Inhibitors of protein kinase C block the alpha 1-adrenergic refractoriness induced by phorbol 12-myristate 13-acetate, vasopressin and angiotensin II.
Vasopressin and angiotensin II inhibited in a dose-dependent fashion the stimulation of ureagenesis induced by alpha 1-adrenergic activation in hepatocytes incubated in medium without calcium and containing 25 microM EGTA. Vasopressin was more potent than angiotensin II. The effect of different inhibitors of protein kinase C on the alpha 1-adrenergic blockade induced by the vasopressor peptides was tested. It was observed that N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W-7), 4-aminoethyl-1-[2,3-bis(n-decloxyl)-n-propyl]-4-phenylpiperadin e dihydrochloride (CP-46,665-1); 8-(N,N-diethylamino)octyl-3,4, 5-trimethoxybenzoate (TMB-8), polymyxin B and 1-(5-isoquinolynsulfonyl)-2-methylpiperazine (H-7) block this effect of the vasopressor peptides in a dose-dependent fashion. The active phorbol ester, phorbol 12-myristate 13-acetate (PMA), also inhibited the alpha 1-adrenergic stimulation of ureagenesis in these cells. The inhibitors of protein kinase also blocked the effect of phorbol esters but a preincubation with the inhibitors before the addition of PMA was required. alpha 1-Adrenergic activation of phosphatidylinositol labeling was also abolished by PMA; the inhibitors of protein kinase partially blocked this effect of PMA. In summary, our data indicate that inhibitors of protein kinase C can block the alpha 1-adrenergic refractoriness induced by active phorbol esters, vasopressin and angiotensin II. The data are consistent with an important role of protein kinase C in modulating the alpha 1-adrenergic responsiveness of hepatocytes.
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D005260:Female; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors*; D014508:Urea / Q000096:biosynthesis; D014667:Vasopressins / Q000037:antagonists & inhibitors*
D010716:Phosphatidylinositols; D011942:Receptors, Adrenergic, alpha; D014667:Vasopressins; D000804:Angiotensin II; D014508:Urea; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate