Objective: Inflammatory Bowel Diseases (IBD), are severe gastrointestinal (GI) disorders, withunknown aetiology, characterized by a chronic intestinal inflammatory reaction, progressivelyaffecting GI functions, as gut motility. During inflammatory events, modifications in thefunctionality of some enteric modulators could contribute to the pathological changes of GI motorpatterns. Angiotensin II (Ang II), the main effector of the renin-angiotensin system (RAS), has beenrecently reported as novel regulator of GI motility, acting on the specific receptors (AT1R andAT2R) located on the gut wall. Since recent studies have pointed out an involvement of RAS systemin GI inflammation, we explored the RAS functionality and its eventual contribution to colonicdismotility in a rat model of IBD. Methods: Colitis was induced in rats by intrarectal administrationof 2,4-Dinitrobenzene sulfonic acid (DNBS). Colonic damage was assessed by disease activity index(DAI), macroscopic and microscopic scores, myeloperoxidase activity (MPO) and TNF- tissuelevels on day 6 after induction of colitis. Effects of Ang II on the contractility of colonic longitudinalmuscle strips was recorded isometrically. Effect of 6- day intraperitoneal treatment with PD123319(3 mg/kg) on amelioration of colitis induced by DNBS was examined in separate group of animals.Results: Colonic strips from IBD rats presented, compared to control preparations, an alteredspontaneous activity, characterised by lower in amplitude contractions, and reduced sensitivity tocarbachol (CCh), a muscarinic cholinergic receptor agonist, and to Isoproterenol (Iso), adrenergicreceptor agonist. Ang II induced a concentration-dependent muscular contraction in both preparation,which was decreased with a rightward shift of the concentration–response curve in IBD animals.Ang II-evoked contraction was reduced, in both preparations, by Losartan, AT1R antagonist.PD123319, AT2R antagonist, caused a significant enhancement of Ang II response only in inflamedtissues. PD123319 effects were mimicked by L-NNA, nitric oxide synthase inhibitor, and by TTX,neural blocker,. The joint application of PD123319 and L-NNA or PD123319 and TTX had noadditive effects. Indeed, in IBD preparations, PD 123319 per se ameliorated the mechanical activityincreasing both the spontaneous contractions and the sensitivity to CCh and Iso. Daily PD123319treatment ameliorated the severity of colitis, specially reducing DAI and improving mechanicalactivity. Conclusions: Ang II contracts longitudinal muscle of rat colon via activation of postjunctionalAT1R. During inflammation, tonic activation of AT2R, coupled to the nitrergic signalling,counteract AT1 excitatory effects and would contribute to the reduction of muscle contractility.Pharmacological manipulation of the RAS system seems to improve some IBD symptoms and couldprovide a future therapeutic strategy for treatment of IBD-associated intestinal dismotility.
|Numero di pagine||1|
|Rivista||NEUROGASTROENTEROLOGY & MOTILITY|
|Stato di pubblicazione||Published - 2015|