Using Carbon Monoxide Releasing Molecules in Models of Preeclampsia: When Should We Be Monitoring Vascular Effects?
Bibliographic record
Abstract
There has been an increasing amount of evidence that the heme oxygenase (HO) system plays an important role in the development or progression of preeclampsia (PE). Carbon monoxide (CO), a byproduct of heme degradation by HO, is actively being studied as a therapeutic in the management of PE.1 In the article entitled “Carbon Monoxide Releasing Molecules Blunt Placental Ischemia-Induced Hypertension,” the authors (George et al.) demonstrated that treatment of pregnant rats with carbon monoxide releasing molecule 3 (CORM-3), can attenuate the hypertension caused by placental ischemia in a reduced uterine perfusion pressure (RUPP) model of PE.2 We have previously demonstrated that chronic exposure to low levels of CO in ambient air lead to significant increases in placental vessel branching and vessel diameter, and prevented hypertension, proteinuria, and renal changes in an anti-angiogenic mouse model of PE.3 CORM-3, and other similar CORMs, have been shown to have a CO dissociation rate of less than 30 minutes in solution.4 In the most recent publication, it is not clear when on gestational day 19 the 30-minute blood pressure measurements were made in relation to CORM-3 administration. Similarly, it is not stated how CORM-3 was administered to the rats (tail vein vs. carotid catheter). It would be useful to know if the effect of CORM-3 on mean arterial pressure is transient or sustained in these pregnant animals. Is the blood pressure effect similar on the first day of CORM-3 administration compared to administration on subsequent days? Similarly, it would be of use to measure mean arterial pressure at multiple time points throughout gestation, both immediately prior to and at intervals following CORM treatment; CORM-3 has previously been shown in rats to cause a dramatic transient decrease in mean arterial pressure which returned to baseline within 10 minutes after CORM-3 administration.4 The title of the article is potentially misleading, in that CORM-3 has likely only very transiently blunted the placental ischemia-induced hypertension. Similarly, the measurement of glomerular filtration rate was made within 1 hour of administration of CORM-3; it would be of use to measure glomerular filtration rate at time points more distant from the CORM administration to see if there is a prolonged effect of CO on the kidneys. Although the dissociation of CO from CORMs occurs very rapidly following CORM treatment, their effects may persist beyond the initial period of CO delivery. The transition metals in CORM-3 and other CORMs may activate HO-1, the inducible form of HO, leading to further endogenous production of CO and potentially contributing to the physiological changes that are observed. The authors (George et al.) suggest that CO may be acting on the maternal kidneys to regulate renal hemodynamics; by what proposed mechanism would the CO released transiently from CORMs act on the kidney to generate the long-term outcomes of increased glomerular filtration rate and reduced mean arterial pressure? The authors declared no conflict of interest.
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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 | 0.004 | 0.014 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.002 | 0.003 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.018 | 0.022 |
| Insufficient payload (model declined to judge) | 0.002 | 0.002 |
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".