Abstract 008: Aldosterone Contributes to the Blood Pressure Elevation, Endothelial Dysfunction, and Norepinephrine Sensitivity Caused by Endothelial Human Endothelin-1 Overexpression in Mice
Bibliographic record
Abstract
Background: The mechanisms of blood pressure (BP) regulation by endothelin (ET)-1 produced by endothelial cells (ECs) are complex and remain unclear. Transgenic mice with tamoxifen-inducible EC-restricted human ET-1 overexpression (ieET-1) exhibited BP elevation 3 months after induction. ET-1 has been shown to stimulate the release of aldosterone from adrenal cortex (AC). Whether aldosterone plays a role in EC ET-1 overexpression-induced BP elevation and vascular injury is still unknown. Methods and results: Nine to 12-week-old male ieET-1 mice and control ieCre mice expressing a tamoxifen-inducible Cre recombinase under the control of EC-specific Tie2 promoter were treated with tamoxifen (1 mg/kg/day, SC) for 5 days and studied 3 months later. Plasma aldosterone levels measured by ELISA was increased in ieET-1 vs. ieCre mice (1.21±0.14 vs. 0.70±0.09 ng/mL, P <0.05). Reverse transcription-quantitative PCR (RT-qPCR) showed that aldosterone synthase ( Cyp11b2 ) was decreased in AC of ieET-1 vs. ieCre mice (fold change: 0.52±0.06 vs. 1.00±0.16, P <0.01). CYP11B2 protein levels measured by Western Blotting was unchanged. Treatment with mineralocorticoid receptor antagonist eplerenone (100 mg/kg/day) during the last 2 weeks decreased daytime systolic BP determined by telemetry in ieET-1 vs. ieCre mice (Systolic after 14 days [mm Hg]: 128±1.6 vs. 137±1.8, P <0.01). The EC50 concentration for norepinephrine-induced MA contraction was reduced in ieET-1 vs. ieCre mice (EC50 [mol/L]: 5x10 -7 ±6x10 -8 vs. 4x10 -6 ±7x10 -7 , P <0.05), which was reversed by elplerenone (EC50 [mol/L]: 8x10 -6 ±5x10 -6 , P <0.05). The MA relaxation response to acetylcholine was decreased in ieET-1 vs. ieCre mice (32.2±5.3% vs. 70.5±5.9%), effect that was reduced by eplerenone (43.1±5.5%). The MA endothelium-independent relaxation response to sodium nitroprusside (SNP) was similar in ieET-1 and ieCre mice. Eplerenone enhanced sensitivity to SNP in iET-1 mice (EC50 [mol/L]: 3x10 -8 ±1x10 -8 vs. 1x10 -7 ±2x10 -8 , P <0.05). Conclusions: Increased aldosterone production contributes to EC human ET-1 overexpression-induced daytime SBP elevation, enhanced contractile response to norepinephrine and endothelial dysfunction.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
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".