OBJECTIVE: To investigate the ability of acute administration of the endogenous cannabinoid, anandamide, in vitro to alter the nonadrenegic noncholinergic (NANC)-mediated relaxation of corpus cavernosum (CC) in diabetic rats and the possible role of nitric oxide (NO), as it is well known that erectile dysfunction (ED) affects 35-75% of men with diabetes mellitus and several studies have been conducted to find appropriate strategies for treating diabetes-induced ED. MATERIALS AND METHODS: Diabetes was induced in rats by streptozotocin administration and was maintained for 8 weeks. The CC were removed and isolated in organ baths for pharmacological studies. Agonist-evoked or electrical-field stimulation (EFS)-evoked smooth muscle tensions in CC strips from control and diabetic rats were measured. RESULTS: The neurogenic relaxation of phenylephrine (7.5 microm)-precontracted isolated CC strips was impaired in diabetic rats. Anandamide (0.3, 1 and 3 microm) enhanced the relaxant responses to EFS in diabetic CC strips in a dose-dependent manner. This effect was antagonized by the selective cannabinoid CB(1) receptor antagonist AM251 (1 microm) and the selective vanilloid receptor antagonist capsazepine (3 microm). Concurrent administration of partially effective doses of l-arginine (10 microm) and anandamide (0.3 microm) exerted a synergistic improvement in EFS-induced relaxation of diabetic CC strips (P < 0.001). The relaxant responses to the NO donor, sodium nitroprusside, were similar between diabetic and control groups. CONCLUSION; For the first time, we show that acute administration of anandamide, an endogenous cannabinoid, alone or combined with l-arginine can improve nitrergic nerve-mediated relaxation of the CC in diabetic rats. This effect was mediated by cannabinoid CB(1) and vanilloid VR(1) receptors within the CC.