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.

• Authors: Manabu Okawada, Hiroyuki Koga, Scott D Larsen, Hollis D Showalter, Anjanette J Turbiak, Xiaohong Jin, Peter C Lucas, Elke Lipka, John Hillfinger, Jae Seung Kim, Daniel H Teitelbaum
• Journal: Digestive diseases and sciences (Dig Dis Sci) Vol. 56 Issue 9 Pg. 2553-65 (Sep 2011) ISSN: 1573-2568 [Electronic] United States
• PMID: 21399927 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin II Type 1 Receptor Blockers
• Benzimidazoles
• Biphenyl Compounds
• Cytokines
• Tetrazoles
• Dextran Sulfate
• Losartan
• candesartan

Topics

• Administration, Oral
• Angiotensin II Type 1 Receptor Blockers (administration & dosage, pharmacology)
• Animals
• Benzimidazoles (administration & dosage, chemistry, pharmacology)
• Biphenyl Compounds
• Colitis (chemically induced, drug therapy, pathology)
• Colon (pathology)
• Cytokines (genetics, metabolism)
• Dextran Sulfate (toxicity)
• Feces (chemistry)
• Gene Expression Regulation (drug effects)
• Losartan (administration & dosage, analogs & derivatives, pharmacology)
• Male
• Mice
• Molecular Structure
• Specific Pathogen-Free Organisms
• Tetrazoles (administration & dosage, chemistry, pharmacology)