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Endothelium-dependency of yohimbine-induced corpus cavernosum relaxation

International Journal of Impotence Research volume 14, pages 295–307 (2002)Cite this article

Abstract

Development and maintenance of penile erection requires the relaxation of the smooth muscle cells in the cavernous bodies and is essentially mediated by nitric oxide (NO). The penile flaccid state is conversely maintained by the alpha adrenergic neuroeffector system and by other vasoconstrictors, such as endothelin-1 (ET-1). In this study we examined the mechanisms involved in yohimbine-induced relaxation in human and rabbit corpora cavernosa (CC). We essentially found that yohimbine not only blocks contractions induced by adrenergic agonists, but also by non-adrenergic substances, such as ET-1. This effect was unrelated to antagonism at the level of ET receptors, because yohimbine did not affect ET-1-induced increase in intracellular calcium in isolated CC cells. Conversely, our data suggest that yohimbine counteracts ET-1-induced contractions by interfering with NO release from the endothelium. In fact, yohimbine-induced CC relaxation was inhibited by the mechanical removing of the endothelium and by blocking NO formation or signalling via guanylate cyclase and cGMP formation. Conversely, yohimbine activity was strongly increased by inhibiting cGMP degradation. In an experimental model of hypogonadism, performed on rabbits by chronic treatment with a long-lasting GnRH agonist, the relaxant yohimbine activity was also decreased, but completely restored by androgen supplementation. This effect was evident only in preparations in which the main source of NO was present (endothelium) or in which NO formation was not impaired by L-NAME. Our data indicate that the relaxant effect of yohimbine is both endothelium and androgen-dependent. This might justify the lack of efficacy of this drug in treatment of some form of organic erectile dysfunction.

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References

  1. Andersson KE, Wagner G . Physiology of penile erection Pharmacol Review 1995 75: 191–236

    CAS  Google Scholar 

  2. Maggi M et al. Erectile dysfunction: from biochemical pharmacology to advances in medical therapy Eur J Endocrinol 2000 143: 143–154

    Article  CAS  PubMed  Google Scholar 

  3. Ignarro LJ et al. Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle Biochem Biophys Res Comm 1990 170: 843–850

    Article  CAS  PubMed  Google Scholar 

  4. Boolell M, Gepi-Attee S, Gingell JC, Allen MJ . Sildenafil, a novel effective oral therapy for male erectile dysfunction Br J Urol 1996 78: 257–261

    Article  CAS  PubMed  Google Scholar 

  5. Traish AM, Kim NN, Goldstein I, Moreland RB . Alpha-adrenergic receptors in the penis: identification, characterization, and physiological function J Andr 1999 20: 671–682

    CAS  Google Scholar 

  6. Langez SZ et al. Role of alpha1-adrenoceptors in the future treatment of urological diseases Eur Urol 1999 36: 66–67

    Article  Google Scholar 

  7. Becker AJ et al. Pharmacological therapy of erectile dysfunction Der Urol Ausg A 1998 37: 503–508

    Article  CAS  Google Scholar 

  8. Hunner M . A practical treatise on disorders of the sexual function of the male and female FA Davis: Philadelphia 1926

  9. Webb DJ, Freestone S, Allen MJ, Muirhead GJ . Sildenafil citrate and blood-pressure-lowering drugs: result of drug interaction studies with an organic nitrate and a calcium antagonist Am J Cardiol 1999 83: 21C–28C

    Article  CAS  PubMed  Google Scholar 

  10. Morales A . Yohimbine in erectile dysfunction: the facts Int J Impot Res 2000 12: S70–S74

    Article  CAS  PubMed  Google Scholar 

  11. Bevilacqua K, Barad D, Youchah J, Witt B . Is affect associated with infertility treatment outcome? Fertil Steril 2000 73: 648–649

    Article  CAS  PubMed  Google Scholar 

  12. Lue TF . Erectile dysfunction New Engl J Med 2000 342: 1802–1813

    Article  CAS  PubMed  Google Scholar 

  13. Ernst E, Pittler MH . Yohimbine for erectile dysfunction: a systematic review and meta-analysis of randomized clinical trials J Urol 1998 159: 433–436

    Article  CAS  PubMed  Google Scholar 

  14. Goldberg MR, Robertson D . Yohimbine: a pharmacological probe for study of the α2 adrenoreceptor Pharmacol Rev 1983 35: 143–180

    CAS  PubMed  Google Scholar 

  15. Riley AJ, Goodman RE, Kellet JM, Orr R . Double blind trial of yohimbine hydrochloride in the treatment of erection inadequacy J Sex Marital Ther 1989 4: 17–26

    Article  Google Scholar 

  16. Sonda LP, Mazo R, Chancellor MB . The role of yohimbine for the treatment of erectile impotence J Sex Marital Ther 1990 1: 15–21

    Article  Google Scholar 

  17. Riley AJ . Local pharmacotherapy for impotence Br J Clin Pract 1993 47: 118–119

    CAS  PubMed  Google Scholar 

  18. Clark J, Smith E, Davidson J . Enhancement of sexual motivation in male rats by yohimbine Science 1984 225: 847–848

    Article  CAS  PubMed  Google Scholar 

  19. Sala M et al. Central effect of yohimbine on sexual behaviour in the rat Physiol Behav 1990 47: 165–173

    Article  CAS  PubMed  Google Scholar 

  20. Rodriguez-Manzo G . Yohimbine interacts with the dopaminergic system to reverse sexual satiation: further evidence for a role of sexual motivation in sexual exhaustion Eur J Pharm 1999 372: 1–8

    Article  CAS  Google Scholar 

  21. Quintin L et al. Catecholamine metabolism in the rat locus coeruleus as studied by in vivo differential pulse voltammetry. III. Evidence for the existence of an alpha 2-adrenergic tonic inhibition in behaving rats Brain Res 1986 375: 235–245

    Article  CAS  PubMed  Google Scholar 

  22. Vogt HJ . Double-blind, placebo-controlled safety and efficacy trial with yohimbine hydrochloride in the treatment of nonorganic erectile dysfunction Int J Impot Res 1997 9: 155–161

    Article  CAS  PubMed  Google Scholar 

  23. Rowland DL, Kallan K, Slob AK . Yohimbine, erectile capacity, and sexual response in men Arch Sex Behav 1997 26: 49–62

    Article  CAS  PubMed  Google Scholar 

  24. Langer S . Presynaptic regulation of catecholamine release Biochem Pharmacol 1974 23: 1793–1800

    Article  CAS  PubMed  Google Scholar 

  25. Starke K, Taube HD, Browski E . Presynaptic receptor systems in catecholaminergic transmission Biochem Pharmacol 1977 26: 259–268

    Article  CAS  PubMed  Google Scholar 

  26. Hedlund H, Andersson KE . Comparison of the responses to drugs acting on adrenoreceptors and muscarinic receptors in human isolated corpus cavernosum and cavernous artery J Aut Pharm 1985 5: 81–88

    Article  CAS  Google Scholar 

  27. Saenz De Tejada I et al. Regulation of adrenergic activity in penile corpus cavernosum J Urol 1989 142: 1117–1121

    Article  CAS  PubMed  Google Scholar 

  28. Christ GJ, Maayani S, Valcic M, Melman A . Pharmacological studies of human erectile tissue: characteristics of spontaneous contractions and alterations in α-adrenoceptor responsiveness with age and disease in isolated tissues Br J Pharmacol 1990 101: 375–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Traish AM, Moreland RB, Huang YH, Goldstein I . Expression of functional alpha2-adrenergic receptor subtypes in human corpus cavernosum and in cultured trabecular smooth muscle cells Recept Signal Transduct 1997 7: 55–67

    CAS  PubMed  Google Scholar 

  30. Gupta S et al. The expression of functional postsynaptic α2-adrenoceptors in the corpus cavernosum smooth muscle Br J Pharmacol 1998 123: 1237–1245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Steers WD, Mcconnell J, Benson GS . Some pharmacological effects of yohimbine on human and rabbit penis J Urol 1984 131: 799–802

    Article  CAS  PubMed  Google Scholar 

  32. Saenz De Tejada I et al. Design and evaluation of nitrosylated α-adrenergic receptor antagonists as potential agents for the treatment of impotence J Pharmacol Exp Ther 1999 290: 121–128

    Google Scholar 

  33. Traish A et al. Phentolamine mesylate relaxes penile corpus cavernosum tissue by adrenergic and non-adrenergic mechanisms Int J Impot Res 1998 10: 215–223

    Article  CAS  PubMed  Google Scholar 

  34. Mills TM, Stopper VS, Reilly CM . Sites of androgenic regulation of cavernosal blood pressure during penile erection in the rat Int J Impot Res 1996 8: 29–34

    CAS  PubMed  Google Scholar 

  35. Reilly CM, Zamorano P, Stopper VS, Mills TM . Androgenic regulation of NO availability in rat penile erection J Androl 1997 18: 110–115

    CAS  PubMed  Google Scholar 

  36. Saenz De Tejada I et al. Cholinergic neurotrasmission in human corpus cavernosum. I. Responses of isolated tissue Am J Physiol 1988 254: H459–467

