Inhibition of nitric oxide synthesis potentiates the colonic permeability increase triggered by luminal bile acids Y. Sun, 1 B.-M. Fihn, 1 M. Jodal 1 and H. Sjo ¨vall 2 1 Department of Physiology, University of Go¨teborg, Go¨teborg, Sweden 2 Department of Internal Medicine, University of Go¨teborg, Go¨teborg, Sweden Received 18 February 2003, accepted 25 September 2003 Correspondence: H. Sjo¨ vall, Department of Internal Medicine, Sahlgren’s University Hospital, S-413 45 Go¨ teborg, Sweden. Abstract Aim: Experiments were performed in anaesthetized rats to clarify the role of nitric oxide (NO) in the control of colonic permeability. Methods: Colonic luminalpressure, the transmucosal potentialdifference (PD) and the clearance of [ 3 H] mannitol and [ 14 C] urea from blood to lumen were measured.NO synthesis was blocked with N x -nitro-l-arginine (l-NNA) i.v. and mucosal permeability was increased by deoxycholic acid (DCA, 4 mm). The involvement of histamine in the response was studied by giving the histamine H 1 receptor blocker pyrilamine. Results: In proximal colon, l-NNA per se increased luminal pressure and PD but had no significant effecton clearance. DCA per se increased luminal pressure, had no significant effect on PD, but increased mannitol and urea clearance and the clearance ratio. l-NNA and pyrilamine both blocked the luminal pressure effect of DCA but l-NNA had no significant effect on the clearance response to DCA. In distal colon, l-NNA per se had no significant effect on pressure and clearance, but increased PD like in proximal colon. DCA had no significant effect on luminal pressure, but markedly reduced PD and increased both clearance and clearance ratio. In this segment, l-NNA signifi- cantly potentiated the clearance response to DCA, and further increased clearance ratio to a value not significantly different from unity (1.00 0.05). Conclusion: The data suggest that in vivo, moderate concentrations of bile acids increase colonic permeability in rats via a mechanism that is inhibited by NO in distal but not in proximal colon.In distalcolon,NO may con- tribute to the maintenance of epithelial barrier function. Keywords bile acids,colonic mucosa, enteric nervous system, histamine receptor, nitric oxide. Nitric oxide (NO) is an inhibitory enteric neurotrans- mitter that contributes to non-adrenergic non-choliner- gic (NANC) relaxation of smooth muscle (Lincoln et al. 1997). NO may also participate in the control of mucosalpermeability, but this function is not well understood. The source of this NO may be neural or epithelial. NO synthase (NOS)-positive neurones inner- vate the colonic epithelium (Ekblad et al. 1994), but the epithelial cells can also express NOS mRNA (Torihashi et al. 1996). Epithelial inducible NO synthesis is prob- ably the main source of the very high NO levels seen in inflammatoryboweldiseaseand collagenouscolitis (Perner et al. 2002).Several observations suggest that NO may have a dominating protective role in permeab- ility control.Blocking endogenous NO synthesis thus increases permeability in the duodenum (Ha ¨llgren et al. 1997) and the small intestine(Kubes 1992), and exacerbates intestinalmucosalinjury caused by,e.g. mesenteric ischaemia (Kubes 1993) and endotoxaemia (Hutcheson et al. 1990).The mechanism behind this protective effect is unknown. One possibility is that NO makesthe tight junction proteinsmoreresistantto chemical damage (Wu et al. 1998).It may also be an indirect mechanism as NO seems to inhibit activation of Acta Physiol Scand 2004, 180, 167–175 Ó 2004 Scandinavian Physiological Society 167