AJP - Regulatory, Integrative and Comparative Physiology, Vol 260, Issue 3 494-R502, Copyright © 1991 by American Physiological Society
Augmentation of endotoxic lethality and glucose dyshomeostasis by phorbol ester
H. Inaba and J. P. Filkins
Department of Physiology, Loyola University Chicago Medical Center, Maywood, Illinois 60153.
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.
