In Vivo Endothelial NO Activation by Losartan Is Independent of Blood Pressure Lowering and EXP3179/EXP3174 Metabolites Yet Require First Passage Metabolism
Bibliographic record
Abstract
Background and Purpose: Losartan is a well‐established anti‐hypertensive angiotensin II (AngII) receptor type 1 (ATR1) blocker (ARB) with unexpected therapeutic properties in a range of diseases not linked to hypertension, such as chronic lung diseases, Alzheimer's disease, muscular dystrophy and viral infections. This suggests that there is more to losartan than simple AngII‐ATR1 inhibition. We have recently shown that losartan can unexpectedly activate endothelial function in vivo via the endothelial release of protective nitric oxide (NO), which is typically associated with aerobic exercise and vascular homeostasis. Hence, losartan activation of endothelial NO release may be behind its protective non‐blood pressure‐related effects, although how this occurs is unknown. Losartan is a prodrug with many active metabolites that might be behind some of its unexpected therapeutic properties. Losartan first‐passage metabolism in the liver converts it to EXP3179 (losartan‐carboxaldehyde) believed to be devoid of ATR1 blocking effects followed by further metabolism into EXP3174 (losartan‐carboxylic acid), the main ATR1 blocker. Our goal is to determine whether first passage metabolism is required for losartan to activate endothelial NO release, or if bypassing liver metabolism via intraperitoneal (IP) injections of losartan metabolites EXP3179/3174 will result is similar biological activites, an indication that metabolites of losartan are not involved in this biological activity. Experimental Approach: C57B6/J mice were treated with 1) losartan potassium‐salt (LOS‐PS) for 2 weeks via drinking water (liver first passage‐dependent; 0.6 g/L) or 2) daily IP injections (first passage‐independent) of LOS‐PS, EXP3179 or EXP3174 (10 mg/kg). Systemic BP was noninvasively measured by a tail cuff system in mice anesthetized with isoflurane. NO‐dependent vasodilatory properties of losartan, EXP3179 and EXP3174 were evaluated in mouse aortic rings using dual‐wire myograph systems. Key Results: When losartan was delivered in drinking water, NO‐dependent vasorelaxation was increased by 57.6%. In stark contrast, IP injection of losartan resulted in unexpected increases in contractility by 124.9% compared to vehicle control, whereas IP EXP3179 and EXP3174 also increased vasoconstriction by 69.8% and 72.2% respectively. Vasodilatory effects of losartan were undetected in the presence of L‐NAME (NO synthase inhibitor), confirming that losartan exerts its effects in a NO‐dependent manner. Moreover, BP was decreased in all drug treated group of mice, confirming that all drugs were biologically active and blocking ATR1. Conclusion and implications: Our data unexpectedly show that losartan increases endothelial function in mice only when given in drinking water, which suggests that non‐EXP3179/74 metabolites may play an important role in endothelial NO activation. This also suggests that losartan‐induced BP lowering is separate from its endothelial NO activating properties.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".