Management of Erectile Function by Penile Purinergic P2 Receptors in the Diabetic Rat Serap Gur, Philip J. Kadowitz, Asim B. Abdel-Mageed, Muammer Kendirci, Suresh C. Sikka, Geoffrey Burnstock and Wayne J. G. Hellstrom* From the Departments of Urology and Pharmacology, Tulane Health Sciences Center, New Orleans, Louisiana, and Autonomic Neuroscience Institute, Royal Free and University College Medical School (GB), London, United Kingdom Purpose: We determined the role of purine and pyrimidine nucleotides in erectile function in diabetic rats. Materials and Methods: A total of 60 adult male rats were divided into 2 groups, including 30 controls and 30 treated with streptozotocin (60 mg/kg) for 8 weeks to induce hyperglycemia. Changes in intracavernous pressure after intracrural injections of adenosine 5=triphosphate and adenosine 5=triphosphate analogues in control and diabetic rats, and the relaxant response to electrical field stimu- lation of precontracted corpus cavernosum smooth muscle in organ baths were investigated. The localization of P2X1, P2Y1 and P2Y2 receptors was assessed in penile tissue via an immunohistochemical approach. Results: Corpus cavernosum smooth muscle relaxation in vivo and by electrical field stimulation in vitro was significantly decreased in diabetic rats. Adenosine 5=triphosphate (P2X, P2Y), 2-methylthioadenosine 5=triphosphate (P2Y1) and uridine 5=-triphosphate (P2Y2) agonists but not ,-methylene adenosine 5=triphosphate (a P2X1 agonist) significantly improved the erectile response to electrical field stimulation in diabetic rat corpus cavernosum smooth muscle. Although intracavernous pressure/mean arterial pressure values in the rats were not restored in the presence of the P2X1 antagonist PPADS, the relaxation response to electrical field stimulation in isolated corpus cavernosum smooth muscle from diabetic rats was improved. Abundant immunoreactivity for PX1 and P2Y2 receptors was observed in penile tissues from diabetic rats compared to that from control rats. Conclusions: These results demonstrate 1) heterogeneous effects of purinergic agonists on corporeal function in diabetic rats, and 2) the activation of P2Y1 and P2Y2 receptor relaxation of corpus cavernosum smooth muscle to induce erection in rats and perhaps improve erectile function in men with diabetes. Key Words: penis; erectile dysfunction; diabetes mellitus; receptors, purinergic; rats, Sprague-Dawley NUCLEOTIDES such as ATP and UTP modulate cellular function by activat- ing membrane bound P2 receptors. These receptors have been divided into P2X (mainly excitatory) and P2Y (mainly inhibitory) types. 1,2 Seven subtypes of P2X receptors and 8 sub- types of P2Y receptors have been characterized. 1,3 ATP is a NANC neurotransmitter that innervates CCSM. 4 Takahashi et al reported that intracavernous injec- tion of ATP increased ICP and in- duced erection in dogs. 5 In 2000 Lee Abbreviations and Acronyms 2-MeSATP = 2-methylthioATP ,-MeATP = ,-methylene ATP ATP = adenosine 5=triphosphate BSA = bovine serum albumin CCSM = corpus cavernosum smooth muscle EC = endothelial cell ED = erectile dysfunction EFS = electrical field stimulation ICP = intracavernous pressure MAP = mean arterial pressure NANC = nonadrenergic noncholinergic NO = nitric oxide PE = polyethylene PKC = protein kinase C PPADS = pyridoxal-phosphate-6- azophenyl-2=,4=-disulfonate RB2 = reactive blue-2 STZ = streptozotocin UTP = uridine 5=-triphosphate Submitted for publication July 9, 2008. Study received Tulane University animal care and use committee approval. * Correspondence: Section of Andrology, De- partment of Urology, Tulane University Health Sci- ences Center, 1430 Tulane Ave., SL-42, New Or- leans, Louisiana 70112 (telephone: 504-988-7308; FAX: 504- 988-5059; e-mail: whellst@tulane.edu). 0022-5347/09/1815-2375/0 Vol. 181, 2375-2382, May 2009 THE JOURNAL OF UROLOGY ® Printed in U.S.A. Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION DOI:10.1016/j.juro.2009.01.002 www.jurology.com 2375