Effects of Protein Kinase C Modulation on Hepatic Hemodynamics and Glucoregulation

Effects of Protein Kinase C Modulation on Hepatic Hemodynamics and Glucoregulation

<P> This study evaluated the effects of PKC activation using phorbol 12-myristate 13-acetate (PMA) and PKC inhibition using the isoquinoline sulfomide derivative H-7 on hemodynamics and glucoregulation in the isolated perfused rat liver. Livers were isolated from fed male Holtzman rats and perfused with Krebs Ringer bicarbonate solution under a constant flow of 50 ml/min at 35<SUP>o</SUP>C. Portal vein pressure, glucose and lactate concentrations in the medium and oxygen consumption rates were continuously monitored by a Grass polygraph, YSI glucose and lactate monitors, and a YSI oxygen monitor, respectively. PMA at concentration of 2 to 200 nM increased the portal vein pressure, glucose and lactate production, but decreased oxygen consumption rate in a dose-dependent fashion. H-7 (200μM) attenuated PMA (50 nM)- induced vasoconstriction (15.1&#8273;1.36 vs 10.56&#8273;1.17 mmHg), glucose production rate (91.3&#8273;6.15 vs 71.8&#8273;2.50μmoles/g/hr), lactate production rate (72.4&#8273;6.82 vs 53.6&#8273;4.82μmoles/g/hr) and oxygen consumption rate (33.7&#8273;1.41 vs 27.9&#8273;1.75μl/g/min). The effects of PMA were blocked either by addition of verapamil (9μM) or perfusion with Ca<SUP>2&#8290;</SUP>-free KRB. <P> These results suggest that the hemodynamic and glucoregulatory changes in the perfused rat liver are mediated by protein kinase C activation and require Ca<SUP>2&#8290;</SUP> influx from the extracellular fluid.