REGIONAL CHANGES IN CONSTITUTIVE NITRIC OXIDE SYNTHASE AND THE HEMODYNAMIC CONSEQUENCES OF ITS INHIBITION IN LIPOPOLYSACCHARIDE-TREATED PIGS
Bibliographic record
Abstract
The role of constitutive nitric oxide synthases (cNOS) in sepsis remains controversial. Part of the problem is that many of the studies have been performed in rats, which respond differently than larger animals. Our objective, therefore, was to determine whether cNOS, i.e. ecNOS (NOS-3) and nNOS (NOS-1) are still active in vessels of pigs treated with lipopolysaccharide (LPS) from Escherichia coli. We also characterized the dose-response relationship of the NOS inhibitor N(G)-nitro-L-arginine-methyl-ester (L-NAME) in the arterial, venous, and pulmonary circuits as a reflection of NO production. We anesthetized and ventilated 14 pigs, which were instrumented for hemodynamic measurements. We measured mean circulatory filling pressure and resistance to venous return by transiently arresting the circulation with a balloon in the right atrium. Animals were given 20 microg/kg of LPS (n = 8) or saline (n = 6) over 2 h. They were then given progressively increasing doses of L-NAME (0.5 to 16 microg/kg). We injected 20 microg boluses of norepinephrine at baseline, after 2 h, and after 0.5, 4, and 16 microg of L-NAME to test the pressor response. Tissue was obtained from six control animals followed for 2 h, eight animals treated with LPS for 2 h and then sacrificed, and four animals treated for 2 h and sacrificed after 2 more h. Cardiac output did not change, and the systemic vascular resistance fell in LPS animals. By Western analysis, ecNOS was increased in LPS animals at 2 and 4 h in the aorta and vena cava, and this was paralleled by changes in nNOS in the vena cava. In contrast, ecNOS decreased in the pulmonary artery and nNOS did not change. Calcium-dependent NOS activity increased with LPS in the aorta and vena cava but decreased in pulmonary artery at 4 h. The dose-response relationships to L-NAME for systemic vascular resistance, resistance to venous return, and cardiac output were shifted to the left after LPS in support of increased sensitivity supporting increased NO. The pressor response to norepinephrine was depressed after LPS and was partially restored with 4 mg/kg of L-NAME, but this dose produced 90% of the fall in cardiac output. In conclusion, in contrast to rats, cNOS activity is present in the systemic vessels of LPS-treated pigs and could play a role in the pathophysiology of sepsis.
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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 | 0.000 | 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".