ROLE OF PROTEIN-KINASE-C IN THE ALPHA(1)-ADRENOCEPTOR-MEDIATED RESPONSES OF PERFUSED-RAT-LIVER

The present work aimed to determine the role played by protein kinase- C (PKC) in the alpha1-adrenoceptor-induced activation of hepatic metab olism. The following observations indicate that activation of PKC is a condition necessary for alpha1-adrenoceptor activation of hepatic fun ctions, but not sufficient to mimic the receptor-mediated effects in t he absence of external physiological stimuli. 1) alpha1-Adrenoceptor a ctivation promoted the translocation of PKC from the cytosol to its ac tive form in the plasma membrane. 2) Activation of PKC by the phorbol ester 12-myristate 13-acetate or exogenous diacylglycerols or by eleva tion of endogenous levels of diacylglycerols by inhibiting diacylglyce rol kinase mimicked the alpha1-adrenoceptor-mediated actions. However, the time course and magnitude of the nonreceptor responses differ fro m those mediated by alpha1-adrenoceptor activation. In addition, nonre ceptor-mediated activation of PKC decreased the alpha1-adrenoceptor re sponsiveness. 3) Inhibition of PKC by either H-7 [1-(5-isoquinolinilsu l-fonyl)2-methylpiperazine] or staurosporine inhibited all of the alph a1-adrenoceptor-induced responses, except gluconeogenesis. The vasopre ssin effects were not inhibited by H-7, indicating that PKC activation is a distinct feature of the hepatic al-adrenoceptor activation that is not shared by all the Ca2+-mobilizing agonists. The diacylglycerol- PKC branch of the al-adrenoceptor signaling pathway seems to control t he sustained phase of stimulation of hepatic functions. In these studi es we have also observed that phorbol 12-myristate 13-acetate produces a concentration-dependent inhibition of hepatic respiration. However, decreased energy availability does not seem to be the cause of its ac tion to decrease alpha1-adrenoceptor responsiveness.