Inhibitors of protein kinase C block the α1‐adrenergic refractoriness induced by phorbol 12‐myristate 13‐acetate, vasopressin and angiotensin II

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Abstract
Vasopressin and angiotensin II inhibited in a dose-dependent fashion the stimulation of ureagenesis unduced by .alpha.1-adrenergic activation in hepatocytes incubated in medium without calcium and containing 25 .mu.M 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-phenylpiperadine 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.

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