Pathophysiological plasma ET-1 levels antagonize β-adrenergic dilation of coronary resistance vessels in conscious dogs
Bibliographic record
Abstract
On the basis of in vitro experiments showing that endothelin (ET)-1 interferes with smooth muscle ATP-sensitive K(+) (K(ATP)) channel opening, which is pivotal in beta-adrenergic coronary dilation, we hypothesized that pathophysiological plasma ET-1 levels impair beta-adrenergic dilation of resistance coronary vessels. In conscious instrumented dogs, graded intravenous doses of dobutamine caused the expected inotropic responses. As myocardial O(2) consumption (MVo(2)) increased, the disproportionate rise in coronary sinus (CS) Po(2) indicates that increases in coronary blood flow (CBF) exceeded metabolic requirements, consistent with beta-adrenergic dilation. ET-1 intravenous infusions, to reach pathophysiological plasma levels, reduced slopes of the Po(2)-MVo(2) and CBF-MVo(2) relations. In contrast, the first derivative of left ventricular pressure over time responses to dobutamine were not impaired during ET-1 delivery. Clazosentan, an ET(A) receptor blocker, prevented reduction of the slope of Po(2)-MVo(2) and CBF-MVo(2) relations. After ganglionic blockade to exclude reflex influences, ET-1 still reduced slopes of Po(2)-MVo(2) and CBF-MVo(2) relations. To assess effects of ET-1 on endothelium-dependent and -independent coronary vascular responses, intracoronary ACh and nitroglycerin were given to directly target coronary vessels. CBF responses to ACh and nitroglycerin were maintained during ET-1 delivery. In contrast, responses to intracoronary K(ATP) channel-dependent dilators adenosine and lemakalim were impaired by ET-1. In conclusion, pathophysiological levels of ET-1 impaired beta-adrenergic dilation of resistance coronary vessels through an ET(A) receptor-dependent process. In contrast, left ventricular inotropic responses to dobutamine were not impaired during ET-1 delivery. Our data suggest that ET-1 may interfere with smooth muscle K(ATP) channels to impair beta-adrenergic coronary dilation.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".