Effects of the ACE2 inhibitor GL1001 on acute dextran sodium sulfate-induced colitis in mice.

Abstract

OBJECTIVE AND DESIGN:

Angiotensin-converting enzyme 2 (ACE2) is expressed in gastrointestinal tissue. Previous studies of GL1001, a potent and selective ACE2 inhibitor, have revealed anti-inflammatory activity in the mouse digestive tract. We hypothesized that GL1001 might also produce beneficial effects in a mouse DSS model of inflammatory bowel disease.

MATERIALS:

Female mice were used for study.

TREATMENT:

Animals were treated for 5 days with 5% DSS in the drinking water to induce colitis. For the following 9 days, animals were treated twice daily with GL1001 (30, 100, 300 mg/kg, s.c.), sulfasalazine (150 mg/kg, p.o.), or vehicle.

METHODS:

Throughout the experiment, body weight, rectal prolapse, stool consistency, and fecal occult blood were monitored. At termination, colon length, histopathology, and myeloperoxidase activity were assessed.

RESULTS:

High-dose GL1001 ameliorated DSS-induced disease activity, including rectal prolapse and intestinal bleeding. The most robust effect of GL1001 was observed 48-96 h post DSS treatment and was comparable in magnitude to that of sulfasalazine. Colon pathology and myeloperoxidase activity were also markedly attenuated by high-dose GL1001 treatment, with the most profound effects observed in the distal segment.

CONCLUSIONS:

The findings support the previously observed anti-inflammatory effects of ACE2 inhibition in gastrointestinal tissue and suggest that GL1001 may have therapeutic utility for inflammatory bowel disease.

• Authors: John J Byrnes, Stefan Gross, Courtney Ellard, Kelly Connolly, Stephen Donahue, Dominic Picarella
• Journal: Inflammation research : official journal of the European Histamine Research Society ... [et al.] (Inflamm Res) Vol. 58 Issue 11 Pg. 819-27 (Nov 2009) ISSN: 1420-908X [Electronic] Switzerland
• PMID: 19517214 (Publication Type: Journal Article)

Chemical References

• 2-(1-carboxy-2-(3-(3,5-dichlorobenzyl)-3H-imidazol-4-yl)ethylamino)-4-methylpentanoic acid
• Angiotensin-Converting Enzyme Inhibitors
• Imidazoles
• Dextran Sulfate
• Peroxidase
• Peptidyl-Dipeptidase A
• ACE2 protein, human
• Ace2 protein, mouse
• Angiotensin-Converting Enzyme 2
• Leucine

Topics

• Angiotensin-Converting Enzyme 2
• Angiotensin-Converting Enzyme Inhibitors (therapeutic use)
• Animals
• Body Weight (drug effects)
• Colitis (chemically induced, drug therapy, pathology, physiopathology)
• Colon (enzymology, pathology)
• Dextran Sulfate (adverse effects)
• Disease Models, Animal
• Female
• Humans
• Imidazoles (therapeutic use)
• Inflammatory Bowel Diseases (drug therapy, pathology)
• Leucine (analogs & derivatives, therapeutic use)
• Mice
• Mice, Inbred BALB C
• Peptidyl-Dipeptidase A (metabolism)
• Peroxidase (metabolism)
• Random Allocation