Role of endothelin-1 in the gastrointestinal tract of horses in health and disease

Abstract

Gastrointestinal tract disease is the leading natural cause of death in horses and horses with ischemic intestinal disease have the greatest mortality. We hypothesized there is basal synthesis of endothelin-1 (ET-1) in the intestinal tract of healthy horses that is likely involved in regulating vasomotor tone, secretion and motility and that ET-1 synthesis increases with gastrointestinal tract disease, which may be involved in the pathophysiology of these disorders. Plasma ET-like immunoreactivity was increased in horses with naturally-acquired gastrointestinal disease, compared with normal horses; values were greatest in horses with large intestinal strangulation obstruction, enterocolitis and peritonitis. There was an association between ET-1 levels and survival, PCV and duration of signs of pain. Immunohistochemical staining for ET-1 was present in surface epithelium, villi, muscularis and serosa of numerous intestinal segments in healthy horses. Staining was also present in submucosal vessels with veins staining more intense than arteries. Staining appeared more diffuse and intense in samples from horses with intestinal strangulation obstruction. Polymerase chain reaction analysis revealed the presence of ET-1 gene expression in numerous intestinal segments of normal horses. These findings suggest ET-1 is involved in physiologic functions such as regulation of secretion, vasomotor tone and motility, and that increased ET-1 with strangulation obstruction may be involved in the pathophysiology of these disorders. ET-1 caused sustained, concentration-dependent increases in cecal longitudinal smooth muscle tone in vitro, but the magnitude of contraction was less than that induced by carbachol. Pre-incubation of tissues with ETA (BQ-123) and ETB (IRL-1038) receptor antagonists alone did not inhibit ET-1 induced contraction. However, contractile responses were inhibited when tissues were incubated with both antagonists (10-5 M) together, suggesting both ETA and ETB receptors mediate the contraction. Electric field stimulation did not change the contractile response. These studies indicate a physiologic role of ET-1 in the equine gastrointestinal tract and that increased synthesis and release occurs with gastrointestinal tract disease, especially ischemic conditions, and may contribute to the pathophysiology of these disorders. Further studies involving ET-1 and ET antagonists appear warranted.