ArticleDigestive diseases and sciences2011
Use of enterally delivered angiotensin II type Ia receptor antagonists to reduce the severity of colitis.
Article in Digestive diseases and sciences, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 25 citations in OpenAlex.
- The Non-Peptide MAS-R Agonist AVE0991 Alleviates Colitis Severity in Mice and Exhibits an Additive Effect with Azathioprine.International journal of molecular sciences · 2025Article
- The angiotensin receptor blocker, losartan, reduces inflammation and fibrosis, and prevents relapse of fibrosis after steroid-induced remission, in mice prone to Crohn's disease-like ileitis.Journal of Crohn's & colitis · 2025Article
- Repurposing of RAS-Pathway Mediated Drugs for Intestinal Inflammation Related Diseases for Treating SARS-CoV-2 Infection.Current microbiology · 2023Review
- The beneficial effect of combination therapy with sulfasalazine and valsartan in the treatment of ulcerative colitis.EXCLI journal · 2021Article
- Changes to the gut microbiota induced by losartan contributes to its antihypertensive effects.British journal of pharmacology · 2020Article
- Impact of Angiotensin II Signaling Blockade on Clinical Outcomes in Patients with Inflammatory Bowel Disease.Digestive diseases and sciences · 2019Observational
- Bidirectional Neural Interaction Between Central Dopaminergic and Gut Lesions in Parkinson's Disease Models.Molecular neurobiology · 2018Article
- Protective effects of resveratrol improve cardiovascular function in rats with diabetes.Experimental and therapeutic medicine · 2018Article
- Blockade of the renin-angiotensin system prevents acute and immunologically relevant colitis in murine models.Pediatric surgery international · 2016Article
- AT1R blocker losartan attenuates intestinal epithelial cell apoptosis in a mouse model of Crohn's disease.Molecular medicine reports · 2016Article
- Article
- Angiotensin converting enzyme-inhibitor reduces colitis severity in an IL-10 knockout model.Digestive diseases and sciences · 2013Article
- Decreased retinal blood flow in experimental colitis; improvement by eye drop administration of losartan.Experimental eye research · 2013Article
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundRenin-angiotensin system blockade reduces inflammation in several organ systems. Having found a fourfold increase in angiotensin II type Ia receptor expression in a dextran sodium sulfate colitis model, we targeted blockade with angiotensin II type Ia receptor antagonists to prevent colitis development. Because hypotension is a major complication of angiotensin II type Ia receptor antagonists use, we hypothesized that use of angiotensin II type Ia receptor antagonists compounds which lack cell membrane permeability, and thus enteric absorption, would allow for direct enteral delivery at far higher concentrations than would be tolerated systemically, yet retain efficacy.
methodsBased on the structure of the angiotensin II type Ia receptor antagonist losartan, deschloro-losartan was synthesized, which has extremely poor cell membrane permeability. Angiotensin II type Ia receptor antagonist efficacy was evaluated by determining the ability to block NF-κB activation in vitro. Dextran sodium sulfate colitis was induced in mice and angiotensin II type Ia receptor antagonist efficacy delivered transanally was assessed.
resultsIn vitro, deschloro-losartan demonstrated near equal angiotensin II type Ia receptor blockade compared to losartan as well as another angiotensin II type Ia receptor antagonist, candesartan. In the dextran sodium sulfate model, each compound significantly improved clinical and histologic scores and epithelial cell apoptosis. Abundance of TNF-α, IL-1β, and IL6 mRNA were significantly decreased with each compound. In vitro and in vivo intestinal drug absorption, as well as measures of blood pressure and mucosal and colonic blood flow, showed significantly lower uptake of deschloro-losartan compared to losartan and candesartan.
conclusionsThis study demonstrated efficacy of high-dose angiotensin II type Ia receptor antagonists in this colitis model. We postulate that a specially designed angiotensin II type Ia receptor antagonist with poor oral absorption may have great potential as a new therapeutic agent for inflammatory bowel disease in the future.
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