Loss of vagally mediated bradycardia and bronchoconstriction in mice lacking M <sub>2</sub> or M <sub>3</sub> muscarinic acetylcholine receptors
Bibliographic record
Abstract
The presence of multiple muscarinic acetylcholine receptor (mAChR) subtypes in the heart and lung, combined with the lack of mAChR subtype-selective ligands, have complicated the task of identifying the mAChR subtypes mediating cardiac slowing (bradycardia) and airway narrowing (bronchoconstriction) due to vagal innervation. To determine which of the five mAChRs are responsible for the cholinergic control of heart rate and airway caliber in vivo, we performed experiments on mutant mice lacking the two prime candidates for such control, the M2 or M3 mAChR. Here, we report that in vivo, bradycardia caused by vagal stimulation or administration of the muscarinic agonist methacholine (MCh) was abolished in mice lacking functional M2 mAChRs (M2-/- mice). In contrast, heart rate responses remained unchanged in M3 receptor-deficient mice (M3-/- mice). The reduced hypotensive response of M3-/- mice to MCh suggests M3 mAChRs contribute to peripheral vasodilation. The M2-/- mice showed significantly enhanced in vivo bronchoconstrictor responses to vagal stimulation or MCh administration. In contrast, bronchoconstrictor responses were totally abolished in M3-/- mice. Because altered cardiac or pulmonary vagal tone is involved in a number of pathophysiological conditions, including cardiac arrhythmias, chronic obstructive pulmonary disease and asthma, these results should be of considerable therapeutic relevance.
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".