The S-nitroso derivative of omapatrilat (Vanlev) can act as a substrate for cell surface protein disulfide isomerase and thus deliver NO to the cytosol of human umbilical endothelial cells,in vitro
Bibliographic record
Abstract
Omapatrilat (Vanlev) is a new vasopeptidase inhibitor. It simultaneously inhibits two key enzymes involved in the regulation of cardiovascular function, neutral endopeptidase and angiotensin-converting enzyme. Omapatrilat contains a free thiol group that can potentially act as a nitric oxide (NO)-carrier. In this study, we explored the ability Omapatrilat-NO to donate NO to the cytosol of by acting as a substrate for the enzyme cell-surface protein disufide isomerase. Methods: These dynamic microscopy studies, were conducted on live human umbilical vein endothelial cells in vitro, with the aid of fluorescent intracellular NO-probe dansylhomocysteine. With this compound the kinetics of cell-surface protein disulfide isomerase-catalyzed NO transfer from S-nitrosothiols, like Omapatrrilat-NO can be directly evaluated. The levels of cell-surface protein disulfide isomerase protein, were also monitored as a function of Omapatrilat by Western blotting. The estimated KM of cell-surface protein disulfide isomerase for Omapatrilat-NO, in the presence of 10 micromolar Omapatrilat was 40 micromolar. When the kinetics were repeated after a 24 h pretreatment of the cells with 10 micromolar Omapatrilat, the KM decreased by 30-fold to 1.4 micromolar. Western blot analysis of secreted protein disulfide isomerase, indicated that the amount of protein also increased by nearly 5-fold upon a 24h incubation with Omapatrilat. These studies show that the NO derivative of Omapatrilat is stable and can donate its NO to the cytosol through the action of the enzyme cell-surface protein disufide isomerase. These studies also demonstrate that Omapatrilat can affect the affinity of the enzyme as well as upregulating its excreteion by and unknown mechanism. The results presented here indicate that apart from vasopeptidase inhibiton, Omapatrilat could potentially act as a vasodilator by its ability to carry NO and to positively affect the enzyme resposible for the release of S-nitrosothiol-bound NO into the cells comprizing the vasculature.
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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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".