Modulation of protein kinase C produces glucose-dependent alterations in hemodynamics and metabolism in the perfused liver in fasted rats.
Protein kinase C (PKC) has been suggested to be involved in the regulation of hepatic blood flow and metabolism. To confirm the role of PKC, we studied the effects of active and inactive PKC modulators on hemodynamics and metabolism in the perfused rat liver. In addition, the influence of glucose concentration in the medium was studied. The liver was isolated from fasted Sprague-Dawley rats and perfused through the portal vein at a constant pressure of 12 cm H2O. 4 alpha-Phorbol 12,13-didecanoate, an inactive phorbol ester for PKC, slightly decreased hepatic flow only when its initial concentration was raised to 20 microM. In contrast, 4 beta-phorbol 12,13-didecanoate, an active phorbol ester for PKC, at initial concentrations of 80 nM to 1.28 microM decreased hepatic flow and oxygen consumption in a dose-dependent manner, and increased lactate production. HA-1004, a relatively inactive PKC inhibitor, at an initial concentration of 33 microM did not modify the effects of phorbol 12-myristate 13-acetate (PMA), a potent PKC activator. However, H-7, a relatively specific PKC inhibitor, at a concentration of 33 microM attenuated the effects of PMA. The effects of PMA were enhanced by an increase in n-glucose concentration from 10 to 25 mM but not by an increase in L-glucose concentration. These results suggest that modulation of PKC exerts glucose-dependent influences on hepatic flow and metabolism.
Inaba
H
H
Department of Anesthesiology, Chiba University School of Medicine.
Araki
M
M
Kon
S
S
Imai
M
M
Mizuguchi
T
T
D000818:Animals; D005215:Fasting / Q000378:metabolism*; D005947:Glucose / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D007546:Isoquinolines / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D010477:Perfusion; D010703:Phorbol Esters / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D007546:Isoquinolines; D010703:Phorbol Esters; D013449:Sulfonamides; C008876:phorbol-12,13-didecanoate; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D011493:Protein Kinase C; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate