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Relaxant effect of a metal-based drug in human corpora cavernosa and its mechanism of action

International Journal of Impotence Research volume 28, pages 20–24 (2016)Cite this article

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Abstract

We studied the mechanisms involved in the human corpora cavernosa (HCC) relaxation induced by a new metal-based nitric oxide (NO) donor, the ruthenium complex cis-[Ru(bpy)2Imn(NO)]+3 (FOR0811). FOR0811 produced relaxation in phenylephrine (PE)-precontracted HCC with a maximal response that achieved 112.9±10.6%. There was no difference between the maximal relaxation induced by FOR0811 when compared with sodium nitroprusside (SNP) (106.8±7.3%), BAY41-2272 (107.6±4.1%) or vardenafil (103.4±3.8%), however, FOR0811 was less potent than SNP and vardenafil. L-NG-nitroarginine methyl ester (L-NAME), a NO synthase inhibitor, had no effect in the concentration–response curve elicited by FOR0811. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a heme-site inhibitor of soluble guanylyl cyclase (sGC) was able to either block or reverse the relaxation induced by FOR0811. On the other hand, the relaxation induced by FOR0811 was not affected by glibenclamide, a blocker of ATP-sensitive potassium channels. FOR0811 (10 μM) was able to increase cyclic guanosine monophosphate (cGMP) levels in corpora cavernosa strips. FOR0811 completely relaxes HCC by a sGC-cGMP-dependent mechanism and can be a lead compound in the development of new stable NO donors.

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References

  1. NIH Consensus Conference. Impotence. NIH Consensus Development Panel on Impotence. JAMA 1993; 7: 83–90.

  2. Johannes CB, Araújo AB, Feldman HA . Incidence of erectile dysfunction in men ages 40-69: longitudinal results from the Massachusetts male aging study. J Urol 2000; 163: 460–469.

    Article  CAS  Google Scholar 

  3. Moreira ED Jr, Abdo CH, Torres EB, Lobo CF, Fittipaldi JA . Prevalence and correlates of erectile dysfunction: results of the Brazilian study of sexual behavior. Urology 2001; 58: 583–588.

    Article  Google Scholar 

  4. Bivalacqua TJ, Champion HC, Hellstrom WJ, Kadowitz PJ . Pharmacotherapy for erectile dysfunction. Trends Pharmacol Sci 2000; 21: 484–489.

    Article  CAS  Google Scholar 

  5. Furchgott RF, Zawadzki JV . The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980; 288: 373–376.

    Article  CAS  Google Scholar 

  6. Palmer RM, Ferrige AG, Moncada S . Nitric oxide accounts for the biological activity of endothelium derived relaxing factor. Nature 1987; 327: 524–526.

    Article  CAS  Google Scholar 

  7. Ignarro LJ, Bush PA, Buga GM, Wood KS, Fukuto JM, Rajfer J . Nitric oxide andcyclic GMP formation upon electrical field stimulation cause relaxation of corpuscavernosum smooth muscle. Biochem Biophys Res Commun 1990; 31: 843–850.

    Article  Google Scholar 

  8. Andersson KE . Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction. Pharmacol Rev 2011; 63: 811–859.

    Article  CAS  Google Scholar 

  9. Corbin JD, Francis SH, Webb DJ . Phosphodiesterase type 5 as a pharmacologic target in erectile dysfunction. Urology 2002; 60 (Suppl 2): 4–11.

    Article  Google Scholar 

  10. Bonaventura D, de Lima RG, Vercesi JA, da Silva RS, Bendhack LM . Comparison of the mechanisms underlying the relaxation induced by two nitric oxide donors: Sodium nitroprusside and a new ruthenium complex. Vascul Pharmacol 2007; 46: 215–222.

    Article  CAS  Google Scholar 

  11. Seidler M, Ückert S, Waldkirch E, Stief CG, Oelke M, Tsikas D et al. In vitro effects of a novel class of nitric oxide (NO) donating compounds on isolated human erectile tissue. Eur Urol 2002; 42: 523–528.

    Article  CAS  Google Scholar 

  12. Tfouni E, Truzzi DR, Tavares A, Gomes AJ, Figueiredo LE, Franco DW . Biological activity of ruthenium nitrosyl complexes. Nitric Oxide 2012; 26: 38–53.

    Article  CAS  Google Scholar 

  13. Silva FON, Araújo SXB, Holanda AKM, Meyer E, Sales FAM, Diógenes ICN et al. Synthesis, characterization, and NO release study of the cis- and trans-[Ru(Bpy)2(SO3)(NO)]+ complexes. Eur J Inorg Chem 2006; 2006: 2020–2026.

    Article  Google Scholar 

  14. Lunardi CN, da Silva RS, Bendhack LM . New nitric oxide donors based on ruthenium complexes. Braz J Med Biol Res 2009; 42: 87–93.

    Article  CAS  Google Scholar 

  15. Cerqueira JB, Gonzaga-Silva LF, Lopes LG, Moraes ME, Nascimento NR . Relaxation of rabbit corpus cavernosum smooth muscle and aortic vascular endothelium induced by new nitric oxide donor substances of the nitrosyl-ruthenium complex. Int Braz J Urol 2008; 34: 638–645.

    Article  Google Scholar 

  16. Baracat JS, Teixeira CE, Okuyama CE, Priviero FB, Faro R, Antunes E et al. Relaxing effects induced by the soluble guanylylcyclasestimulator BAY41-2272 in human and rabbit corpus cavernosum. Eur J Pharmacol 2003; 477: 163–169.

