Abstract Amiloride, an inhibitor of Na +/H + exchange, inhibited down-regulation of protein kinase C in HL60 cells induced by tumor-promoting phorbol ester in dose-dependent manner judging from immunoblot analysis. This inhibition was observed with regard to type I (γ), type II (β), and type III (α) isozymes of protein kinase C. On the other hand, monensin, a Na + ionophore, accelerated the down-regulation of protein kinase C induced by phorbol ester. When we examined 22Na + uptake by HL60 cells, the higher uptake was observed after stimulation with phorbol ester compared to the control cells and this 22Na + uptake was strongly inhibited by the addition of amiloride. However, monensin further stimulated the 22Na + uptake observed in phorbol ester-treated cells. These data suggest that the increase in intracellular Na + concentration may be one of the triggers for the induction of down regulation of protein kinase C.