Inhibitory effect of sildenafil on pyloric sphincter from streptozotocin-diabetic rats: role of no-cGMP transduction pathway

Long-standing and poorly controlled diabetes may result disturbances in gastrointestinal function of which gastroparesis is one of the more common. Previous studies have shown that nitric oxide-cyclic guanosine monophosphate transduction pathway has a regulatory role in gastrointestinal motility. But, this drive is adversely affected by diabetes mellitus. Sildenafil, as a selective inhibitor of cyclic guanosine monophosphate-selective phosphodiesterase type 5, has also beneficial effect in diabetic patients with gastrointestinal symptoms. In this study, we aimed to investigate the effect of sildenafil and its underlying mechanisms on pylorus motility of diabetic rats. Acetylcholine (10(-8)-10(-3) M) produced concentration-dependent contraction responses that is significantly attenuated by sildenafil (10(-6) M) incubation. On the other hand, sildenafil elicited relaxant effect in rat pylorus precontracted by acetylcholine. The relaxant responses to sildenafil partially, but significantly, inhibited by nitric oxide synthase blocker N-nitro-L-arginine methyl ester (L-NAME, 10(-4) M) or soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10(-5) M). These results demonstrated that sildenafil continue to relax diabetic rat pylorus despite a nitric oxide-cyclic guanosine monophosphate pathway inhbition. Hence, other mechanisms (calcium dynamics, acetylcholine metabolism) may also contribute to its relaxant effect. The results also suggest the potential use of sildenafil for improving gastroparesis in diabetic patients.