Beneficial anti-inflammatory effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker in the treatment of dextran sulfate sodium-induced colitis in mice.

The renin-angiotensin system (RAS) in the intestine is involved in the regulation of inflammation, apoptosis and tissue fibrosis in experimental models of colitis; the inhibition of local RAS by pharmacologic interventions has been claimed to prevent and alleviate colitis. In this study, we compared the benefits of an angiotensin-converting enzyme (ACE) inhibitor, enalapril, an angiotensin receptor blocker, losartan and their combination in dextran sodium sulfate (DSS)-induced colitis in mice by assessing the histopathological and macroscopic changes in the colon, and by measuring the expression of the pro-inflammatory interleukin 1beta (IL-1β) and tumor necrosis factor alpha (Tnf-α) genes. We also examined the consequences of these interventions on colonic angiotensin-converting enzyme protein and its ectodomain shedding as well as gene expression of RAS components, Agt and Ace, and corticosterone synthesis and its components, Lrh-1 and Cyp11b1. Both enalapril and losartan alleviated colitis by reducing the inflammatory cell infiltrate in colon. In addition, enalapril downregulated the pro-inflammatory IL-1β expression whereas losartan treatment resulted in lower macroscopic scores, but the effects of the medications were not synergistic when the drugs were combined. ACE-ectodomain shedding was enhanced in the distal colon in DSS colitis. We found no evidence that ACE inhibition or angiotensin receptor blockade altered intestinal RAS or corticosterone synthesis. We conclude that some of the benefits of ACE inhibition and angiotensin receptor blockade might differ in the treatment of colitis, but their combination is unlikely to confer additional benefits.