Role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy in bile duct‐ligated rats
Bibliographic record
Abstract
Cardiac contractility in cirrhosis is normal at baseline but hyporesponsive to stimuli, a phenomenon known as 'cirrhotic cardiomyopathy'. The pathogenesis remains unclear. Endocannabinoids are vasoactive, but have not previously been examined in the cirrhotic heart. We therefore aimed to systematically clarify a possible role of endocannabinoids in the pathogenesis of cirrhotic cardiomyopathy. Cirrhosis was induced in Sprague-Dawley rats by bile duct ligation; controls underwent a sham operation. At 4 weeks after operation, isolated left ventricular papillary muscle contractility was studied. Dose-response curve for a beta-adrenergic agonist isoproterenol was constructed in the presence and absence of a CB-1 antagonist AM251 (1 microM). Cirrhotic muscles had a blunted response to isoproterenol, which was completely restored by AM251. Dose-response curves to anandamide, and CB-1 and CB-2 protein and mRNA expression in Western blot and reverse transcriptase-polymerase chain reaction experiments were not significantly different between cirrhotic and sham muscles. Force-frequency relationship studies were performed in cirrhotic and normal muscles. At higher frequencies, anandamide reuptake blockers (VDM11 and AM404) significantly enhanced muscle relaxation in cirrhotic muscles, but not in controls. This effect was completely blocked by AM251 and pertussis toxin, whereas tetrodotoxin partially reversed it. Taken together, these results indicate a pathogenic role for increased local (neuronal) production of endocannabinoids, mediated by a G(i)-protein-dependent CB-1-responsive pathway in cirrhotic cardiomyopathy. The increased tachycardia-stress-induced release of endocannabinoids may help explain why contractility is normal at baseline but attenuated with stress.
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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) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 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".