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Side-by-side with inhibition of the Na
+
,K
+
-ATPase ouabain and other cardiotonic steroids (CTS) can affect cell functions by mechanisms other than regulation of the intracellular Na
+
and K
+
ratio ([Na
+
]
i
/[K
+
]
i
). Thus, we compared the doseand time-dependences of the effect of ouabain on intracellular [Na
+
]
i
/[K
+
]
i
ratio, Na
+
,K
+
-ATPase activity, and proliferation of human umbilical vein endothelial cells (HUVEC). Treatment of the cells with 1-3 nM ouabain for 24-72 h decreased the [Na
+
]
i
/[K
+
]
i
ratio and increased cell proliferation by 20-50%. We discovered that the same ouabain concentrations increased Na
+
,K
+
-ATPase activity by 25-30%, as measured by the rate of
86
Rb
+
influx. Higher ouabain concentrations inhibited Na
+
,K
+
-ATPase, increased [Na
+
]
i
/[K
+
]
i
ratio, suppressed cell growth, and caused cell death. When cells were treated with low ouabain concentrations for 48 or 72 h, a negative correlation between [Na
+
]
i
/[K
+
]
i
ratio and cell growth activation was observed. In cells treated with high ouabain concentrations for 24 h, the [Na
+
]
i
/[K
+
]
i
ratio correlated positively with proliferation inhibition. These data demonstrate that inhibition of HUVEC proliferation at high CTS concentrations correlates with dissipation of the Na
+
and K
+
concentration gradients, whereas cell growth stimulation by low CTS doses results from activation of Na
+
,K
+
-ATPase and decrease in the [Na
+
]
i
/[K
+
]
i
ratio.