Use of Enterally Delivered Angiotensin II Type Ia Receptor Antagonists to Reduce the Severity of Colitis

Abstract

Background Renin-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. Methods Based 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. Results In 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. Conclusions This 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.

Angiotensin Converting Enzyme-Inhibitor Reduces Colitis Severity in an IL-10 Knockout Model

“…Inflammatory cytokines were then measured as a marker of the pro-inflammatory response in this colitis model [26]. As a trend, drug treatment led to a reduction in the abundance of several of the pro-inflammatory cytokines and chemokine.…”

“…Although several authors have used the DSS colitis model to investigate Renin-Angiotensin System (RAS) blockade and colitis [26, 33–36], the data presented here are the first which demonstrate RAS blockade efficacy using an immune-based model. In the present study we utilized an IL-10−/− colitis immune-based model and demonstrated that ACE-I treatment was as good, or far superior, to that of conventional steroid treatment.…”

Decreased retinal blood flow in experimental colitis; improvement by eye drop administration of losartan

“…With respect to the latter, IBD patients have been found to produce higher than normal levels of angiotensin II (Jaszewski et al, 1990), with experimentally-induced colitis alleviated in angiotensinogen knockout mice (Inokuchi et al, 2005) and also attenuated by inhibition with the angiotensin II receptor antagonists losartan and candesartan (Inokuchi et al, 2005; Okawada et al, 2011). …”

Protective effects of resveratrol improve cardiovascular function in rats with diabetes

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