Inhibition of normal human granulopoiesis in vitro by amiloride: evidence for the involvement of facilitated sodium influx in the induction of differentiation.

The formation of colonies by normal human bone marrow granulopoietic progenitor cells in vitro in soft agar was inhibited in a simple, dose-dependent manner by amiloride (50% inhibitory concentration 26.4 +/- 3.4 microM, n = 9). Such inhibition was reversible and is evidence for the involvement of amiloride-sensitive sodium influx in granulopoietic cell proliferation. Colony-forming cells were capable of some proliferation at concentrations of amiloride 3-fold in excess of that required to inhibit full colony formation. A two-stage model is invoked to explain this observation: an early amiloride-insensitive stage and a late amiloride-sensitive stage which includes terminal differentiation. We conclude that the cellular mechanism by which differentiation is induced includes activation of the amiloride-sensitive sodium influx channel, which would indicate a new approach to the therapeutic induction of differentiation in vivo.