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Effects of the endothelinconverting enzyme inhibitor SM19712 in a mouse model of dextran sodium sulfateinduced colitis

Lee, Seungjun PhD1; Carter, Patsy R. BS1; Watts, Megan N. BS1; Bao, Jianxiong R. MD, PhD2; Harris, Norman R. PhD1,*

doi: 10.1002/ibd.20877
Original Article: Original Basic Science Articles

Background:: Ingestion by mice of dextran sodium sulfate (DSS) induces colonic vasoconstriction and inflammation, with some of the effects potentially mediated by the vasoconstrictor endothelin‐1 (ET‐1).

Methods:: In this study, mice given 5% 40 kD DSS for 5–6 days had elevated colonic immunostaining for ET‐1 and platelet endothelial cell adhesion molecule‐1 (PECAM‐1). Increased ET‐1 can induce microvascular constriction; however, the increase in PECAM‐1 is consistent with angiogenesis that could decrease flow resistance.

Results:: Our measurements of intestinal blood flow, via infused microspheres, suggests that these 2 factors may offset each other, with only a nonsignificant tendency for a DSS‐induced decrease in flow. Daily administration of the endothelin converting enzyme inhibitor SM‐19712 (15 mg/kg) attenuated DSS‐induced increases in colonic immunostaining of ET‐1 and PECAM‐1.

Conclusions:: SM‐19712 attenuated histologic signs of tissue injury and inflammation induced by DSS, and decreased the extent of loose stools and fecal blood. However, the inhibitor did not significantly decrease DSS‐induced colon shortening or tissue levels of myeloperoxidase (an indicator of neutrophil infiltration).

1Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center in Shreveport, Shreveport, Louisiana

2Department of Pathology, Louisiana State University Health Sciences Center in Shreveport, Shreveport, Louisiana

*Reprints: LSU Health Sciences Center, Department of Molecular & Cellular Physiology, 1501 Kings Highway, Shreveport, LA 71130

Email: nharr6@lsuhsc.edu

Received 16 December 2008; Accepted 18 December 2008

Published online 7 February 2009 in Wiley InterScience (www.interscience.wiley.com).

Grant sponsor: National Institute of Diabetes and Digestive and Kidney Diseases; Grant Number: P01DK043785; Project 2 plus Cores B and C.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Diabetes and Digestive and Kidney Diseases or the National Institutes of Health.

© Crohn's & Colitis Foundation of America, Inc.
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