For erection to take place, the penile arteries and sinusoids have to dilate, thereby increasing the blood flow into the penis. There is increasing evidence that release of L-arginine derived nitric oxide (NO) from nonadrenergic-noncholinergic (NANC) nerves and from the sinusoidal endothelium is a major event in penile smooth muscle relaxation and promotes the endogenous formation of cyclic guanosine monophosphate (cGMP). Nitrovasodilators can be attributed to the activation of soluble guanylate cyclase, resulting in an increase in intracellular level of cyclic guanosine monophosphate, but prolonged exposure to high levels of nitroglycerine and other organic nitroesters induces tolerance against the cardiovascular effect. In this study, the aim was to determine the effect of diabetes on the corporal smooth muscle relaxant effect of ISDN and the effect of diabetes on the process of tolerance to the drug. For this purpose, alloxan-induced diabetic rabbits were used to form diabetes group. The responses of the corpus cavernous strips obtained from control and alloxan-induced diabetic rabbit were studied in organ chamber. In conclusion, prolonged in vitro exposure of corpus cavernosum strips obtained from control and diabetic groups to high concentrations of ISDN caused significant desensitization to the relaxant effect the drug. So, prolonged exposure of corporal tissue to the agents like nitroglycerine, used for treatment of impotence, may render ineffective the therapy in diabetic erectile impotence. However, intolerance to nitric oxide provides a rationale for the concept of using nitro oxide agents (like SNP) in the treatment of diabetic erectile dysfunction. (C) 2000 Academic Press.