Abstract
The clitoris contributes to the normal female sexual response cycle. A significance of cyclic guanosine monophosphate (GMP) has been assumed in the control of clitoral vascular smooth muscle. As only a few investigations on the physiology of the vascular and non-vascular clitoral tissue have been carried out, knowledge on the mechanisms controlling this particular female genital organ is still vague. It has been suggested that human clitoral corpus cavernosum smooth muscle is regulated by nitric oxide (NO)/cyclic GMP and related key enzymes, such as NO synthases (NOSs) and the phosphodiesterase type 5 (PDE5). The present study evaluated in the human clitoris, by means of immunohistochemistry, the expression and distribution of key enzymes of the cyclic GMP pathway, such as the endothelial NOS, PDE2, PDE11 and cyclic GMP-dependent protein kinase type I (cGKI) in relation to the PDE5. Immunohistochemistry revealed the presence of PDE2, PDE5 and cGKI in the smooth muscle wall of blood vessels transversing the supepithelial and stromal space. Immunosignals specific for PDE2 were also identified in interstitial-like cells located in the basal epithelial layer. Staining for PDE11A was observed in single nerve trunks located in the clitoral stroma. The results are in favor of a role of the cyclic GMP signaling in the control of clitoral blood flow. It seems likely that PDE2 and PDE11 are also involved in the mechanism of local (neuro)transmission in the clitoris.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 8 print issues and online access
$259.00 per year
only $32.38 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Meston CM, Frohlich PF . Update on female sexual function. Curr Opin Urol 2001; 11: 603–609.
Levin RJ . The physiology of sexual response in the human female: a recreational and procreational synthesis. Arch Sex Behav 2002; 31: 405–411.
Graziottin A . Sexuality in postmenopause and senium. In: Lauritzen C, Studd J (eds). Current Management of the Menopause. Taylor & Francis: London, 2003, pp 185–203.
Tarcan T, Park K, Goldstein I, Maio G, Fassina A, Krane RJ et al. Histomorphometric analysis of age-related structural changes in human clitoral cavernosum tissue. J Urol 1999; 161: 940–944.
Burnett AL, Calvin DC, Silver RI, Peppas DS, Docimo SG . Immunohistochemical description of nitric oxide synthase isoforms in human clitoris. J Urol 1997; 158: 75–78.
Park K, Moreland RB, Goldstein I, Atala A, Traish A . Sildenafil inhibits phosphodiesterase type 5 in human clitoral corpus cavernosum smooth muscle. Biochem Biophys Res Comm 1998; 49: 612–617.
Oelke M, Hedlund P, Albrecht K, Ellinghaus P, Stief CG, Jonas U et al. Expression of cAMP- and cGMP-phosphodiesterase isoenzymes 3, 4, and 5 in the human clitoris: immunohistochemical and molecular biology study. Urology 2006; 67: 1111–1116.
Soderling SH, Beavo JA . Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions. Curr Opin Cell Biol 2000; 12: 174–179.
Taher A, Meyer M, Stief CG, Jonas U, Forssmann WG . Cyclic nucleotide phosphodiesterase in human cavernous smooth muscle. World J Urol 1997; 15: 32–35.
Stief CG, Taher A, Meyer M, Schulz-Knappe P, Becker AJ, Truss MC et al. Phosphodiesterase isoenzymes in human ureteral smooth muscle: identification, characterization, and functional effects of various phosphodiesterase inhibitors in vitro. Urol Int 1995; 55: 183–189.
Truss MC, Ückert S, Stief CG, Kuczyk MA, Jonas U . Cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human detrusor smooth muscle: I. Identification and characterization. Urol Res 1996; 24: 123–128.
Ückert S, Küthe A, Jonas U, Stief CG . Characterization and functional relevance of cyclic nucleotide phosphodiesterase isoenzymes of the human prostate. J Urol 2001; 166: 2484–2490.
Kostin S, Popescu LM . A distinct type of cell in myocardium: interstitial Cajal-like cells. J Cell Mol Med 2009; 13: 295–308.
García-Pascual A, Sancho M, Costa G, Triguero D . Interstitial cells of Cajal in the urethra are cGMP-mediated targets of nitrergic neurotransmission. Am J Physiol Renal Physiol 2008; 295: F971–F983.
