The protective effect of endothelin receptor antagonists against surgically induced impairment of gastrointestinal motility in rats

Abstract

Endothelin (ET) receptor antagonists: BQ-123 (ETA), BQ-788 (ETB), tezosentan (dual ET receptor antagonist) protect against the development of postoperative ileus (POI) evoked by ischemia-reperfusion (I/R). The current experiments explored whether ET antagonists prevent the occurrence of POI evoked by surgical gut manipulation. Intestinal transit was assessed by measuring the rate of dye migration subsequent to skin incision (SI), laparotomy (L), or laparotomy and surgical gut handling (L+M) in diethyl ether anaesthesized rats (E). Experimental animals were randomly sub-divided into two groups depending on the time of recovery following surgery: viz. either 2 or 24 h (early or late phase POI). E and SI did not affect the gastrointestinal (GI) transit. In contrast, L and L+M significantly reduced GI motility in comparison to untreated group (UN). Tezosentan (10 mg/kg), BQ-123 and BQ-788 (1 mg/kg) protected against development of L+M evoked inhibition of intestinal motility in the course of late phase, but not early phase POI. Furthermore, tezosentan alleviated the decrease in the contractile response of the longitudinal jejunal smooth muscle strips to carbachol in vitro induced by L+M. The serum ET(1–21) concentration was not increased in either the early or the late phase POI groups after surgery compared to control animals. This study indicates that delay in the intestinal transit in late phase of surgically induced POI involves an ET-dependent mechanism.

BQ788 reveals glial ETB receptor modulation of neuronal cholinergic and nitrergic pathways to inhibit intestinal motility: Linked to postoperative ileus

“…Disruption of glial functions leads to abnormal intestinal motility (Ługowska-Umer et al, 2019;Nasser et al, 2006). Alterations in glial ET-1/ ET B receptor signalling is a property of 'reactive' glia in the inflamed gut of POI as demonstrated in our study.…”

“…Earlier pharmacological studies on endothelin in guinea pig or rat suggested that ET‐1 was involved in modulating motility, although the cellular distribution and function of ET B receptors in neurons, glia or muscle were unclear (Egidy et al, 2000; Shahbazian & Holzer, 2000; Lin & Lee, 1992; Yoshimura et al, 1996; Ługowska‐Umer et al, 2019; Yoshinaga et al, 1992). Tg‐Ednrb‐EGFP reporter mice (Gong et al, 2003) for Ednrb (ET B receptor) were instrumental in the identification of ET B receptors in the gut because antisera were not suitable for labelling ET B receptors in gut tissues.…”

“…Enteric glia serve an essential role in intestinal function (Grubišić & Gulbransen, 2017; MacEachern et al, 2015; Rao et al, 2017), motility and diseases (Grubišić & Gulbransen, 2017; Gulbransen & Christofi, 2018; Lilli et al, 2018; Liñán‐Rico et al, 2016; McClain et al, 2014; Nasser et al, 2006; Ochoa‐Cortes et al, 2016; Rao et al, 2017; Schneider et al, 2021, 2022; Stoffels et al, 2014). Disruption of glial functions leads to abnormal intestinal motility (Ługowska‐Umer et al, 2019; Nasser et al, 2006). Alterations in glial ET‐1/ ET B receptor signalling is a property of ‘reactive’ glia in the inflamed gut of POI as demonstrated in our study.…”