The Na+/K+-ATPase as [K+]o sensor: Role in cardiovascular disease pathogenesis and augmented production of endogenous cardiotonic steroids

Current evidence demonstrates that augmented production of endogenous cardiotonic steroids (CTS) such as ouabain and marinobufagenin is involved in the pathogenesis of hypertension and other cardiovascular diseases associated with volume expansion. It is also well documented that the development of hypertension and the cardiovascular complications of this disease are provoked by hypokalemia and suppressed by high-K+ diet. We hypothesized that altered extracellular K+ (K+)o handling contributes to the pathogenesis of hypertension via modulation of interaction of endogenous CTS with Na+/K+-ATPase. To examine this hypothesis, experiments were performed with C7-Madin-Darby canine kidney epithelial cells at [K+]o detected in plasma under control conditions (4.5 mM), severe hypokalemia (2 mM), and hyperkalemia (7 mM). Elevation of [K+]o from 2 to 7 mM increased the threshold of modulation of intracellular (Na+)i and (K+)i content by ouabain from 1 to 10 nM, which corresponds to the range of endogenous CTS detected in plasma from patients with volume-expanded disorders. In control medium, ∼30% activation of cell proliferation was observed with 3 nM ouabain, whereas the addition of 0.3 nM ouabain was sufficient to induce about the same increment of cell proliferation in K+-depleted medium. [K+]o elevation up to 7 mM completely abolished the proliferative effect of ouabain. At [K+]o = 2, 4.5 and 7 mM, the death of ouabain-treated cells was indicated in the presence of 10, 30 and 300 nM ouabain, respectively. In conclusion, our results showed that modulation of [K+]o in a pathophysiologically reasonable range sharply affected efficacy of endogenous CTS in the elevation of the [Na+]i/[K+]i ratio and in triggering (Na+)i,(K+)i-independent signaling resulting in cell proliferation and death. We propose that Na+/K+-ATPase may be considered as a [K+]o sensor involved in the crosstalk of (K+)o handling with the pathogenesis of cardiovascular diseases.