Endothelin-1 receptor antagonist (LU-135252) improves the microcirculation and course of TNBS colitis in rats

• Published in: Digestive diseases and sciences Vol. 51; no. 8; pp. 1461 - 1470
• Main Authors: KRUSCHEWSKI, Martin, ANDERSON, Tanja, LODDENKEMPER, Christoph, BUHR, Heinz J
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 01.08.2006; Springer Nature B.V
• Subjects: Animals; Biological and medical sciences; Blood Flow Velocity - drug effects; Capillary Permeability - drug effects; Colitis - drug therapy; Colitis - pathology; Colitis - physiopathology; Colon - blood supply; Disease Models, Animal; Endothelin A Receptor Antagonists; Feeding. Feeding behavior; Fundamental and applied biological sciences. Psychology; Male; Microcirculation - drug effects; Phenylpropionates - therapeutic use; Pyrimidines - therapeutic use; Rats; Rats, Sprague-Dawley; Treatment Outcome; Trinitrobenzenesulfonic Acid - toxicity; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Endothelin; Rat; Rodentia; Metabolic diseases; Endothelin 1; IBD; Microcirculation; Vertebrata; Mammalia; Animal; Gastroenterology; Digestive diseases; Intestinal disease; Antagonist; Colitis; Microcirculation TBNS
• DOI: 10.1007/s10620-005-9019-7
• ISSN: 0163-2116

The role of microcirculation in the pathogenesis and course of chronic inflammatory bowel disease is still unclear. The aim of this study was the evaluation of the role of microcirculation in colitis activity in the rat TNBS (trinitrobenzenesulfonic acid) colitis model using endothelin-1 and a selective endothelin-1 receptor antagonist (LU-135252). Target parameters were capillary blood flow, functional capillary density, vascular permeability, and leukocyte sticking as well as recording of hematocrit, weight course, diuresis, stool quality, and degree of inflammation using a histological colitis score. The acute phase of TNBS colitis is characterized by an extensive disturbance of microcirculation (a significant decrease in capillary blood flow and capillary density and a significant increase in capillary permeability and leukocyte sticking in the mucosa). There is also a significant increase in hematocrit and a significant decrease in diuresis and weight. An exogenous supply of endothelin-1 does not lead to an aggravation of these disorders because of a possible blockage of the endothelin-1 receptors by endogenous endothelin-1 in this florid inflammatory phase. Applying the selective endothelin-1 receptor A antagonist LU-135252 leads to a significant improvement of all microcirculatory parameters and clinical findings compared to the untreated colitis group. Direct improvement of capillary blood flow in the early phase of colitis leads to reduced colitis activity, which underscores the pathogenetic role of the microcirculation in the progression of colitis.