    Article  CAS  Google Scholar 

  17. Bischoff E, Schramm M, Straub A, Feurer A, Stasch JP . BAY 41–2272: a stimulator of soluble guanylylcyclase induces nitric oxide-dependent penile erection in vivo. Urology 2003; 61: 464–467.

    Article  CAS  Google Scholar 

  18. Wanstall JC, Homer KL, Doggrell SA . Evidence for, and importance of, cGMP-independent mechanisms with NO and NO donors on blood vessels and platelets. Curr Vasc Pharmacol 2005; 3: 41–53.

    Article  CAS  Google Scholar 

  19. Zhao Y, Brandish PE, Divalentim M, Schelvis JP, Babcok GT, Marletta MA . Inhibition of soluble guanylatecyclaseby ODQ. Biochemistry 2000; 39: 10848–10854.

    Article  CAS  Google Scholar 

  20. Feelish M, Kotsonis P, Siebe J . The soluble guanylylcyclase inhibitor 1-H-[1,2,4] oxadiazolo-[4,3-a] quinoxaline 1-one is a non selectivehaem protein inhibitor of nitric oxide synthase and other cytochrome P450 enzymes involved in nitric oxide donor bioactivation. Mol Pharmacol 1999; 56: 243–253.

    Article  Google Scholar 

  21. Badejo AM Jr, Nossaman VE, Pankey EA, Bhartiya M, Kannadka CB, Murthy SN et al. Pulmonary and systemic vasodilator responses to the soluble guanylylcyclase stimulator, BAY 41-8543, are modulated by nitric oxide. Am J Physiol Heart Circ Physiol 2010; 299: H1153–H1159.

    Article  CAS  Google Scholar 

  22. Evgenov OV, Ichinose F, Evgenov NV, Gnoth MJ, Falkowski GE, Chang Y et al. Soluble guanylatecyclase activator reverses acute pulmonary hypertension and augments the pulmonary vasodilator response to inhaled nitricoxide in awake lambs. Circulation 2004; 110: 2253–2259.

    Article  CAS  Google Scholar 

  23. Hobbs AJ . Soluble guanylatecyclase: the forgotten sibling. Trends Pharmacol Sci 1997; 18: 484–491.

    Article  CAS  Google Scholar 

  24. Filippi S, Crescioli C, Vannelli GB, Fazzini A, Natali A, Riffaud JP et al. Effects of NCX 4050, a new NO donor, in rabbit and human corpus cavernosum. Int J Androl 2003; 26: 101–108.

    Article  CAS  Google Scholar 

  25. Höppner CK, Stief CG, Jonas U, Mandrek K, Noack T, Golenhofen K . Eletrical and chemical control of smooth muscle activity of rabbit corpus cavernosum in vitro. Urology 1996; 48: 512–518.

    Article  Google Scholar 

  26. Videbaek LM, Aalkjaer C, Mulvany MJ . Pinacidil opens K-selective channels causing hyperpolarization andrelaxation of noradrenaline contractions in rat mesenteric resistance vessels. Br J Pharmacol 1988; 95: 103–108.

    Article  CAS  Google Scholar 

  27. Freitas FC, Nascimento NR, Cerqueira JB, Morais ME, Regadas RP, Gonzaga-Silva LF . Yohimbine relaxes the human corpus cavernosum through a non-adrenergic mechanism involving the activation of K+ATP-dependent channels. Int J Impot Res 2009; 21: 356–361.

    Article  CAS  Google Scholar 

  28. Gonzaga-Silva LF, Nascimento NR, Fonteles MC, deNucci G, Moraes ME, Vasconcelos PR et al. Phentolamine relaxes human corpus cavernosumby a nonadrenergicmechanism activating ATP-sensitive K channel. Int J Impot Res 2005; 17: 27–32.

    Article  Google Scholar 

  29. Cerqueira JB, Gonzaga-Silva LF, Silva FO, Cerqueira JV, Oliveira RR, Moraes ME et al. Identification of mechanisms involved in the relaxation of rabbit cavernous smooth muscle by a new nitric oxide donor ruthenium compound. Int Braz J Urol 2012; 38: 687–694.

    Article  Google Scholar 

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Acknowledgements

This study was funded by the Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnólogico (FUNCAP). FOR0811 was synthesized by the bioinorganic chemistry lab of the Federal University of Ceará funded by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico(CNPq) (LGF Lopes 470054/2011-5) and FUNCAP-MS-CNPq (PPSUS).

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Authors and Affiliations

  1. Departamento de Cirurgia, Divisão de Urologia, Universidade Federal do Ceará, Fortaleza, Brazil

    A S Leitão Junior, J B G Cerqueira & L F Gonzaga-Silva

  2. Physiology and Pharmacology, Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, Brazil

    R M Campos, C F Santos & N R F Nascimento

  3. Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, Brazil

    M C Fonteles

  4. Departamento de Farmacologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil

    G de Nucci

  5. Departamento de Química Orgânica e Inorgânica, Universidade Federal do Ceará, Fortaleza, Brazil

    E H S Sousa & L G F Lopes

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  1. A S Leitão Junior
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Correspondence to N R F Nascimento.

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Leitão Junior, A., Campos, R., Cerqueira, J. et al. Relaxant effect of a metal-based drug in human corpora cavernosa and its mechanism of action. Int J Impot Res 28, 20–24 (2016). https://doi.org/10.1038/ijir.2015.27

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