Endothelin-1 Receptor Antagonist (LU-135252) Improves the Microcirculation and Course of TNBS Colitis in Rats

Abstract

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.

Relationship between inflammation and tissue hypoxia in a mouse model of chronic colitis

“…While this may be the first demonstration of enhanced hypoxia in a T-cell transfer model of colitis, previous reports indicate that the inflammatory response to rectal installation of TNBS also induces elevations in colonic hypoxia (3, 4), and also reduces capillary density and mucosal blood flow (11–13). In contrast to our T-cell transfer model, enhanced hypoxia with TNBS is not likely related to hematocrit, with the TNBS-induced increase in hematocrit speculated to be due to a fluid shift out of the circulation due to increased vascular permeability (12).…”

Vasopressin Induces Rectosigmoidal Mucosal Ischemia During Cardiopulmonary Bypass

“…ET‐1 causes vasoconstriction through ET A receptors located on vascular smooth muscle cells and results in microcirculatory disturbances of the colon . Accordingly, ET receptor blockade has been shown to improve the gastrointestinal microcirculation in inflammatory diseases, most probably by interrupting the ET‐1/ET A receptor interaction . ET‐1, however, may also act vasodilatory by binding to ET B receptors .…”

eNOS involved in colitis-induced mucosal blood flow increase

“…Buhr and colleagues (7,(21)(22)(23), using intravital microscopy, have repeatedly observed an increased mucosal blood flow within 24 h after induction of colitis with TNBS and a reduced blood flow after 3 days. Deniz et al (6) recorded decreased arterial mesenteric blood flow at early stages in TNBS-induced colitis in mice.…”

“…The regulation of colonic mucosal blood flow is poorly understood, and its importance during colonic injury is still unclear. Studies in recent years have yielded contradictory data, showing either an increased (8,11,14,27) or a decreased (7,11,21,22,38) blood flow in different animal models of colitis, using a variety of measuring techniques. The few blood flow studies conducted in humans with IBD have indicated that the mucosal blood flow is increased in inflamed regions (3,15).…”