Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Paper
  • Published:

Dual mechanism of action of nicorandil on rabbit corpus cavernosal smooth muscle tone

International Journal of Impotence Research volume 13, pages 240–246 (2001)Cite this article

Abstract

The potential of ATP-sensitive potassium channel openers (KCOs) for the treatment of male erectile dysfunction has recently been suggested based on positive clinical outcomes following intra-cavernosal administration of pinacidil. Agents that increase the levels of cGMP via elevation of nitric oxide (NO) nitroglycerin, for example, are also effective in improving erectile function preclinically and clinically. The aim of the present study was to determine the effects and mechanism of the action of nicorandil on rabbit corpus cavernosum. The in vitro regulation of smooth muscle tone was assessed in isolated cavernosal tissues pre-contracted with phenyl-ephrine. Nicorandil, but not its major metabolite, relaxed phenylephrine-precontracted cavernosum smooth muscle with an EC50 of 15 μM. The effects of nicorandil were only partially reversed by the KATP channel blocker glyburide (10 μM) or by a soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4] oxadiazole [4,3-a] quinoxalin-1-one (ODQ, 3 μM). However, a combination of ODQ and glyburide completely blocked the relaxant effects of nicorandil. The results of the present study indicate that nicorandil can relax rabbit cavernosal tissue in vitro via a mechanism that involves activation of KATP channels and stimulation of soluble guanylate cyclase.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Moreland RB, Nakane M, Hsieh GC, Brioni JD . Prospectives for pharmacotherapy of male erectile dysfunction. Current Opinions CPNS Drugs 2000 2, 283–302

    CAS  Google Scholar 

  2. Traish AM, Kim NN, Goldstein I, Moreland, RB . Alpha adrenergic receptors in the penis. J Androl 1999 20, 671–682

    CAS  PubMed  Google Scholar 

  3. Burnett A . Nitric oxide in the penis: physiology and pathology. J Urol 1997 157, 320–324

    Article  CAS  Google Scholar 

  4. Meinhardt W, Kropman RF, Vermeij P . Comparative tolerability and efficacy of treatment for impotence. Drug Safety 1999 20, 133–146

    Article  CAS  Google Scholar 

  5. Leopold JA, Loscalzo J . New developments in nitrosovasodilator therapy. Vasc Med 1997 2, 190–202

    Article  CAS  Google Scholar 

  6. Lawson K . Potassium channel openers as potential therapeutic weapons in ion channel disease. Kidney Int 2000 57, 838–845

    Article  CAS  Google Scholar 

  7. Lee SW, Wang HZ, Christ GJ . Characterization of ATP-sensitive potassium channels in human corporal smooth muscle cells. Int J Impot Res 1999 11, 179–188

    Article  CAS  Google Scholar 

  8. Trigo-Rocha F et al. The effect of intracavernous injection of potassium channel openers in monkeys and dogs. Int J Impot Res 1995 7, 41–48

    CAS  PubMed  Google Scholar 

  9. Giraldi A, Wagner G . Effects of pinacidil upon penile erectile tissue, in vitro and in vivo Pharmacol Toxicol 1990 67, 235–238

    Article  CAS  Google Scholar 

  10. Holmquist F, Andersson KE, Fovaeus M, Hedlund H . K (+)-channel openers for relaxation of isolated penile erectile tissue from rabbit. J Urol 1990 144, 146–151

    Article  CAS  Google Scholar 

  11. Moon DG, Byun HS, Kim JJ . A K-ATP channel opener as a potential treatment modality for erectile dysfunction. Br J Urol Int 1999 83, 837–841

    Article  CAS  Google Scholar 

  12. Goldschmidt M, Landzberg BR, Frishman WH . Nicorandil: a potassium channel opening drug for treatment of ischemic heart disease. J Clin Pharmacol 1996 36, 559–572

    Article  CAS  Google Scholar 

  13. Hedlund P, Holmquist F, Hedlund H, Andersson KE . Effects of nicorandil on human isolated corpus cavernosum and cavernous artery. J Urol 1994 151, 1107–1113

    Article  CAS  Google Scholar 

  14. Gopalakrishnan M et al. Characterization of the ATP-sensitive potassium channels (K-ATP) expressed in guinea pig bladder smooth muscle cells. J Pharmacol Exp Ther 1999 289, 551–558

    CAS  PubMed  Google Scholar 

  15. Christ GJ et al. Intracorporal injection of hSIo cDNA in rats produces physiologically relevent alterations in penile function. Am J Physiol 1998 275, H600–H608

    CAS  Google Scholar 

  16. Lee SW, Wang HZ, Christ GJ . Characterization of ATP-senstive potassium channels in human corporal smooth muscle cells. Int J Impot Res 1999 11, 179–198

    Article  CAS  Google Scholar 

  17. Fan SF, Brink PR, Melman A, Christ GJ . An analysis of the maxi-K+ (KCa) channel in cultured human corporal smooth muscle cells. J Urol 1995 153, 818–825

    Article  CAS  Google Scholar 

  18. Giraldi A et al. Differential relaxation of human corpus cavernosum smooth muscle by potassium openers: evidence that relaxation is both agonist dependent and altered by diabetes melitus. Int J Impot Res 1995 7, 1–10

    Google Scholar 

  19. Vick RN, Patel M, Benevides M, Carson CC . The efficacy, safety, and tolerability of intracavernosal PNU-83587 in the treatment of erectile dysfunction. J Urol 2000 163, 20

    Google Scholar 

  20. Quast U . Potassium channel openers: pharmacological and clinical aspects. Fundam Clin Pharmacol 1992 6, 279–293

    Article  CAS  Google Scholar 

  21. 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 

  22. Denninger JW, Marletta MA . Guanylate cyclase and the NO/cGMP signaling pathway. Biochim Biophys Acta 1999 1411, 334–350

    Article  CAS  Google Scholar 

  23. Zhao Y, Brandish PE, Ballou DP, Marletta MA . A molecular basis for nitric oxide sensing by soluble guanylate cyclase. Proc Natl Acad Sci USA 1999 96, 14753–14758

    Article  CAS  Google Scholar 

  24. Denninger JW et al. Interaction of soluble guanylate cyclase with YC-1: kinetic and resonance Raman studies. Biochemistry 2000 39, 4191–4198

    Article  CAS  Google Scholar 

  25. Berdeaux A et al. Differential effects of nitrovasolidators, K channel openers and nicorandil on large and small coronary arteries in conscious dogs. J Cardiovasc Pharmacol 1992 20, (Suppl 3): S17–S21

    Article  Google Scholar 

Download references

Acknowledgements

The authors are grateful to Dr Robert B Moreland for his valuable comments on the manuscript.

Author information

Authors and Affiliations

  1. Neurological and Urological Diseases Research, Abbott Laboratories, Illinois, USA

    GC Hsieh, T Kolasa, JP Sullivan & JD Brioni

Authors
  1. GC Hsieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Kolasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. JP Sullivan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. JD Brioni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to GC Hsieh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hsieh, G., Kolasa, T., Sullivan, J. et al. Dual mechanism of action of nicorandil on rabbit corpus cavernosal smooth muscle tone. Int J Impot Res 13, 240–246 (2001). https://doi.org/10.1038/sj.ijir.3900702

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.ijir.3900702

Keywords

This article is cited by

Search

Advanced search

Quick links