Effects of the endothelin-converting enzyme inhibitor SM-19712 in a mouse model of dextran sodium sulfate-induced colitis.
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).
Lee
Seungjun
S
Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center in Shreveport, Shreveport, Louisiana 71130, USA.
Carter
Patsy R
PR
Watts
Megan N
MN
Bao
Jianxiong R
JR
Harris
Norman R
NR
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001794:Blood Pressure; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D003106:Colon / Q000098:blood supply / Q000187:drug effects; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007082:Ileum / Q000098:blood supply / Q000187:drug effects; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D013453:Sulfonylurea Compounds / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C419789:SM 19712; D013449:Sulfonamides; D013453:Sulfonylurea Compounds; D016264:Dextran Sulfate; D009195:Peroxidase; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes