The Na+/K+-ATPase as [K+]o sensor: Role in cardiovascular disease pathogenesis and augmented production of endogenous cardiotonic steroids
Bibliographic record
Abstract
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 (4.5mM), severe hypokalemia (2mM), and hyperkalemia (7mM). Elevation of [K(+)](o) from 2 to 7mM increased the threshold of modulation of intracellular (Na(+))(i) and (K(+))(i) content by ouabain from 1 to 10nM, which corresponds to the range of endogenous CTS detected in plasma from patients with volume-expanded disorders. In control medium, approximately 30% activation of cell proliferation was observed with 3nM ouabain, whereas the addition of 0.3nM ouabain was sufficient to induce about the same increment of cell proliferation in K(+)-depleted medium. [K(+)](o) elevation up to 7mM completely abolished the proliferative effect of ouabain. At [K(+)](o)=2, 4.5 and 7mM, the death of ouabain-treated cells was indicated in the presence of 10, 30 and 300nM 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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".