Regular Papers

Asian Journal of Andrology (2008) 10, 433–440; doi:10.1111/j.1745-7262.2008.00396.x

Review

Molecular Yin and Yang of erectile function and dysfunction

Ching-Shwun Lin1, Zhong-Cheng Xin2, Zhong Wang3, Guiting Lin1 and Tom F Lue1

  1. 1Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, CA 94143, USA
  2. 2Andrology Center, Peking University First Hospital, Beijing 100009, China
  3. 3Department of Urology, Ninth Hospital, Shanghai Second Medical University, Shanghai 200011, China

Correspondence: Dr Ching-Shwun Lin, Knuppe Molecular Urology Laboratory, University of California, San Francisco, CA 94143, USA. Fax: +1-415-476-3803. E-mail: clin@urology.ucsf.edu

Received 21 December 2007; Accepted 21 January 2008.

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Abstract

In regard to erectile function, Yin is flaccidity and Yang erection. In the past decade, research has mostly focused on the Yang aspect of erectile function. However, in recent years, the Yin side is attracting increasingly greater attention. This is due to the realization that penile flaccidity is no less important than penile erection and is actively maintained by mechanisms that play critical roles in certain types of erectile dysfunction (ED); for example, in diabetic patients. In addition, there is evidence that the Yin and Yang signaling pathways interact with each other during the transition from flaccidity to erection, and vice versa. As such, it is important that we view erectile function from not only the Yang but also the Yin side. The purpose of this article is to review recent advances in the understanding of the molecular mechanisms that regulate the Yin and Yang of the penis. Emphasis is given to the Rho kinase signaling pathway that regulates the Yin, and to the cyclic nucleotide signaling pathway that regulates the Yang. Discussion is organized in such a way so as to follow the signaling cascade, that is, beginning with the extracellular signaling molecules (e.g., norepinephrin and nitric oxide) and their receptors, converging onto the intracellular effectors (e.g., Rho kinase and protein kinase G), branching into secondary effectors, and finishing with contractile molecules and phosphodiesterases. Interactions between the Yin and Yang signaling pathways are discussed as well.

Keywords:

erectile function, erectile dysfunction, molecular mechanisms, Rho kinase signaling, cyclic nucleotide signaling, Yin-Yang

