PURPOSE: This study was designed to investigate the role of chronic endothelin receptor antagonism to preserve erectile function in diabetic rats. MATERIALS AND METHODS: Forty adult male Sprague-Dawley rats (250-350 gm) were divided into 4 groups: Group 1, non-diabetic control rats (n=5); Group 2, non-diabetic rats fed 10 mg/kg of RO-485695, a combined endothelin receptor antagonist (n=5); Group 3, diabetic control (n=15); Group 4, diabetic rats fed 10 mg/kg of RO-485695 (n=15). Streptozotocin, 65 mg/kg, was used for development of diabetes mellitus. Body weight and blood glucose levels were measured every 2 weeks and drug feeding was done by oral gavage. Twelve weeks after induction of diabetes and RO-485695 treatment, erectile function was determined by measurement of intracavernosal pressure (ICP) and maximal arterial pressure (MAP) after electrical stimulation of the cavernosal nerve. RT-PCR analysis for detection of mRNA of endothelin-1, endothelin receptor A (ET-A), and endothelin receptor B (ET-B), and Western blot analysis and immunohistochemical evaluation of the eNOS protein were performed. RESULTS: Body weight and blood glucose levels were not influenced by 10 mg/kg of RO-485695. Erectile function after 5 volts stimulation was significantly decreased in the diabetic rat (group 3 & 4) compared with the non-diabetic rat (group 1 & 2) (64.3+/-9.6 vs 41.9+/-14.8 mmHg), but increased in group 4 compared with group 3 (44.3+/-16.9 vs 36.6+/-10.1 mmHg). The mRNA expression of endothelin-1 was up-regulated significantly in group 3 & 4 when compared with group 1 & 2. However this endothelin expression was down-regulated in group 4 compared with group 3. The mRNA expression of ET-A among 4 groups was not significantly different. ET-B band in rat cavernosal tissue could not be observed in any group under these conditions. eNOS protein expression was increased in group 4 compared with group 3. CONCLUSIONS: Chronic endothelin receptor antagonism in the experimental diabetic rat model has been demonstrated to preserve cavernosal erectile function, suggesting a possible therapeutic role for endothelin receptor antagonists in diabetic erectile dysfunction.