title: Augmentation of endotoxic lethality and glucose dyshomeostasis by phorbol ester.
abstract: To investigate the role of protein kinase C (PKC) activation in the pathogenesis of endotoxin (ETX) shock, the in vivo effects of phorbol 12-myristate 13-acetate (PMA) on ETX-induced lethality and glucose dyshomeostasis were determined. Fed rats (300-400 g) were treated intravenously with incremental doses of Salmonella enteritidis ETX and either the vehicle, 110 mg/kg ip dimethyl sulfoxide (DMSO), or 0.5 mg/kg ip PMA dissolved in DMSO. PMA significantly increased ETX-induced lethality to doses of 1.0-20 mg/kg. PMA augmented the initial hyperglycemia, late hypoglycemia, and hyperlactacidemia after 1 mg/kg iv ETX to rats anesthetized with pentobarbital sodium. In contrast, 4 alpha-phorbol, a phorbol derivative that does not activate PKC, had no effect on either lethality or the glucose and lactate responses. Hyperinsulinemia after 1 mg/kg iv ETX was prolonged by PMA but not by 4 alpha-phorbol. Insulin tolerance testing (0.5 U/kg iv) produced an exaggerated hypoglycemic response in PMA-treated endotoxic (0.33 mg/kg) rats. Glucose tolerance to 1.2 g/kg iv was increased by ETX and PMA attenuated the increased tolerance. Thus PKC activation may be involved in the pathogenesis of lethal endotoxicosis and associated glucose dyshomeostasis.
authors.affiliation: Department of Physiology, Loyola University Chicago Medical Center, Maywood, Illinois 60153.
authors.forename: H
authors.initials: H
authors.lastname: Inaba
authors.forename: J P
authors.initials: JP
authors.lastname: Filkins
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis*; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007773:Lactates / Q000097:blood; D019344:Lactic Acid; D008297:Male; D051381:Rats; D012772:Shock, Septic / Q000097:blood / Q000503:physiopathology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D007773:Lactates; D019344:Lactic Acid; D013755:Tetradecanoylphorbol Acetate