Modulation of protein kinase C alters hemodynamics and metabolism in the isolated liver in fed and fasted rats.
The activation of protein kinase C (PKC) has been implicated in the pathogenesis of gram-negative sepsis. The effects of PKC modulation on hepatic flow and metabolism were studied using isolated liver perfusion. The liver was isolated from well-fed or overnight-fasted, male Sprague-Dawley rats weighing 250-310 g, and perfused at a constant pressure of 12 cmH2O using a recirculating system. Phorbol 12-myristate 13-acetate (PMA), a potent activator of PKC, decreased hepatic flow and oxygen consumption, and increased net lactate production. It enhanced net glucose production in fed animals. Neither 4 alpha-phorbol didecanoate, an inactive phorbol ester for PKC nor 4 alpha-phorbol, an inactive phorbol had any significant effect. The effects of PMA were augmented by increasing calcium concentration in the medium. PMA at an initial concentration of 4 x 10(-8) M stimulated net lactate and/or glucose production more than a reduction of perfusion pressure from 12 to 6 cmH2O. Staurosporine, a potent PKC inhibitor, significantly attenuated the PMA-induced alterations of hepatic flow and oxygen consumption. These results indicate that modulation of PKC exerts significant effects on hepatic flow and metabolism, which are dependent on extracellular calcium concentrations and feeding conditions, and that the effect of PMA on carbohydrate metabolism is not merely attributed to decreases in hepatic flow and oxygen consumption. It is suggested that PKC activation may be involved in the alterations of hepatic flow and metabolism during severe sepsis.
Inaba
H
H
Department of Anesthesiology, Chiba University School of Medicine, Japan.
Araki
M
M
Numai
T
T
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D004789:Enzyme Activation; D005215:Fasting; D005502:Food; D006439:Hemodynamics / Q000502:physiology*; D066298:In Vitro Techniques; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects / Q000201:enzymology*; D008102:Liver Circulation / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000502:physiology; D010477:Perfusion; D010703:Phorbol Esters; D010704:Phorbols; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000470:Alkaloids; D010703:Phorbol Esters; D010704:Phorbols; C008876:phorbol-12,13-didecanoate; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; C033085:phorbol