Losartan, an Angiotensin Type I Receptor, Restores Erectile Function by Downregulation of Cavernous Renin-Angiotensin System in Streptozocin-Induced Diabetic Rats Rong Yang, MD,* Bin Yang, MD,* Yanting Wen, MD,* Feng Fang, PhD, † Souxi Cui, MD, ‡ Guiting Lin, MD, PhD, § Zeyu Sun, MD,* Run Wang, MD, FACS, ¶ and Yutian Dai, MD, PhD* *Affiliated Drum Tower Hospital of Nanjing University, School of Medicine—Urology, Nanjing, China; † Institution of Biology, Nanjing University, Nanjing, China; ‡ Nanjing Medical School—Clinical Medicine, Nanjing, China; § University of California, San Francisco—Urology, San Francisco, China: ¶ University of Texas Medical School at Houston and M.D. Anderson Cancer Center—Urology, Houston, Texas, USA DOI: 10.1111/j.1743-6109.2008.01054.x ABSTRACT Introduction. The high incidence of erectile dysfunction (ED) in diabetes highlights the need for good treatment strategies. Recent evidence indicates that blockade of the angiotensin type I receptor (AT1) may reverse ED from various diseases. Aim. To explore the role of cavernous renin-angiotensin system (RAS) in the pathogenesis of diabetic ED and the role of losartan in the treatment of diabetic ED. Methods. The AT1 blocker (ARB) losartan (30 mg/kg/d) was administered to rats with streptozocin (65 mg/kg)- induced diabetes. Erectile function, cavernous structure, and tissue gene and protein expression of RAS in the corpora cavernosa were studied. Main Outcome Measure. We sought to determine the changes of cavernous RAS in the condition of diabetes and after treatment with losartan. Results. RAS components (angiotensinogen, [pro]renin receptor, angiotensin-converting enzyme [ACE], and AT1) were expressed in cavernosal tissue. In diabetic rats, RAS components were upregulated, resulting in the increased concentration of angiotensin II (Ang II) in the corpora. A positive feedback loop for Ang II formation in cavernosum was also identified, which could contribute to overactivity of cavernous RAS in diabetic rats. Administration of losartan blocked the effect of Ang II, downregulated the expression of AT1 and Ang II generated locally, and partially restored erectile function (losartan-treated group revealed an improved intracavernous pressure/mean systemic arterial pressure ratio as compared with the diabetic group (0.480  0.031 vs. 0.329  0.020, P < 0.01). However, losartan could not elevate the reduced smooth muscle/collagen ratio in diabetic rats. Conclusions. The cavernous RAS plays a role in modulating erectile function in corpora cavernosa and is involved in the pathogenesis of diabetic ED. ARB can restore diabetic ED through downregulating cavernous RAS. Yang R, Yang B, Wen Y, Fand F, Cui S, Lin G, Sun Z, Wang R, and Dai Y. Losartan, an angiotensin type I receptor blocker, restores erectile function by down-regulation of cavernous renin-angiotensin system in streptozocin-induced diabetic rats. J Sex Med 2009;6:696–707. Key Words. Angiotensin; Losartan; Animal Model Diabetes Introduction E rectile dysfunction (ED) is a common com- plication of diabetes mellitus (DM). The prevalence of erectile dysfunction in male diabetic patients is estimated to be between 35% and 75%, which is three times the incidence in nondiabetic men [1]. The high incidence of ED in diabetes underscores the need for optimal treatment strategies. The pathophysiology of diabetic ED is multi- factorial (including neural, vascular, endocrine, 696 J Sex Med 2009;6:696–707 © 2008 International Society for Sexual Medicine