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References

  1. Saenz de Tejada I, Kim N, Lagan I, Krane RJ, Goldstein I. Regulation of adrenergic activity in penile corpus cavernosum. J Urol 1989; 142: 1117–21. | PubMed | ChemPort |
  2. Traish AM, Netsuwan N, Daley J, Padman-Nathan H, Goldstein I, Saenz de Tejada I. A heterogeneous population of alpha 1 adrenergic receptors mediates contraction of human corpus cavernosum smooth muscle to norepinephrine. J Urol 1995; 153: 222–7. | Article | PubMed | ISI | ChemPort |
  3. Tong YC, Cheng JT. Subtyping of alpha1-adrenoceptors responsible for the contractile response in the rat corpus caver-nosum. Neurosci Lett 1997; 228: 159–62. | Article | PubMed | ISI | ChemPort |
  4. Veronneau-Longueville F, Rampin O, Jardin A, Benoit G, Giuliano F. Expression of alpha 1 adrenoceptor subtypes in rat corpus cavernosum. Int J Impot Res 1998; 10: 187–94. | Article | PubMed | ISI | ChemPort |
  5. Goepel M, Krege S, Price DT, Michelotti GA, Schwinn DA, Michel MC. Characterization of alpha-adrenoceptor subtypes in the corpus cavernosum of patients undergoing sex change surgery. J Urol 1999; 162: 1793–9. | Article | PubMed | ISI | ChemPort |
  6. El-Gamal OM, Sandhu DP, Terry T, Elliott RA. Alpha-Adrenoceptor subtypes in isolated corporal tissue from patients undergoing gender re-assignment. BJU Int 2006; 97: 329–32. | Article | PubMed | ChemPort |
  7. Husain S, Young D, Wingard CJ. Role of PKCalpha and PKCiota in phenylephrine-induced contraction of rat corpora cavernosa. Int J Impot Res 2004; 16: 325–33. | Article | PubMed | ChemPort |
  8. Larsson C. Protein kinase C and the regulation of the actin cytoskeleton. Cell Signal 2006; 18: 276–84. | Article | PubMed | ChemPort |
  9. Holmquist F, Andersson KE, Hedlund H. Actions of endothelin on isolated corpus cavernosum from rabbit and man. Acta Physiol Scand 1990; 139: 113–22. | Article | PubMed | ISI | ChemPort |
  10. Saenz de Tejada I, Carson MP, de las Morenas A, Goldstein I, Traish AM. Endothelin: localization, synthesis, activity, and receptor types in human penile corpus cavernosum. Am J Physiol 1991; 261: H1078–85. | PubMed | ChemPort |
  11. Christ GJ, Lerner SE, Kim DC, Melman A. Endothelin-1 as a putative modulator of erectile dysfunction: I. Characteristics of contraction of isolated corporal tissue strips. J Urol 1995; 153: 1998–2003. | Article | PubMed | ISI | ChemPort |
  12. Becker AJ, Uckert S, Stief CG, Truss MC, Hartmann U, Jonas U. Systemic and cavernosal plasma levels of endothelin (1-21) during different penile conditions in healthy males and patients with erectile dysfunction. World J Urol 2001; 19: 371–6. | Article | PubMed | ISI | ChemPort |
  13. Chang S, Hypolite JA, Changolkar A, Wein AJ, Chacko S, DiSanto ME. Increased contractility of diabetic rabbit corpora smooth muscle in response to endothelin is mediated via Rho-kinase beta. Int J Impot Res 2003; 15: 53–62. | Article | PubMed | ISI | ChemPort |
  14. Mumtaz FH, Lau DH, Siddiqui EJ, Thompson CS, Morgan RJ, Mikhailidis DP. Pharmacological properties of endothelin-1 in the rabbit corpus cavernosum. In Vivo 2006; 20: 243–6. | PubMed | ChemPort |
  15. Kifor I, Williams GH, Vickers MA, Sullivan MP, Jodbert P, Dluhy RG. Tissue angiotensin II as a modulator of erectile function. I. Angiotensin peptide content, secretion and effects in the corpus cavernosum. J Urol 1997; 157: 1920–5. | Article | PubMed | ISI | ChemPort |
  16. Comiter CV, Sullivan MP, Yalla SV, Kifor I. Effect of angiotensin II on corpus cavernosum smooth muscle in relation to nitric oxide environment: in vitro studies in canines. Int J Impot Res 1997; 9: 135–40. | Article | PubMed | ISI | ChemPort |
  17. Park JK, Kim SZ, Kim SH, Park YK, Cho KW. Renin angio-tensin system in rabbit corpus cavernosum: functional characterization of angiotensin II receptors. J Urol 1997; 158: 653–8. | Article | PubMed | ISI | ChemPort |
  18. Becker AJ, Uckert S, Stief CG, Scheller F, Knapp WH, Hartmann U, et al. Plasma levels of angiotensin II during different penile conditions in the cavernous and systemic blood of healthy men and patients with erectile dysfunction. Urology 2001; 58: 805–10. | Article | PubMed | ISI | ChemPort |
