Modification of hepatic protein kinase C with phorbol myristate acetate and staurosporine alters hemodynamics in the perfused rat liver.

Activation of protein kinase C (PKC) has been implicated in the pathogenesis of endotoxicosis and severe sepsis. Since hepatic blood flow and metabolism have been known to be altered in endotoxicosis and sepsis, we studied the hemodynamic effect of PKC modulation with phorbol 12-myristate 13-acetate (PMA) and staurosporine (St) on the perfused rat liver. The liver was isolated from overnight-fasted male Sprague-Dawley rats and placed in a recirculating perfusion apparatus. The liver was perfused with Krebs-Ringer-bicarbonate solution at a constant pressure of 12 cmH2O. Flow to the liver was continuously monitored with an electric magnetic flowmeter. PMA at an initial concentration of 2 x 10(-8) M significantly decreased hepatic flow. Staurosporine (St), a potent PKC inhibitor at 4 x 10(-7) M produced a small increase in hepatic flow. Pretreatment with St significantly attenuated the flow reduction by PMA. St significantly suppressed the flow reductions by 4 x 10(-6) M of prostaglandin E2 and D2. These results suggest that the PKC inside the liver may play an important role in the regulation of hepatic blood flow during endotoxicosis and sepsis.