cotreatment does not alter the pharmacokinetic disposition of bromobenzene in mice nor its bioactivation to reactive metabolites. In the present study, the possible role of hypothermia in the phentolamine antagonism of bromobenzene-induced hepatotoxicity was investigated. Bromobenzene alone caused a significant, dose-related hypothermia. The high dosage regimen (10 mg/kg per dose) of phentolamine or idazoxan that had been found to be hepatoprotective in earlier studies potentiated this hypothermia and more than doubled the net decrease in core body temperature experienced by the animals. Placing mice receiving bromobenzene in an environment with an ambient temperature of 10 degrees C likewise increased the hypothermia experienced by animals receiving bromobenzene. The magnitude of the net change in core body temperature elicited by exposure to cold was similar to but slightly less than the net change produced by cotreatment with either alpha-adrenoreceptor antagonist and the magnitude of the hepatoprotection this procedure provided against bromobenzene hepatotoxicity was equivalent to that observed with phentolamine cotreatment. In contrast, a lower dosage regimen of either adrenoreceptor antagonist (2.5 mg/kg per dose) resulted in no additional hypothermia yet still produced a near maximal antagonism of bromobenzene-induced hepatotoxicity. Further, increasing the ambient temperature to 30 degrees C completely reversed the phentolamine-induced (10 mg/kg per dose) increase in hypothermia, but did not affect phentolamine's antagonism of the bromobenzene-induced changes in hepatic glutathione levels, serum alanine aminotransferase activity, or 24-hr mortality. Therefore, we conclude that while the hepatoprotective intervention of phentolamine can be mimicked by an exposure to cold that results in hypothermia, it is clear that alpha-adrenergic antagonists diminish the hepatotoxicity induced by bromobenzene by a mechanism that is independent of hypothermia.
Kerger
B D
BD
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock 72205.
Roberts
S M
SM
Harbison
R D
RD
James
R C
RC
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001831:Body Temperature / Q000187:drug effects*; D001969:Bromobenzenes / Q000633:toxicity*; D004146:Dioxanes / Q000494:pharmacology*; D004147:Dioxins / Q000494:pharmacology*; D019329:Idazoxan; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010646:Phentolamine / Q000494:pharmacology*; D013564:Sympathetic Nervous System / Q000502:physiology
D000317:Adrenergic alpha-Antagonists; D001969:Bromobenzenes; D004146:Dioxanes; D004147:Dioxins; C032036:bromobenzene; D019329:Idazoxan; D010646:Phentolamine