    Article  CAS  PubMed  Google Scholar 

  37. Itoh Y et al. Cloning and sequence analysis of cDNA enconding the precursor of a human endothelium-derived vasoconstrictor peptide, endothelin: identity of human and porcine endothelin FEBS Lett 1988 231: 440–444

    Article  CAS  PubMed  Google Scholar 

  38. Hosoda K et al. Cloning and expression of human endothelin-1 receptor cDNA FEBS Lett 1991 287: 23–26

    Article  CAS  PubMed  Google Scholar 

  39. Ogawa Y et al. Molecular cloning of a non-isopeptide selective human endothelin receptor Biochem Biophys Res Commun 1991 178: 248–255

    Article  CAS  PubMed  Google Scholar 

  40. Ercolani L, Florence B, Denaro M, Alexander M . Isolation and complete sequence of a functional human glyceraldehydes-3-phosphate dehydrogenase gene J Biol Chem 1988 263: 15335–15341

    CAS  PubMed  Google Scholar 

  41. Maggi M et al. Platelet-activating factor mediates an autocrine proliferative loop in the endometrial adenocarcinoma cell line HEC-1A Cancer Res 1994 54: 4777–4784

    CAS  PubMed  Google Scholar 

  42. Grynkiewicz G, Poenie M, Tsien RY . A generation of a Ca2+ indicators with greatly improved fluorescence properties J Biol Chem 1985 260: 3440–3450

    CAS  PubMed  Google Scholar 

  43. Motulsky HJ, Ransnas LA . Fitting curves to data using nonlinear regression: a practical and nonmathematical review FASEB J 1987 1: 365–374

    Article  CAS  PubMed  Google Scholar 

  44. Garthwaite J et al. Potent and selective inhibition of nitric oxide-sensitive guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one Mol Pharmacol 1995 48: 184–188

    CAS  PubMed  Google Scholar 

  45. Traish AM et al. Effects of castration and androgen replacement on erectile function in a rabbit model Endocrinology 1999 140: 1861–1868

    Article  CAS  PubMed  Google Scholar 

  46. Sturgill MG et al. Yohimbine elimination in normal volunteers is characterized by both one-and two-compartment behavior J Cardiovasc Pharmacol 1997 29: 697–703

    Article  CAS  PubMed  Google Scholar 

  47. Kunelius P, Hakkinen J, Lukkarinen O . Is high-dose yohimbine hydrochloride effective in the treatment of mixed-type impotence? A prospective, randomized, controlled double-blind crossover study Urology 1997 49: 441–444

    Article  CAS  PubMed  Google Scholar 

  48. Teloken C . Therapeutics effects of high dose yohimbine hydrochloride on organic erectile dysfunction J Urol 1998 159: 122–124

    Article  CAS  PubMed  Google Scholar 

  49. Tam SW, Worcel M, Wyllie M . Yohimbine: a clinical review Pharmacol Ther 2001 91: 215–243

    Article  CAS  PubMed  Google Scholar 

  50. Chamness SL et al. The effect of androgen on nitric oxide synthase in the male reproductive tract of the rat Fertil Steril 1995 63: 1101–1107

    Article  CAS  PubMed  Google Scholar 

  51. Marin R, Escrig A, Abreu P, Mas M . Androgen-dependent nitric oxide release in rat penis correlates with levels of constitutive nitric oxide synthase isoenzymes Biol Reprod 1999 61: 1012–1016

    Article  CAS  PubMed  Google Scholar 

  52. Lugg JA, Gonzalez-Cadavid NF, Rajfer J . The role of nitric oxide in erectile function J Androl 1995 16: 2–4

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Clara Crescioli (Department of Clinical Physiopathology, Endocrinology Unit, University of Florence) for cell cultures, Dr Elisabetta Baldi (Department of Clinical Physiopathology, Andrology Unit, University of Florence) for technical assistance in calcium measurement and Dr Monica Muratori (Department of Clinical Physiopathology, Andrology Unit, University of Florence) for technical assistance in testosterone measurements.

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Authors and Affiliations

  1. Department of Clinical Physiopathology, Andrology Unit, University of Florence, Florence, Italy

    S Filippi, M Luconi, S Granchi, G Forti & M Maggi

  2. Department of Urology, University of Florence, Florence, Italy

    A Natali

  3. Azienda Ospedaliera Careggi, Florence, Italy

    P Tozzi

  4. Department of Pharmacology, University of Florence, Florence, Italy

    F Ledda

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  1. S Filippi
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  2. M Luconi
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Correspondence to M Maggi.

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Filippi, S., Luconi, M., Granchi, S. et al. Endothelium-dependency of yohimbine-induced corpus cavernosum relaxation. Int J Impot Res 14, 295–307 (2002). https://doi.org/10.1038/sj.ijir.3900890

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