Dose-Dependence of 4-Aminopyridine Plasma Concentrations and Electrophysiological Effects in Dogs
Bibliographic record
Abstract
BACKGROUND: Previous investigators have administered 4-aminopyridine (4AP) to dogs to evaluate the role of transient outward current (I(to)) in vivo; however, plasma concentrations of 4AP were not measured, and it is therefore uncertain which cardiac ion channels were blocked at the concentrations achieved. METHODS AND RESULTS: We applied high-performance liquid chromatography to measure 4AP concentrations produced by intravenous 4AP administration to dogs. A previously described dose regimen produced plasma concentrations that increased during the maintenance infusion but never exceeded 250 micromol/L and caused significant mortality. Whole-cell patch-clamp experiments on isolated canine myocytes showed that even the maximum 4AP concentrations achieved in vivo failed to alter ventricular I(to) and had very small effects on atrial I(to); however, concentrations achieved in vivo had a strong inhibitory effect on the dog ultrarapid delayed rectifier (I(Kur.d)), present only in atrial cells. We designed a loading and maintenance infusion regimen to produce stable 4AP plasma concentrations. At concentrations in the range of 25 and 50 micromol/L, 4AP had no effect on ventricular refractory period but increased atrial refractoriness significantly, consistent with the results of voltage clamp studies. CONCLUSIONS: The interpretation of previous studies using intravenous 4AP administration to inhibit I(to) in dogs in vivo needs to be reevaluated in light of the fact that the infusion regimens used produce plasma concentrations that are inadequate to affect ventricular I(to). Our findings also support the concept that selective inhibition of ultrarapid delayed rectifier current can prolong atrial refractory periods without affecting ventricular refractoriness.
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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 | 0.001 | 0.002 |
| 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 | 0.001 |
| 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".