Inhibition of reverse‐mode sodium‐calcium exchange by the anti‐anginal agent ranolazine.
Bibliographic record
Abstract
Myocardial calcium overload observed during ischemia‐reperfusion is largely mediated via reverse mode cardiac sodium‐calcium exchange (NCX1.1), resulting from intracellular sodium overload that occurs via sodium‐hydrogen exchange and induction of late sodium current (late I Na ). The anti‐anginal agent Ranolazine (Ranexa™) is thought to act by selective inhibition of late I Na thus reducing the NCX1.1‐mediated intracellular calcium overload occurs. In preliminary studies, we observed that ranolazine reduces ouabain‐induced calcium overload in rat hearts perfused in working‐mode, that is likely independent of late I Na . Therefore, we hypothesized that ranolazine may also directly inhibit reverse‐mode sodium‐calcium exchange. To test this notion, we investigated the effect of ranolazine on recombinant NCX1.1 currents using the inside‐out excised patch‐clamp technique. Interestingly, we observed that ranolazine is a selective and potent inhibitor of the inactivating reverse‐mode NCX1.1 currents (IC 50 = 40.8 ± 3.9 nM), with no effect on the non‐inactivating forward‐mode NCX1.1 currents. To further probe the inactivation dependence of ranolazine, we examined the effects of ranolazine on reverse‐mode currents from the NCX1.1 mutants F258E and K264Q that display either no inactivation or accelerated inactivation. Furthermore, ranolazine inhibits reverse‐mode evoked NCX1.1 activity in intact neonatal rat cardiac myoyctes. These results strongly suggest that, at therapeutic concentrations in the micromolar range, ranolazine may exert some of its cardioprotective efficacy via direct inhibition of reverse‐mode NCX1.1 in addition to inhibition of late I Na . Source of Research Support: Canadian Institutes for Health Research.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".