Abstract
Penile erection involves a complex interaction between the central nervous system and local factors. It is a neurovascular event modulated by psychological and hormonal factors. The discovery of nitric oxide (NO) as an intercellular messenger or neurotransmitter paved the way for identifying important mechanisms underlying physiological and pathophysiological events in the penis, in addition to providing the knowledge for the development of new therapeutics based on a novel concept of molecule and cell interaction. Despite the fact that sinusoidal endothelial cells also produce and release NO in response to chemical and possibly physical stimuli, roles of neurogenic NO in penile erection appear to be more attractive and convincing, since the pharmacological neuromodulation represents an essential step to attaining penile erection. Erectile dysfunction (ED) is caused by a variety of pathogenic factors, particularly impaired formation and action of NO. Hence, a thorough knowledge of the physiology of erection is essential for future pharmacological innovations in the field of male ED, particularly targeting NO or intracellular cyclic GMP, which represent the most promising therapeutic approach to treat patients with ED.
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References
Lue TF . Erectile dysfunction. N Engl J Med, 2000; 342: 1802–13.
Shabsigh R, Anastasiadis AG . Erectile dysfunction. Annu Rev Med, 2003; 54: 153–68.
Lundberg JM . Pharmacology of cotransmission in the autonomic nervous system: integrative aspects on amines, neuropeptides, adenosine triphosphate, amino acids and nitric oxide. Pharmacol Rev, 1996; 48: 113–78.
Burnstock G . Comparative studies of purinergic nerves. J Exp Zool, 1975; 194: 103–33.
Owman C . Peptidergic vasodilator nerves in the peripheral circulation and in the vascular beds of the heart and brain. Blood Vessels, 1990; 27: 73–93.
Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G . Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA, 1987; 84: 9265–9.
Furchgott RF . Studies on relaxation of rabbit aorta by sodium nitrite: the basis for the proposal that the acid-activatable inhibitory factor from retractor penis is inorganic nitrite and the endotheliumderived relaxing factor is nitric oxide. In: Vanhoutte PM, editor. Vasodilatation: vascular smooth muscle, peptides, autonomic nerve and endothelium. New York: Raven Press; 1988. p401–14.
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.
Burnett AL . Nitric oxide in the penis: physiology and pathology. J Urol, 1997; 157: 320–4.
Rajfer J, Aronson WJ, Bush PA, Dorey FJ, Ignarro LJ . Nitric oxide as a mediator of relaxation of the corpus cavernosum in response to nonadrenergic, noncholinergic neurotransmission. N Engl J Med, 1992; 326: 90–4.
Francis SH, Turko IV, Corbin JD . Cyclic nucleotide phosphodiesterases: relating structure and function. Prog Nucleic Acid Res Mol Biol, 2001; 65: 1–52.
Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, et al. Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treatment of penile erectile dysfunction. Int J Impot Res, 1996; 8: 47–52.
Turko IV, Ballard SA, Francis SH, Corbin JD . Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. Mol Pharmacol, 1999; 56: 124–30.
NIH Consensus Conference. Impotence: NIH consensus development panel on impotence. JAMA 1993; 270: 83–9.
Benet AE, Melman A The epidemiology of erectile dysfunction. Urol Clin North Am 1995; 22: 699–709.
Laumann EO, Paik A, Rosen RC . Sexual dysfunction in the United States: prevalence and predictors. JAMA, 1999; 281: 537–44.
Jonler M, Moon T, Brannan W, Stone NN, Heisey D, Bruskewitz RC . The effect of age, ethnicity and geographical location on impotence and quality of life. Br J Urol, 1995; 75: 651–5.
Lewis RW . Definitions, classification, and epidemiology of sexual dysfunction. In: Lue TF, Basson R, Rosen R, Giuliano F, Khoury S, Montorsi F, editors. Sexual Medicine: Sexual Dysfunction in Men and Women. Health Publications: Paris; 2004. p 39–72.
Behr-Roussel D, Gorny D, Mevel K, Compagnie S, Kern P, Sivan V, Bernabe J, Bedigian MP, Alexandre L, Giuliano F . Erectile dysfunction: an early marker for hypertension? A longitudinal study in spontaneously hypertensive rats. Am J Physiol, 2005; 288: R276–83.
Kaya C, Uslu Z, Karaman I . Is endothelial function impaired in erectile dysfunction patients? Int J Impot Res 2006; 18: 55–60.
Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, Snyder SH . Nitric oxide: a physiologic mediator of penile erection. Science, 1992; 257: 401–3.
Burnett AL, Tillman SL, Chang TS, Epstein JI, Lowenstein CJ, Bredt DS, et al. Immunohistochemical localization of nitric oxide synthase in the autonomic innervation of the human penis. J Urol, 1993; 150: 73–6.
Burnett AL, Nelson RJ, Calvin DC, Liu JX, Demas GE, Klein SL, et al. Nitric oxide-dependent penile erection in mice lacking neuronal nitric oxide synthase. Mol Med, 1996; 2: 288–96.
Alm P, Larsson B, Ekblad E, Sundler F, Andersson KE . Immunohistochemical localization of peripheral nitric oxide synthase-containing nerves using antibodies raised against synthesized C-and N-terminal fragments of a cloned enzyme from rat brain. Acta Physiol Scand, 1993; 148: 421–9.
Dail WG, Barba V, Leyba L, Galindo R . Neural and endothelial nitric oxide synthase activity in rat penile erectile tissue. Cell Tissue Res, 1995; 282: 109–16.
Hedlund P, Ny L, Alm P, Andersson KE . Cholinergic nerves in human corpus cavernosum and spongiosum contain nitric oxide synthase and heme oxygenase. J Urol, 2000; 164: 868–75.
Stanarius A, Uckert S, Machtens SA, Stief CG, Wolf G, Jonas U . Immunocytochemical distribution of nitric oxide synthase in the human corpus cavernosum: an electron microscopical study using the tyramide signal amplification technique. Urol Res, 2001; 29: 168–72.
Bush PA, Gonzalez NE, Ignarro LJ . Biosynthesis of nitric oxide and citrulline from L-arginine by constitutive nitric oxide synthase present in rabbit corpus cavernosum. Biochem Biophys Res Commun, 1992; 186: 308–14.
Sommer F, Klotz T, Steinritz D, Bloch W . Evaluation of tetrahydrobiopterin (BH4) as a potential therapeutic agent to treat erectile dysfunction. Asian J Androl, 2006; 8: 159–67.
Jones RW, Rees RW, Minhas S, Ralph D, Persad RA, Jeremy J Y . Oxygen free radicals and the penis. Expert Opin Pharmacother, 2002; 3: 889–97.
Gocmen C, Secilmis A, Kumcu EK, Ertug PU, Onder S, Dikmen A, et al. Effects of vitamin E and sodium selenate on neurogenic and endothelial relaxation of corpus cavernosum in the diabetic mouse. Eur J Pharmacol, 2000; 398: 93–8.
Gur S, Karahan ST, Ozturk B, Badilli M . Effect of ascorbic acid treatment on endothelium-dependent and neurogenic relaxation of corpus cavernosum from middle-aged non-insulin dependent diabetic rats. Int J Urol, 2005; 12: 821–8.
Claudino MA, Priviero FB, Teixeira CE, De Nucci G, Antunes E, Zanesco A . Improvement in relaxation response in corpus cavernosum from trained rats. Urology, 2004; 63: 1004–8.
Claudino MA, Priviero FB, Camargo EA, Teixeira CE, De Nucci G, Antunes E, Zanesco A . Protective effect of prior physical conditioning on relaxing response of corpus cavernosum from rats made hypertensive by nitric oxide inhibition. Int J Impot Res, 2007; 19: 189–95.
Kalsi JS, Ralph DJ, Thomas P, Bellringer J, Minhas S, Kell PD, Cellek S . A nitric oxide-releasing PDE5 inhibitor relaxes human corpus cavernosum in the absence of endogenous nitric oxide. J Sex Med, 2005; 2: 53–7.
Shukla N, Jones R, Persad R, Angelini GD, Jeremy JY . Effect of sildenafil citrate and a nitric oxide donating sildenafil derivative, NCX 911, on cavernosal relaxation and superoxide formation in hypercholesterolaemic rabbits. Eur J Pharmacol, 2005; 517: 224–31.
Teixeira CE, Ying Z, Webb RC . Proerectile effects of the Rho-kinase inhibitor (S)-(+)-2-methyl-1-[(4-methyl-5-isoquinolinyl) sulfonyl]homopiperazine (H-1152) in the rat penis. J Pharmacol Exp Ther, 2005; 315: 155–62.
Rajasekaran M, White S, Baquir A, Wilkes N . Rho-kinase inhibition improves erectile function in aging male Brown-Norway rats. J Androl, 2005; 26: 182–8.
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.
Park K, Kim SW, Rhu KS, Paick JS . Chronic administration of an oral rho kinase inhibitor prevents the development of vasculogenic erectile dysfunction in a rat model. J Sex Med, 2006; 3: 996–1003.
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, 2003; 284: R1572–9.
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This work was supported by a grant from the National Institute of Health (No HL-71138). Dr Cleber E Teixeira is the recipient of a postdoctoral fellowship from the American Heart Association.
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Priviero, F., Leite, R., Webb, R. et al. Neurophysiological basis of penile erection. Acta Pharmacol Sin 28, 751–755 (2007). https://doi.org/10.1111/j.1745-7254.2007.00584.x
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DOI: https://doi.org/10.1111/j.1745-7254.2007.00584.x
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