Slow delayed rectifier K<sup>+</sup> current block by HMR 1556 increases dispersion of repolarization and promotes Torsades de Pointes in rabbit ventricles
Bibliographic record
Abstract
BACKGROUND AND PURPOSE: The slow delayed rectifier K(+) current (I(Ks)) contributes to ventricular repolarization when the action potential (AP) is prolonged. I(Ks) block during drug-induced AP prolongation may promote Torsades de Pointes (TdP), but whether this is due to additional AP prolongation is uncertain. EXPERIMENTAL APPROACH: In bradycardic perfused rabbit ventricles, the incidence of spontaneous TdP, monophasic AP duration at 90% repolarization (MAPD(90)) and ECG interval between the peak and the end of T wave (T(peak-end)) (index of dispersion of repolarization) were measured after the administration of veratridine (125 nM, slows Na(+) channel inactivation), dofetilide (7.5 or 10 nM, a rapid delayed rectifier blocker) and HMR 1556 (HMR, 100 nM, an I(Ks) blocker), alone or in combinations (n=6 each). KEY RESULTS: HMR did not prolong MAPD(90), whereas veratridine or 7.5 nM dofetilide prolonged MAPD(90) (P<0.01) without inducing TdP. Veratridine+7.5 nM dofetilide additively prolonged MAPD(90) (P<0.05), induced 4+/-6 TdP per heart and prolonged T(peak-end) by 12+/-10 ms. Subsequent addition of HMR did not further prolonged MAPD(90), but increased the number of TdP to 22+/-18 per heart and increased T(peak-end) by 39+/-21 ms (P<0.05). Increasing dofetilide concentration from 7.5 to 10 nM (added to veratridine) produced a longer MAPD(90), but fewer TdP (5+/-5 per heart) and less T(peak-end) prolongation (17+/-8 ms) compared to the veratridine+7.5 nM dofetilide+HMR group (P<0.05). CONCLUSIONS AND IMPLICATIONS: Adding I(Ks) block markedly increases TdP incidence in hearts predisposed to TdP development by increasing the dispersion of repolarization, but without additional AP prolongation.
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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 | 0.000 |
| 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".