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

Br J Pharmacol. 2023 Oct;180(19):2550-2576. doi: 10.1111/bph.16145. Epub 2023 Jun 25.

ABSTRACT

BACKGROUND AND PURPOSE: ET-1 signalling modulates intestinal motility and inflammation, but the role of ET-1/ET_B receptor signalling is poorly understood. Enteric glia modulate normal motility and inflammation. We investigated whether glial ET_B signalling regulates neural-motor pathways of intestinal motility and inflammation.

EXPERIMENTAL APPROACH: We studied ET_B signalling using: ET_B drugs (ET-1, SaTX, BQ788), activity-dependent stimulation of neurons (high K⁺ -depolarization, EFS), gliotoxins, Tg (Ednrb-EGFP)EP59Gsat/Mmucd mice, cell-specific mRNA in Sox10^CreERT2 ;Rpl22-HAflx or ChAT^Cre ;Rpl22-HAflx mice, Sox10^CreERT2 ::GCaMP5g-tdT, Wnt1^Cre2 ::GCaMP5g-tdT mice, muscle tension recordings, fluid-induced peristalsis, ET-1 expression, qPCR, western blots, 3-D LSM-immunofluorescence co-labelling studies in LMMP-CM and a postoperative ileus (POI) model of intestinal inflammation.

KEY RESULTS: In the muscularis externa ET_B receptor is expressed exclusively in glia. ET-1 is expressed in RiboTag (ChAT)-neurons, isolated ganglia and intra-ganglionic varicose-nerve fibres co-labelled with peripherin or SP. ET-1 release provides activity-dependent glial ET_B receptor modulation of Ca²⁺ waves in neural evoked glial responses. BQ788 reveals amplification of glial and neuronal Ca²⁺ responses and excitatory cholinergic contractions, sensitive to L-NAME. Gliotoxins disrupt SaTX-induced glial-Ca²⁺ waves and prevent BQ788 amplification of contractions. The ET_B receptor is linked to inhibition of contractions and peristalsis. Inflammation causes glial ET_B up-regulation, SaTX-hypersensitivity and glial amplification of ET_B signalling. In vivo BQ788 (i.p., 1 mg·kg^-1 ) attenuates intestinal inflammation in POI.

CONCLUSION AND IMPLICATIONS: Enteric glial ET-1/ET_B signalling provides dual modulation of neural-motor circuits to inhibit motility. It inhibits excitatory cholinergic and stimulates inhibitory nitrergic motor pathways. Amplification of glial ET_B receptors is linked to muscularis externa inflammation and possibly pathogenic mechanisms of POI.

PMID:37198101 | DOI:10.1111/bph.16145