title: 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.affiliation: Section of Pediatric Surgery, Department of Surgery, The University of Michigan Medical School, Mott Children's Hospital, F3970, Ann Arbor, MI 48109-0245, USA. manabuo@med.umich.edu
authors.forename: Manabu
authors.initials: M
authors.lastname: Okawada
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koga
authors.forename: Scott D
authors.initials: SD
authors.lastname: Larsen
authors.forename: Hollis D
authors.initials: HD
authors.lastname: Showalter
authors.forename: Anjanette J
authors.initials: AJ
authors.lastname: Turbiak
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Jin
authors.forename: Peter C
authors.initials: PC
authors.lastname: Lucas
authors.forename: Elke
authors.initials: E
authors.lastname: Lipka
authors.forename: John
authors.initials: J
authors.lastname: Hillfinger
authors.forename: Jae Seung
authors.initials: JS
authors.lastname: Kim
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Teitelbaum
mesh_terms: D000284:Administration, Oral; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001713:Biphenyl Compounds; D003092:Colitis / Q000139:chemically induced* / Q000188:drug therapy / Q000473:pathology; D003106:Colon / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D016264:Dextran Sulfate / Q000633:toxicity; D005243:Feces / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects; D019808:Losartan / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology*; D008297:Male; D051379:Mice; D015394:Molecular Structure; D013047:Specific Pathogen-Free Organisms; D013777:Tetrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D016207:Cytokines; D013777:Tetrazoles; D016264:Dextran Sulfate; D019808:Losartan; C081643:candesartan