Vardenafil and Resveratrol Synergistically Enhance the Nitric Oxide/Cyclic Guanosine Monophosphate Pathway in Corpus Cavernosal Smooth Muscle Cells and Its Therapeutic Potential for Erectile Dysfunction in the Streptozotocin-Induced Diabetic Rat: Preliminary Findings Shinichiro Fukuhara, MD, Akira Tsujimura, MD, PhD, Hidenobu Okuda, MD, Keisuke Yamamoto, MD, Tetsuya Takao, MD, PhD, Yasushi Miyagawa, MD, PhD, Norio Nonomura, MD, PhD, and Akihiko Okuyama, MD, PhD Department of Urology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan DOI: 10.1111/j.1743-6109.2010.02193.x ABSTRACT Introduction. Phosphodiesterase type 5 (PDE5) inhibitors are very effective agents for erectile dysfunction; however, specific patient populations are hard to treat. The efficacy of PDE5 inhibitors is limited because a minimum amount of nitric oxide (NO) is necessary. Resveratrol, a plant polyphenol, is reported to activate endothelial NO synthase (eNOS) through activation of sirtuin 1. We previously reported that human corpus cavernosal smooth muscle cells (CCSMCs) express eNOS and synthesize cyclic guanosine monophosphate (cGMP) via the NO/cGMP pathway. Aim. To investigate the ability of resveratrol and/or vardenafil to increase cGMP in an in vitro model using CCSMCs and to improve erectile function in an in vivo rat model of streptozotocin (STZ)-induced diabetes. Methods. CCSMCs were treated with resveratrol and/or vardenafil. Twenty male Sprague-Dawley rats were ran- domly divided into five groups (N = 4 in each group): age-matched controls, diabetic controls, and diabetic rats treated with resveratrol, vardenafil, or both in combination for the last 4 weeks of an 8-week period of diabetes induction. Main Outcome Measures. Intracellular cGMP measurement, intracovernous pressure (ICP)/mean arterial pressure (MAP) ratio, and smooth muscle/collagen ratio. Results. Intracellular cGMP level was elevated by resveratrol treatment in CCSMCs. The combination treatment of resveratrol and vardenafil had a synergistic effect. Diabetic rats showed impairment of erectile function. Treatment with either resveratrol or vardenafil improved ICP/MAP ratio, and combination therapy with resveratrol and vardenafil had a synergistic effect in improvement of ICP/MAP. Conclusions. Treatment with either resveratrol or vardenafil elevated cGMP level in CCSMCs and improved erectile function in STZ-induced diabetic rats. Furthermore, a synergistic effect was observed in vitro and in vivo. Resveratrol or combination therapy of resveratrol and vardenafil can improve erectile function in which NO release is impaired, although further study is needed to confirm the results. Fukuhara S, Tsujimura A, Okuda H, Yamamoto K, Takao T, Miyagawa Y, Nonomura N, and Okuyama A. Vardenafil and resveratrol synergisti- cally enhance the nitric oxide/cyclic guanosine monophosphate pathway in corpus cavernosal smooth muscle cells and its therapeutic potential for erectile dysfunction in the streptozotocin-induced diabetic rat: Preliminary findings. J Sex Med 2011;8:1061–1071. Key Words. Resveratrol; Vardenafil; Nitric Oxide; Cyclic GMP; Phosphodiesterase Type 5 Inhibitors 1061 © 2011 International Society for Sexual Medicine J Sex Med 2011;8:1061–1071