Cavernosal hydrogen sulfide levels are associated with nitric oxide and hemeoxygenase levels in diabetic rats

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Penile erection is a neuromuscular event modulated by psyche, hormones as well as neurotransmitters. This pre-clinical study aimed to assess hydrogen sulfide (H2S) relationship with nitric oxide (NO) and hemeoxygenase (HO) in the cavernous tissues of diabetic rats. Overall, 90 adult male rats were investigated (6 groups, n = 15 each). They were subdivided into the following groups; untreated rats, rats treated with H2S donor/inhibitor, induced diabetic rats, diabetic rats treated with H2S donor/inhibitor. At the 6th week, the rats were killed to assess cavernous tissue cGMP, NO, H2S, HO enzyme activity levels. The rats treated with H2S donor showed increased mean cavernous tissue cGMP, NO, H2S, and HO enzyme activity levels whereas induced diabetic rats and rats treated with H2S inhibitor showed significant decreases in these parameters compared with the untreated rats. On the other hands, diabetic rats treated with H2S donor showed elevated mean cavernous tissue cGMP, NO, H2S, and HO enzyme activity levels whereas diabetic rats treated with H2S inhibitor showed significant decreases in these parameters compared with diabetic rats. Cavernous tissue H2S levels exhibited significant positive correlations with the cavernous tissue levels cGMP, NO, and HO enzyme activity levels. From these results, it could be concluded that cavernous tissues H2S plays a role of male sexual health by affecting cavernous tissues NO and HO enzyme activity in general and in diabetics in particular.

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  1. 1.

    Hatzimouratidis K, Hatzichristou D. How to treat erectile dysfunction in men with diabetes: from pathophysiology to treatment. Curr Diab Rep. 2014;14:545.

  2. 2.

    Andersson DP, Ekström U, Lehtihet M. Rigiscan evaluation of men with diabetes mellitus and erectile dysfunction and correlation with diabetes duration, age, BMI, lipids and HbA1c. PLoS ONE. 2015;10:e0133121.

  3. 3.

    Vandiver M, Snyder SH. Hydrogen sulfide: a gasotransmitter of clinical relevance. J Mol Med. 2012;90:255–63.

  4. 4.

    Yetik-Anacak G, Sorrentino R, Linder AE, Murat N. Gas what: NO is not the only answer to sexual function. Br J Pharmacol. 2015;172:1434–54.

  5. 5.

    van den Born JC, Hammes HP, Greffrath W, van Goor H, Hillebrands JL. DFG GRK International research training group 1874 Diabetic microvascular complications (DIAMICOM). Gasotransmitters in vascular complications of diabetes. Diabetes. 2016;65:331–45.

  6. 6.

    Polhemus DJ, Lefer DJ. Emergence of hydrogen sulfide as an endogenous gaseous signaling molecule in cardiovascular disease. Circ Res. 2014;114:730–7.

  7. 7.

    Shibuya N, Koike S, Tanaka M, Ishigami-Yuasa M, Kimura Y, Ogasawara Y, et al. A novel pathway for the production of hydrogen sulfide from D-cysteine in mammalian cells. Nat Commun. 2013;4:1366.

  8. 8.

    d’Emmanuele diVilla, Bianca R, Sorrentino R, Maffia P, Mirone V, Imbimbo C, et al. Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation. Proc Natl Acad Sci USA. 2009;106:4513–8.

  9. 9.

    Kimura H. Hydrogen sulfide: it’s production and function. Exp Physiol. 2011;96:833–5.

  10. 10.

    Meng J, Ganesan Adaikan P, Srilatha B. Hydrogen sulfide promotes nitric oxide production in corpus cavernosum by enhancing expression of endothelial nitric oxide synthase. Int J Impot Res. 2013;25:86–90.

  11. 11.

    Gur S, Kadowitz PJ, Trost L, Hellstrom WJG. Optimizing nitric oxide production by time dependent L-arginine administration in isolated human corpus cavernosum. J Urol. 2007;178:1543–8.

  12. 12.

    Zhao H, Jiang R. Relaxation mechanism of smooth muscle cells and its relationship with penile erection. Zhonghua Nan Ke Xue. 2016;22:838–42.

  13. 13.

    Abraham NG, Kappas A. Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev. 2008;60:79–127.

  14. 14.

    Wang J, Lu S, Moenne P, Montellano OR. Interaction of nitric oxide with human heme oxygenase-1. J Biol Chem. 2003;278:2341–7.

  15. 15.

    Abdel Aziz MT, El Asmer MF, Mostafa T, Atta H, Mahfouz S, Fouad H, et al. Effects of losartan, HO-1 inducers or HO-1 inhibitors on erectile signaling in diabetic rats. J Sex Med. 2009;6:3254–64.

  16. 16.

    Abdel Aziz MT, Mostafa T, Atta H, Wassef MA, Fouad HH, Rashed LA, et al. Putative role of carbon monoxide signaling pathway in penile erectile function. J Sex Med. 2009;6:49–60.