  19. Jin L, Burnett AL. RhoA/Rho-kinase in erectile tissue: mechanisms of disease and therapeutic insights. Clin Sci (Lond) 2006; 110: 153–65. | PubMed | ChemPort |
  20. Ignarro LJ, Bush PA, Buga GM, Wood KS, Fukuto JM, Rajfer J. Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Commun 1990; 170: 843–50. | Article | PubMed | ISI | ChemPort |
  21. McDonald LJ, Murad F. Nitric oxide and cyclic GMP signaling. Proc Soc Exp Biol Med 1996; 211: 1–6. | PubMed | ChemPort |
  22. Murad F. Cyclic GMP: synthesis, metabolism, and function. Introduction and some historical comments. Adv Pharmacol 1994; 26: 1–5. | PubMed | ChemPort |
  23. Lincoln TM, Cornwell TL. Intracellular cyclic GMP receptor proteins. FASEB J 1993; 7: 328–38. | PubMed | ISI | ChemPort |
  24. Christ GJ. The penis as a vascular organ. The importance of corporal smooth muscle tone in the control of erection. Urol Clin North Am 1995; 22: 727–45. | PubMed | ISI | ChemPort |
  25. Christ GJ, Melman A. Molecular studies of human corporal smooth muscle: implications for the understanding, diagnosis, and treatment of erectile dysfunction. Mol Urol 1997; 1: 45–54. | ChemPort |
  26. Murray RK. Muscle. In: Murray RK, Granner DK, Mayes PA, Rodwell VW, editors. Harper's Biochemistry, 24th edn. Stamford: Appleton and Lange; 1996.
  27. Lin CS, Lin G, Lue TF. Cyclic nucleotide signaling in cavernous smooth muscle. J Sex Med 2005; 2: 478–91. | Article | PubMed | ChemPort |
  28. Burnett AL. Novel nitric oxide signaling mechanisms regulate the erectile response. Int J Impot Res 2004; 16 (Suppl 1): S15–9. | Article | PubMed | ISI | ChemPort |
  29. Fournier GR Jr, Juenemann KP, Lue TF, Tanagho EA. Mechanisms of venous occlusion during canine penile erection: an anatomic demonstration. J Urol 1987; 137: 163–7. | PubMed |
  30. Lin CS, Lin G, Xin ZC, Lue TF. Expression, distribution and regulation of phosphodiesterase 5. Curr Pharm Des 2006; 12: 3439–57. | Article | PubMed | ChemPort |
  31. Lue TF. Erectile dysfunction. N Engl J Med 2000; 342: 1802–13. | Article | PubMed | ISI | ChemPort |
  32. Narumiya S, Fitz Gerald GA. Genetic and pharmacological analysis of prostanoid receptor function. J Clin Invest 2001; 108: 25–30. | Article | PubMed | ISI | ChemPort |
  33. Kim SZ, Kim SH, Park JK, Koh GY, Cho KW. Presence and biological activity of C-type natriuretic peptide-dependent guanylate cyclase-coupled receptor in the penile corpus cavernosum. J Urol 1998; 159: 1741–6. | Article | PubMed | ISI | ChemPort |
  34. Kuthe A, Reinecke M, Uckert S, Becker A, David I, Heitland A, et al. Expression of guanylyl cyclase B in the human corpus cavernosum penis and the possible involvement of its ligand C-type natriuretic polypeptide in the induction of penile erection. J Urol 2003; 169: 1918–22. | Article | PubMed | ChemPort |
  35. Sauzeau V, Le Jeune H, Cario-Toumaniantz C, Smolenski A, Lohmann SM, Bertoglio J, et al. Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sen-sitization of contraction in vascular smooth muscle. J Biol Chem 2000; 275: 21722–9. | Article | PubMed | ISI | ChemPort |
  36. Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 1998; 273: 24266–71. | Article | PubMed | ISI | ChemPort |
  37. Ming XF, Viswambharan H, Barandier C, Ruffieux J, Kaibuchi K, Rusconi S, et al. Rho GTPase/Rho kinase negatively regulates endothelial nitric oxide synthase phosphorylation through the inhibition of protein kinase B/Akt in human endothelial cells. Mol Cell Biol 2002; 22: 8467–77. | Article | PubMed | ISI | ChemPort |
  38. Bivalacqua TJ, Champion HC, Usta MF, Cellek S, Chitaley K, Webb RC, et al. RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction. Proc Natl Acad Sci USA 2004; 101: 9121–6. | Article | PubMed | ChemPort |
  39. Dahiya R, Lin A, Bakircioglu ME, Huang ST, Lue TF. mRNA and protein expression of nitric oxide synthase and adrenoceptor alpha 1 in young and old rat penile tissues. Br J Urol 1997; 80: 300–6. | PubMed | ChemPort |