Ückert S, Kedia GT, Satzger I, Geismar U, Sohn M, Kuczyk MA et al. c-kit-positive multipolar cells in human penile erectile tissue: expression of connexin 43 and relation to trabecular smooth muscle cells. Georgian Med News (GMN) 2010; 3: 13–19.
Shafik A . Study of interstitial cells in the penis: human study. J Sex Med 2007; 4: 66–71.
Sui GP, Rothery S, Dupont E, Fry CH, Severs NJ . Gap junctions and connexin expression in human suburothelial interstitial cells. BJU Int 2002; 90: 118–129.
Katevuo K, Kanto J, Kleimola T . Aminophylline in ureterolithiasis: preliminary report. Int J Clin Pharmacol Ther Toxicol 1981; 19: 512–513.
Truss MC, Stief CG, Ückert S, Becker AJ, Wefer J, Schultheiss D et al. Phosphodiesterase 1 inhibition in the treatment of lower urinary tract dysfunction: from bench to bedside. World J Urol 2001; 19: 344–350.
Wang C . Phosphodiesterase 5 inhibitors and benign prostatic hyperplasia. Curr Opin Urol 2010; 20: 49–54.
Chiver ML, Rosen RC . Phosphodiesterase type 5 inhibitors and female sexual response: faulty protocols or paradigms. J Sex Med 2010; 7: 858–872.
Yuasa K, Kotera J, Fujishige K, Michibata H, Sasaki T, Omori K . Isolation and characterization of two novel phosphodiesterase PDE11A variants showing unique structure and tissue-specific expression. J Biol Chem 2000; 275: 31469–31479.
Hedlund P, Aszodi A, Pfeifer A, Alm P, Hofman F, Ahmad M et al. Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. Proc Natl Acad Sci (PNAS) USA 2000; 97: 2349–2354.
Waldkirch E, Ückert S, Sigl K, Imkamp F, Langnäse K, Richter K et al. Expression and distribution of cyclic GMP-dependent protein kinase-1 (cGK1) isoforms in human penile erectile tissue. J Sex Med 2008; 5: 536–543.
Ückert S, Waldkirch ES, Albrecht K, Sonnenberg J, Langnäse K, Richter K et al. Expression and distribution of cyclic AMP- and cyclic GMP-binding protein kinases in the human vagina—an immunohistochemical study. J Sex Med 2010; 7 (Part II): 888–895.
Wang XY, Berezin I, Mikkelsen HB, Der T, Bercik P, Collins SM et al. Pathology of interstitial cells of Cajal in relation to inflammation revealed by ultrastructure but not immunohistochemistry. Am J Pathol 2002; 160: 1529–1540.
Torihashi S, Horisawa M, Watanabe Y . c-Kit immunoreactive interstitial cells in the human gastrointestinal tract. J Auton Nerv Sys 1999; 75: 38–50.
Huizinga JD, Faussone-Pellegrini MS . About the presence of interstitial cells of Cajal outside the musculature of the gastrointestinal tract. J Cell Mol Med 2005; 9: 468–473.
Collins C, Klausner AP, Herrick B, Koo HP, Miner AS, Henderson SC et al. Potential for control of detrusor smooth muscle spontaneous rhythmic contraction by cyclooxygenase products released by interstitial cells of Cajal. J Cell Mol Med 2009; 13: 3236–3250.
Acknowledgements
To Mrs Nicola Jane Hitchcock-van Dornick, Hannover, Germany, for editing the linguistic style of the manuscript. This study was supported by the Institutional Funding Program Excellence in Research of the Board of the Hannover Medical School.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Ückert, S., Oelke, M., Albrecht, K. et al. Expression and distribution of key enzymes of the cyclic GMP signaling in the human clitoris: relation to phosphodiesterase type 5 (PDE5). Int J Impot Res 23, 206–212 (2011). https://doi.org/10.1038/ijir.2011.29
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ijir.2011.29
Keywords
This article is cited by
-
Testosterone positively regulates vagina NO-induced relaxation: an experimental study in rats
Journal of Endocrinological Investigation (2022)
-
Expression and distribution of the transient receptor potential cationic channel A1 (TRPA1) in the human clitoris—comparison to male penile erectile tissue
International Journal of Impotence Research (2017)