RESUMEN
Angiotensin II (Ang II) regulates colon contraction, acting not only directly on smooth muscle but also indirectly, interfering with myenteric neuromodulation mediated by the activation of AT1 /AT2 receptors. In this article, we aimed to explore which mediators and cells were involved in Ang II-mediated colonic contraction in the TNBS-induced rat model of colitis. The contractile responses to Ang II were evaluated in distinct regions of the colon of control animals or animals with colitis in the absence and presence of different antagonists/inhibitors. Endogenous levels of Ang II in the colon were assessed by ELISA and the number of AT1/AT2 receptors by qPCR. Ang II caused AT1 receptor-mediated colonic contraction that was markedly decreased along the colons of TNBS-induced rats, consistent with reduced AT1 mRNA expression. However, the effect mediated by Ang II is much more intricate, involving (in addition to smooth muscle cells and nerve terminals) ICC and EGC, which communicate by releasing ACh and NO in a complex mechanism that changes colitis, unveiling new therapeutic targets.
Asunto(s)
Angiotensina II/genética , Colitis/genética , Enfermedades Inflamatorias del Intestino/genética , Sistema Renina-Angiotensina/genética , Antagonistas de Receptores de Angiotensina/farmacología , Animales , Colitis/fisiopatología , Colon/metabolismo , Colon/patología , Sistema Nervioso Entérico/metabolismo , Sistema Nervioso Entérico/patología , Humanos , Enfermedades Inflamatorias del Intestino/patología , Células Intersticiales de Cajal/metabolismo , Células Intersticiales de Cajal/patología , Masculino , Contracción Muscular/genética , Contracción Muscular/fisiología , Músculo Liso Vascular/efectos de los fármacos , Neuroglía/metabolismo , Neuroglía/patología , Óxido Nítrico/metabolismo , Ratas , Receptor de Angiotensina Tipo 1/genética , Receptor de Angiotensina Tipo 2/genética , Transmisión Sináptica/genéticaRESUMEN
Reproducibility in animal research is crucial for its reliance and translational relevance. The 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced model of inflammatory bowel disease (IBD) is widely used but inconsistently and incompletely characterized throughout the literature. This hinders comparisons between studies and influences the low rate of translation of effective preclinical molecules. The purpose of this study was to categorize TNBS-induced colitis, based on macroscopic and microscopic scoring systems, and to identify basic routine parameters that could anticipate those categories. We retrospectively analysed male Wistar Rattus norvegicus (n=28 for the control group and n=87 for the TNBS group) and categorized TNBS-induced colitis in three phenotypes: Mild, Moderate and Severe colitis, as for human IBD. Also, we showed that the time course of food intake and fecal excretion (but not body weight, fluid intake or welfare scores) could foresee those categories. So, routine evaluation of food intake and fecal excretion may guide researchers in planning their experiments, selecting the animals with the severity of colitis that better matches their aims, or applying early humane endpoints to animals that will not be used in the experiments. In conclusion, categorizing TNBS-induced colitis enhances the reproducibility of data gathered with this experimental model and strengths its translational relevance.