  40. Musicki B, Kramer MF, Becker RE, Burnett AL. Inactivation of phosphorylated endothelial nitric oxide synthase (Ser-1177) by O-GlcNAc in diabetes-associated erectile dysfunction. Proc Natl Acad Sci USA 2005; 102: 11870–5. | Article | PubMed | ChemPort |
  41. Chang S, Hypolite JA, Velez M, Changolkar A, Wein AJ, Chacko S, et al. Downregulation of cGMP-dependent protein kinase-1 activity in the corpus cavernosum smooth muscle of diabetic rabbits. Am J Physiol Regul Integr Comp Physiol 2004; 287: R950–60. | PubMed | ISI | ChemPort |
  42. Park KH, Kim SW, Kim KD, Paick JS. Effects of androgens on the expression of nitric oxide synthase mRNAs in rat corpus cavernosum. BJU Int 1999; 83: 327–33. | Article | PubMed | ISI | ChemPort |
  43. Marin R, Escrig A, Abreu P, Mas M. Androgen-dependent nitric oxide release in rat penis correlates with levels of con stitutive nitric oxide synthase isoenzymes. Biol Reprod 1999; 61: 1012–6. | Article | PubMed | ChemPort |
  44. Liu WJ, Xin ZC, Xin H, Yuan YM, Tian L, Guo YL. Effects of icariin on erectile function and expression of nitric oxide synthase isoforms in castrated rats. Asian J Androl 2005; 7: 381–8. | Article | PubMed | ChemPort |
  45. Traish AM, Park K, Dhir V, Kim NN, Moreland RB, Goldstein I. Effects of castration and androgen replacement on erectile function in a rabbit model. Endocrinology 1999; 140: 1861–8. | Article | PubMed | ISI | ChemPort |
  46. Shen Z, Chen Z, Lu Y, Chen F, Chen Z. Relationship between gene expression of nitric oxide synthase and androgens in rat corpus cavernosum. Chin Med J (Engl) 2000; 113: 1092–5. | PubMed | ChemPort |
  47. Bakircioglu ME, Hsu K, El-Sakka A, Sievert KD, Lin CS, Lue TF. Effect of a Chinese herbal medicine mixture on a rat model of hypercholesterolemic erectile dysfunction. J Urol 2000; 164: 1798–801. | Article | PubMed | ChemPort |
  48. Ryu JK, Shin HY, Song SU, Oh SM, Piao S, Han JY, et al. Downregulation of angiogenic factors and their downstream target molecules affects the deterioration of erectile function in a rat model of hypercholesterolemia. Urology 2006; 67: 1329–34. | Article | PubMed |
  49. Bakircioglu ME, Lin CS, Fan P, Sievert KD, Kan YW, Lue TF. The effect of adeno-associated virus mediated brain derived neurotrophic factor in an animal model of neurogenic impotence. J Urol 2001; 165: 2103–9. | Article | PubMed | ISI | ChemPort |
  50. Podlasek CA, Gonzalez CM, Zelner DJ, Jiang HB, McKenna KE, McVary KT. Analysis of NOS isoform changes in a post radical prostatectomy model of erectile dysfunction. Int J Impot Res 2001; 13 (Suppl 5): S1–15. | Article | PubMed | ISI |
  51. Jin L, Liu T, Lagoda GA, Champion HC, Bivalacqua TJ, Burnett AL. Elevated RhoA/Rho-kinase activity in the aged rat penis: mechanism for age-associated erectile dysfunction. FASEB J 2006; 20: 536–8. | PubMed | ChemPort |
  52. Chitaley K, Webb RC, Mills TM. RhoA/Rho-kinase: a novel player in the regulation of penile erection. Int J Impot Res 2001; 13: 67–72. | Article | PubMed | ISI | ChemPort |
  53. Wilkes N, White S, Stein P, Bernie J, Rajasekaran M. Phos-phodiesterase-5 inhibition synergizes rho-kinase antagonism and enhances erectile response in male hypertensive rats. Int J Impot Res 2004; 16: 187–94. | Article | PubMed | ISI | ChemPort |
  54. Wingard CJ, Johnson JA, Holmes A, Prikosh A. Improved erectile function after Rho-kinase inhibition in a rat castrate model of erectile dysfunction. Am J Physiol Regul Integr Comp Physiol 2003; 284: R1572–9. | PubMed | ChemPort |
  55. Bochinski DJ, Deng DY, Lue TF. The treatment of priapism – when and how? Int J Impot Res 2003; 15 (Suppl 5): S86–90. | Article | PubMed | ISI |
  56. Broderick GA, Gordon D, Hypolite J, Levin RM. Anoxia and corporal smooth muscle dysfunction: a model for ischemic priapism. J Urol 1994; 151: 259–62. | PubMed | ISI | ChemPort |
  57. Lin G, Xin ZC, Lue TF, Lin CS. Up and down-regulation of phosphodiesterase-5 as related to tachyphylaxis and priapism. J Urol 2003; 170: S15–8; discussion S19. | Article | PubMed |

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