Pharmrev Fast Forward. Published on August 31, 2011 as DOI:10.1124/pr.111.004515 0031-6997/11/6304-A–AW$25.00 PHARMACOLOGICAL REVIEWS Vol. 63, No. 4 Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics 4515/3704955 Pharmacol Rev 63:A–AW, 2011 Printed in U.S.A. ASSOCIATE EDITOR: MARTIN C. MICHEL Mechanisms of Penile Erection and Basis for Pharmacological Treatment of Erectile Dysfunction K.-E. Andersson Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, North Carolina Abstract............................................................................... C I. Introduction ........................................................................... C II. Central regulation ..................................................................... D III. Central mediators...................................................................... D A. 5-hydroxytryptamine ................................................................ D B. Dopamine .......................................................................... F C. Oxytocin ........................................................................... G D. Noradrenaline ...................................................................... G E. Excitatory amino acids .............................................................. H F. GABA ............................................................................. H G. Adrenocorticotropin and related peptides .............................................. I H. Opioid peptides ..................................................................... I I. Acetylcholine ....................................................................... J J. Hexarelin analog peptides ........................................................... J K. Cannabinoids....................................................................... J L. Pro-vGF-derived peptides ............................................................ J M. Nitric oxide......................................................................... K N. Prolactin ........................................................................... K O. Sexual hormones.................................................................... K IV. Peripheral regulation................................................................... L V. Transmitters and mediators............................................................. L A. Noradrenaline ...................................................................... L B. Endothelins ........................................................................ M C. The renin-angiotensin system ........................................................ N D. Acetylcholine ....................................................................... O E. Dopamine .......................................................................... O F. Serotonin .......................................................................... P G. Vasoactive intestinal peptide and related peptides ..................................... P H. Prostanoids......................................................................... Q I. ATP and adenosine ................................................................. Q J. Nitric oxide and cGMP signaling ..................................................... R 1. Nitric-oxide synthases in the penis................................................. R 2. Guanylyl cyclases ................................................................ S 3. CGMP signaling ................................................................. T 4. Phosphodiesterases............................................................... T 5. Other gaseous mediators.......................................................... U K. Other agents ....................................................................... U 1. Adrenomedullin, calcitonin gene-related peptide, nociceptin .......................... U 2. Endocannabinoids................................................................ V 3. Tumor necrosis factor-␣........................................................... V Address correspondence to: Dr. K.-E. Andersson, Wake Forest Institute for Regenerative Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston Salem, NC 27157. E-mail: [email protected] This article is available online at http://pharmrev.aspetjournals.org. doi:10.1124/pr.111.004515. A Copyright 2011 by the American Society for Pharmacology and Experimental Therapeutics. B ANDERSSON VI. Impulse transmission................................................................... W A. Electrophysiology ................................................................... W In vivo............................................................................. W In vitro ............................................................................ W VII. Excitation-contraction coupling .......................................................... W A. Ionic distribution ................................................................... W B. Kϩ channels ........................................................................ W 1. The BKCa channel................................................................ W 2. The KATP channel ................................................................ X 3. Calcium channels ................................................................ X 4. Chloride channels ................................................................ Y E. Contractile machinery ............................................................... Y 1. Contraction...................................................................... Y a. The RhoA/Rho kinase pathway ................................................. AA 2. Relaxation....................................................................... AB VIII. Pharmacology of current and future therapies ............................................ AB A. Risk factors and conditions associated with erectile dysfunction ......................... AB 1. Endothelial dysfunction........................................................... AB 2. Aging ........................................................................... AB 3. Diabetes mellitus ................................................................ AC 4. Atherosclerosis................................................................... AC 5. Hypercholesterolemia............................................................. AC 6. Smoking ........................................................................ AC 7. Radical prostatectomy ............................................................ AC B. Drugs for treatment of erectile dysfunction ............................................ AC C. Drugs for nonintracavernosal administration .......................................... AD 1. Phosphodiesterase inhibitors ...................................................... AD a. Sildenafil ..................................................................... AE b. Tadalafil ..................................................................... AE c. Vardenafil .................................................................... AE d. Udenafil...................................................................... AE e. Mirodenafil ................................................................... AF f. Lodenafil carbonate ........................................................... AF g. Avanafil ...................................................................... AF h. SLx-2101 ..................................................................... AF 2. Prostaglandin E1 ................................................................. AF 3. Organic nitrates ................................................................. AG 4. Kϩ-channel openers .............................................................. AG 5. ␣-adrenoceptor antagonists. ....................................................... AG a. Phentolamine ................................................................. AG b. Yohimbine .................................................................... AG 6. Opioid receptor antagonists ....................................................... AH 7. Apomorphine .................................................................... AH 8. Trazodone ....................................................................... AH 9. Melanocortin receptor agonists .................................................... AI D. Drugs for intracavernosal administration.............................................. AI 1. Papaverine ...................................................................... AI 2. ␣-adrenoceptor antagonists........................................................ AI a. Phentolamine ................................................................. AI b. Thymoxamine................................................................. AJ 3. Prostaglandin E1 (Alprostadil)..................................................... AJ 4. Vasoactive intestinal polypeptide .................................................. AJ 5. Apomorphine .................................................................... AK 6. Linsidomine chlorhydrate and other NO donors ..................................... AK 7. Combination therapy ............................................................. AL E. Gene therapy ....................................................................... AL F. Angiogenesis therapy...............................................................