Acute vascular effects of the selective estrogen receptor modulator EM-652 (SCH 57068) in the rat mesenteric vascular bed
Bibliographic record
Abstract
OBJECTIVE: Selective estrogen receptor modulators (SERMs) represent a class of compounds that act as either estrogen receptor agonist or antagonist in a tissue-selective manner. SERMs exert beneficial effects on bone and lipids but are not associated with an increased risk of breast or uterine carcinoma. 17beta-estradiol (E2) and SERMs such as raloxifene and tamoxifen acutely relax coronary arteries. EM-652 (SCH 57068) is a 4th generation SERM acting as pure antiestrogen in the mammary gland and endometrium. The effects of SERMs on the mesenteric vasculature are unknown. In the present study, the vascular effects of EM-652 and E2 on the rat mesentery were investigated. METHODS: Isolated perfused (5 ml/min) mesenteric vascular bed (MVB) was preconstricted with methoxamine. Increasing doses (0.1-10 microM) of EM-652 or E2 were infused into the perfusate. RESULTS: EM-652 and E2 relaxed MVBs removed from intact and gonadectomized female and male rats. The amplitude of EM-652 responses was consistently greater than those of E2 and its potency was similar or greater than that of other SERMs. EM-652 and E2 relaxed MVB by an endothelium-independent mechanism. The estrogen receptor (ER) antagonist ICI 182,780 attenuated E2-induced relaxations but only partially block the effects of EM-652. Inhibition of the nitric oxide synthase/cGMP pathway with N(G)-nitro-arginine-methyl-ester (L-NAME) and 1H-(1,2,4)oxadiazolo(4,3-a)quinoxaline-1-one (ODQ) or of prostanoid synthesis with indomethacin failed to reduce EM-652 responses. The vascular effects of EM-652 were also unaffected by potassium channels blockers or inhibitors/scavengers of reactive oxygen species. EM-652 attenuated the vasoconstrictor responses induced by adrenergic agonists and endothelin-1. CONCLUSIONS: EM-652 acutely relaxes the mesenteric vasculature by an endothelium-independent pathway which is partly mediated by ER, providing a novel mechanism by which this SERM may exert beneficial actions on the vascular system.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.005 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.000 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".