Objective: Inflammatory Bowel Diseases (IBD), are severe gastrointestinal (GI) disorders, with unknown aetiology, characterized by a chronic intestinal inflammatory reaction, progressively affecting GI functions, as gut motility. During inflammatory events, modifications in the functionality of some enteric modulators could contribute to the pathological changes of GI motor patterns. Angiotensin II (Ang II), the main effector of the renin-angiotensin system (RAS), has been recently reported as novel regulator of GI motility, acting on the specific receptors (AT1R and AT2R) located on the gut wall. Since recent studies have pointed out an involvement of RAS system in GI inflammation, we explored the RAS functionality and its eventual contribution to colonic dismotility in a rat model of IBD. Methods: Colitis was induced in rats by intrarectal administration of 2,4-Dinitrobenzene sulfonic acid (DNBS). Colonic damage was assessed by disease activity index (DAI), macroscopic and microscopic scores, myeloperoxidase activity (MPO) and TNF- tissue levels on day 6 after induction of colitis. Effects of Ang II on the contractility of colonic longitudinal muscle 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 altered spontaneous activity, characterised by lower in amplitude contractions, and reduced sensitivity to carbachol (CCh), a muscarinic cholinergic receptor agonist, and to Isoproterenol (Iso), adrenergic receptor 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 inflamed tissues. 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 no additive effects. Indeed, in IBD preparations, PD 123319 per se ameliorated the mechanical activity increasing both the spontaneous contractions and the sensitivity to CCh and Iso. Daily PD123319 treatment ameliorated the severity of colitis, specially reducing DAI and improving mechanical activity. Conclusions: Ang II contracts longitudinal muscle of rat colon via activation of postjunctional AT1R. 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 could provide a future therapeutic strategy for treatment of IBD-associated intestinal dismotility.

zizzo mg, auteri m, caldara g , serio r (2015). Differential recruitment of Angiotensin II receptors in the modulation of rat colonic contractile activity in experimental inflammation. NEUROGASTROENTEROLOGY & MOTILITY(27), 109-109.

Differential recruitment of Angiotensin II receptors in the modulation of rat colonic contractile activity in experimental inflammation

ZIZZO, Maria Grazia;AUTERI, Michelangelo;Caldara, Gaetano Felice;SERIO, Rosa Maria
2015-01-01

Abstract

Objective: Inflammatory Bowel Diseases (IBD), are severe gastrointestinal (GI) disorders, with unknown aetiology, characterized by a chronic intestinal inflammatory reaction, progressively affecting GI functions, as gut motility. During inflammatory events, modifications in the functionality of some enteric modulators could contribute to the pathological changes of GI motor patterns. Angiotensin II (Ang II), the main effector of the renin-angiotensin system (RAS), has been recently reported as novel regulator of GI motility, acting on the specific receptors (AT1R and AT2R) located on the gut wall. Since recent studies have pointed out an involvement of RAS system in GI inflammation, we explored the RAS functionality and its eventual contribution to colonic dismotility in a rat model of IBD. Methods: Colitis was induced in rats by intrarectal administration of 2,4-Dinitrobenzene sulfonic acid (DNBS). Colonic damage was assessed by disease activity index (DAI), macroscopic and microscopic scores, myeloperoxidase activity (MPO) and TNF- tissue levels on day 6 after induction of colitis. Effects of Ang II on the contractility of colonic longitudinal muscle 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 altered spontaneous activity, characterised by lower in amplitude contractions, and reduced sensitivity to carbachol (CCh), a muscarinic cholinergic receptor agonist, and to Isoproterenol (Iso), adrenergic receptor 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 inflamed tissues. 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 no additive effects. Indeed, in IBD preparations, PD 123319 per se ameliorated the mechanical activity increasing both the spontaneous contractions and the sensitivity to CCh and Iso. Daily PD123319 treatment ameliorated the severity of colitis, specially reducing DAI and improving mechanical activity. Conclusions: Ang II contracts longitudinal muscle of rat colon via activation of postjunctional AT1R. 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 could provide a future therapeutic strategy for treatment of IBD-associated intestinal dismotility.
2015
Settore BIO/09 - Fisiologia
Neurogastro 2015
istanbul
4-6 giugno 2015
zizzo mg, auteri m, caldara g , serio r (2015). Differential recruitment of Angiotensin II receptors in the modulation of rat colonic contractile activity in experimental inflammation. NEUROGASTROENTEROLOGY & MOTILITY(27), 109-109.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10447/199049
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