enalaprilat-anhydrous and Colitis

Blockade of the renin-angiotensin system (RAS) has been shown to alleviate inflammatory processes in the gastrointestinal tract. The aim of this study was to determine if blockade of the RAS would be effective in an immunologically relevant colitis model, and to compare outcome with an acute colitis model.. In the DSS model, weight loss and histologic score for CCG-203025 were better than with placebo. In the IL10-/-model, ACE-I suppressed histologic damage better than CCG-203025. Both ACE-I and CCG-203025 reduced pro-inflammatory cytokines and chemokines.. This study demonstrated the therapeutic efficacy of both ACE-I and AT1aR-A for preventing the development of both acute and immunologically relevant colitis.

Topics: Acute Disease; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Colitis; Cyclooxygenase Inhibitors; Disease Models, Animal; Enalaprilat; Losartan; Mice; Mice, Inbred C57BL; Piroxicam; Renin-Angiotensin System

We previously demonstrated angiotensin converting enzymes (ACE) over-expression in a dextran-sodium sulfate colitis model; ACE inhibitor (ACE-I) treatment reduced colitis severity in this model. However, ACE-I has not been tested in more immunologically relevant colitis models.. We hypothesized that ACE-I would decrease disease severity in an IL-10 knockout (-/-) colitis model.. Colitis was induced by giving 10-week old IL-10-/- mice piroxicam (P.O.) for 14 days. The ACE-I enalaprilat was given transanally at a dose of 6.25 mg/kg for 21 days. Prednisolone (PSL) with or without enalaprilat were used as therapeutic, comparative groups. All groups were compared to a placebo treated group. Outcome measures were clinical course, histology, abundance of pro-inflammatory cytokines/chemokines, and epithelial barrier function.. Enalaprilat exhibited better survival (91 %) versus other treatment groups (PSL: 85.7 %, PSL + ACE-I: 71.4 %, placebo: 66.6 %). The ACE-I and PSL + ACE-I groups showed significantly better histological scores versus placebo mice. ACE-I and the PSL groups significantly reduced several pro-inflammatory cytokines versus placebo mice. FITC-dextran permeability was reduced in the ACE-I and PSL + ACE-I groups. Blood pressure was not affected in ACE-I treated mice compared to placebo mice.. ACE-I was effective in reducing severity of colitis in an IL-10-/- model. The addition of prednisolone minimally augmented this effect. The findings suggest that appropriately dosed ACE-I with or without steroids may be a new therapeutic agent for colitis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Colitis; Dextran Sulfate; Enalaprilat; Interleukin-10; Mice; Mice, Inbred C57BL; Mice, Knockout; Real-Time Polymerase Chain Reaction

We have previously shown that angiotensin converting enzyme-inhibitor (ACE-I) improved colonic inflammation and apoptosis in a dextran sodium sulfate (DSS)-induced colitis model. This study attempted to determine whether ACE-I could prevent the development of colonic fibrosis.. Colitis was induced in C57BL/6 mice with 2.5% DSS water for 7 days, followed by 7 days without DSS (fibrosis development). Study groups: Control (naive or non-treated), DSS+Placebo (polyethylene glycol (PEG), and DSS+ACE-I (using enalaprilat and PEG which are not absorbed through intact mucosa). Placebo and ACE-I were delivered daily via transanal route. Colonic mucosal fibrosis and inflammation were evaluated based on histological findings and cytokine expression.. Transanal administration of ACE-I/PEG dose-dependently decreased the severity of fibrosis and pro-inflammatory cytokine expression. We next investigated if ACE-I acted on the TGF-beta/Smad signaling pathway as a mechanism of this anti-fibrosis action. Results showed a significant down-regulation of TGF-beta1 expression; as well, downstream signaling of the Smad family, known to mediate fibrosis, showed a decline in Smad 3 and 4 expression with ACE-I/PEG.. ACE-I/PEG is effective in preventing colonic fibrosis and pro-inflammatory cytokine expression in a DSS colitis model, most likely by down-regulating the TGF-beta signaling pathway. ACE-I/PEG may be a potential new option for treating inflammatory bowel disease.

Topics: Administration, Rectal; Angiotensin-Converting Enzyme Inhibitors; Animals; Colitis; Collagen; Colon; Dextran Sulfate; Dose-Response Relationship, Drug; Enalaprilat; Fibrosis; Interleukin-1beta; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Smad Proteins; Tumor Necrosis Factor-alpha

Ulcerative colitis is characterized by elevated rates of epithelial cell apoptosis, and an up-regulation of pro-apoptotic cytokines including tumor necrosis factor alpha (TNF-alpha). Recently, angiotensin converting enzyme (ACE) has been shown to promote apoptosis. In addition, pharmacologic ACE inhibition (ACE-I) both prevents apoptosis and reduces TNF-alpha expression in vitro. We hypothesized that ACE-I, using enalaprilat, would decrease colonic epithelial cell apoptosis and reduce colitis severity in the dextran sulfate sodium (DSS)-induced colitis model in mice. We assessed the severity of colitis, and colonic epithelial cell apoptosis, after administration of DSS. Mice were given either daily ACE-I treatment or daily placebo. ACE-I treatment markedly improved clinical outcomes. In addition, ACE-I treatment significantly reduced the maximum histopathologic colitis grade. ACE-I also dramatically reduced the epithelial apoptotic rate. To investigate the mechanism by which ACE-I reduced apoptosis; we measured TNF-alpha, Bcl-2, and Bax expression. TNF-alpha mRNA was significantly lower with ACE-I treatment compared to placebo at every time point, as was the ratio of Bax to Bcl-2. We conclude that ACE-I reduces the severity of DSS-induced colitis and reduces epithelial cell apoptosis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; bcl-2-Associated X Protein; Colitis; Colon; Dextran Sulfate; Enalaprilat; Epithelial Cells; Flow Cytometry; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; Peptidyl-Dipeptidase A; Proto-Oncogene Proteins c-bcl-2; Regional Blood Flow; Tumor Necrosis Factor-alpha