Study on the cyclic GMP-dependency of relaxations to endogenous and exogenous nitric oxide in the mouse gastrointestinal tract

Background and purpose: cGMP mediates nitrergic relaxations of intestinal smooth muscle, but several studies have indicated that cGMP-independent mechanisms may also be involved. We addressed this contention by studying the effect of ODQ and NS2028, specific inhibitors of soluble guanylate cyclase, on nitrergic relaxations of the mouse gut. Experimental approach: Mouse gastric fundus and small intestinal muscle preparations were mounted in organ baths to study relaxations to exogenous NO, NO donors and electrical field stimulation (EFS) of enteric nerves. Key results: In gastric fundus longitudinal muscle strips, ODQ and NS2028 abolished the L-nitroarginine-sensitive relaxations to EFS and the relaxations to NO and NO donors, glyceryl trinitrate (GTN), SIN-1 and sodium nitroprusside (SNP). EFS of intestinal segments and muscle strips showed L-nitroarginine-resistant relaxations, which were abolished by the purinoceptor blocker suramin. In the presence of suramin, ODQ and NS2028 abolished all relaxations to EFS in intestinal segments and strips. ODQ and NS2028 abolished the relaxations to exogenous NO and to the NO donors GTN, SIN-1 and SNP in circular and longitudinal intestinal muscle strips. Intestinal segments showed residual relaxations to NO and GTN. Conclusions and Implications: Our results indicate that relaxations to endogenous NO in the mouse gastric fundus and small intestine are completely dependent on cGMP. ODQ and NS2028 incompletely blocked nitrergic relaxations to exogenous NO in intact intestinal segments. However, it is unlikely that this is due to the involvement of cGMP-independent pathways because ODQ and NS2028 abolished all relaxations to endogenous and exogenous NO in intestinal muscle strips.