Van Crombruggen Koen, Van Nassauw Luc, Demetter Pieter, Cuvelier Claude, Timmermans Jean-Pierre, Lefebvre Romain A
Heymans Institute of Pharmacology, Ghent University, De Pintelaan 185, 900 Ghent, Belgium.
Eur J Pharmacol. 2008 Jan 28;579(1-3):337-49. doi: 10.1016/j.ejphar.2007.10.021. Epub 2007 Oct 25.
Nitric oxide (NO) has been associated with a spectrum of harmful to protective roles in inflammatory bowel disease. The involvement of soluble guanylate cyclase (sGC)--the downstream effector of NO--in the negative effect of NO in inflammatory models has been proposed but this has not been evaluated in inflammatory bowel diseases. The present study investigates therefore the influence of colonic inflammation on sGC activity, as well as the effect of in vivo sGC inhibition on colonic inflammation and on in vitro changes in colonic motility in the dextran sulfate sodium (DSS)-model of colitis in rat. Administration of 7% DSS in the drinking water for 6 days resulted in colonic inflammation as judged from histology and myeloperoxidase activity, accompanied by weight loss and bloody stools. Plasma and colonic tissue cyclic guanosine 3',5'-monophosphate (cGMP) levels were decreased in DSS-treated rats. Colonic levels of neuronal NO synthase (nNOS) mRNA and immunoreactivity were not influenced, while those of inducible NO synthase (iNOS) and colonic nitrite/nitrate levels were increased by DSS exposure. Circular muscle strips from inflamed distal colon showed decreased inhibitory responses towards electrical field stimulation and exogenous NO, while methacholine-induced phasic activity was suppressed. Inhibition of sGC by in vivo treatment with ODQ further reduced cGMP levels but did not prevent the inflammation and motility alterations. These results suggest that DSS-induced colitis in rats is accompanied by a reduced sensitivity of sGC, leading to reduced basal cGMP levels and decreased colonic responsiveness towards nitrergic stimuli, but pharmacological reduction of cGMP generation does not prevent the development of DSS-induced colitis.
一氧化氮（NO）在炎症性肠病中具有一系列从有害到保护性的作用。可溶性鸟苷酸环化酶（sGC）作为NO的下游效应器，其在炎症模型中对NO负面影响的参与已被提出，但尚未在炎症性肠病中进行评估。因此，本研究调查了结肠炎症对sGC活性的影响，以及体内抑制sGC对大鼠葡聚糖硫酸钠（DSS）结肠炎模型中结肠炎症和结肠运动体外变化的影响。饮用含7% DSS的水6天导致结肠炎症，从组织学和髓过氧化物酶活性判断，同时伴有体重减轻和血便。DSS处理的大鼠血浆和结肠组织环磷酸鸟苷（cGMP）水平降低。结肠神经元型一氧化氮合酶（nNOS）mRNA水平和免疫反应性不受影响，而诱导型一氧化氮合酶（iNOS）水平和结肠亚硝酸盐/硝酸盐水平因DSS暴露而升高。来自炎症远端结肠的环形肌条对电场刺激和外源性NO的抑制反应降低，而乙酰甲胆碱诱导的相性活动受到抑制。用ODQ进行体内处理抑制sGC可进一步降低cGMP水平，但不能预防炎症和运动改变。这些结果表明，DSS诱导的大鼠结肠炎伴有sGC敏感性降低，导致基础cGMP水平降低和结肠对硝化刺激的反应性降低，但药理学上降低cGMP生成并不能预防DSS诱导的结肠炎的发展。
