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 pa thogenesis of gram-negative sepsis. The effects of PKC modulation on h epatic flow and metabolism were studied using isolated liver perfusion . The liver was isolated from well-fed or overnight-fasted, male Sprag ue-Dawley rats weighing 250-310 g, and perfused at a constant pressure of 12 cmH(2)O using a recirculating system. Phorbol 12-myristate 13-a cetate (PMA), a potent activator of PKC, decreased hepatic flow and ox ygen consumption, and increased net lactate production. It enhanced ne t glucose production in fed animals. Neither 4 alpha-phorbol didecanoa te, 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 pr oduction more than a reduction of perfusion pressure from 12 to 6 cmH( 2)O. Staurosporine, a potent PKC inhibitor, significantly attenuated t he PMA-induced alterations of hepatic flow and oxygen consumption. The se results indicate that modulation of PKC exerts significant effects on hepatic flow and metabolism, which are dependent on extracellular c alcium concentrations and feeding conditions, and that the effect of P MA on carbohydrate metabolism is not merely attributed to decreases in hepatic flow and oxygen consumption. It is suggested that PKC activat ion may be involved in the alterations of hepatic flow and metabolism during severe sepsis.