  17. 17.

    Kim DW, Zhao C, Kim MK, Park JK. Direct effect of carbon monoxide on relaxation induced by electrical field stimulation in rat corpus cavernosum. Korean J Urol. 2010;51:572–8.

  18. 18.

    Abdel Aziz MT, El-Asmer MF, Mostafa T, Mostafa S, Atta H, Wassef MA, et al. Heme oxygenase vs. nitric oxide synthase in signaling mediating sildenafil citrate action. J Sex Med. 2007;4:1098–107.

  19. 19.

    Chaudhry ZZ, Morris DL, Moss DR, Sims EK, Chiong Y, Kono T, et al. Streptozotocin is equally diabetogenic whether administered to fed or fasted mice. Lab Anim. 2013;47:257–65.

  20. 20.

    Samajdar S, Becker FF, Banik BK. Surface-mediated highly efficient regioselective nitration of aromatic compounds by bismuth nitrate. Tetrahedron Lett. 2000;41:8017–20.

  21. 21.

    Stipanuk MH, Beck PW. Characterization of the enzymic capacity for cysteine desulphydration in liver and kidney of the rat. Biochem J. 1982;206:267–77.

  22. 22.

    Mingone CJ, Gupte SA, Quan S, Abraham NG, Wolin MS. Influence of heme and hemeoxygenase-1 transfection of pulmonary microvascular endothelium on oxidant generation and cGMP. Exp Biol Med. 2003;228:535–9.

  23. 23.

    Abraham NG, Lutton JD, Levere RD. Hememetabolism and erythropoiesis in abnormal iron states. Role of aminolevulinic acid synthetase and heme oxygenase. Exp Haematol. 1985;13:833–43.

  24. 24.

    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193:265–75.

  25. 25.

    Coletta C, Papapetropoulos A, Erdelyi K, Olah G, Modis K, Panopoulos P, et al. Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation. Proc Natl Acad Sci USA. 2012;109:9161–6.

  26. 26.

    Kida K, Ichinose F. Hydrogen sulfide and neuroinflammation. Handb Exp Pharmacol. 2015;230:181–9.

  27. 27.

    Kida M, Sugiyama T, Yoshimoto T, Ogawa Y. Hydrogen sulfide increases nitric oxide production with calcium-dependent activation of endothelial nitric oxide synthase in endothelial cells. Eur J Pharm Sci. 2013;48:211–5.

  28. 28.

    Jamroz-Wiśniewska A, Gertler A, Solomon G, Wood ME, Whiteman M, Bełtowski J. Leptin-induced endothelium-dependent vasorelaxation of peripheral arteries in lean and obese rats: role of nitric oxide and hydrogen sulfide. PLoS ONE. 2014;9:e86744.

  29. 29.

    Srilatha B, Adaikan P-G, Li L, Moore P-K. Hydrogen sulfide: a novel endogenous gasotransmitter facilitates erectile function. J Sex Med. 2007;4:1304–11.

  30. 30.

    Jupiter RC, Yoo D, Pankey EA, Reddy VV, Edward JA, Polhemus DJ, et al. Analysis of erectile responses to H2S donors in the anesthetized rat. Am J Physiol Heart Circ Physiol. 2015;309:H835–843.

  31. 31.

    Elshorbagy AK, Kozich V, Smith AD, Refsum H. Cysteine and obesity: consistency of the evidence across epidemiologic, animal and cellular studies. Curr Opin Clin Nutr Metab Care. 2012;15:49–57.

  32. 32.

    Zhao WM, Wang R. H2S-induced vasorelaxation and underlying cellular and molecular mechanisms. Am J Physiol Heart Circ Physiol. 2002;283:H474–80.

  33. 33.

    Akrouh A, Halcomb SE, Nichols CG, Sala-Rabanal M. Molecular biology of K(ATP) channels and implications for health and disease. IUBMB Life. 2009;61:971–8.

  34. 34.

    Yetik-Anacak G, Dikmen A, Coletta C, Mitidieri E, Dereli M, Donnarumma E, et al. Hydrogen sulfide compensates nitric oxide deficiency in murine corpus cavernosum. Pharmacol Res. 2016;113:38–43.

  35. 35.

    Aziz MT, Mostafa T, Atta H, Rashed L, Marzouk SA, Obaia EM, et al. The role of PDE5 inhibitors in heme oxygenase -cGMP relationship in rat cavernous tissues. J Sex Med. 2008;5:1636–45.

  36. 36.

    Abdel Aziz MT, El-Asmar MF, Mostafa T, Atta H, Fouad HH, Roshdy NK, et al. Effect of hemin and carbon monoxide releasing molecule (CORM-3) on cGMP in rat penile tissue. J Sex Med. 2008;5:336–43.

  37. 37.

    Abdel Aziz MT, Al-Asmar MF, Mostafa T, Atta H, Wassef MA, Fouad H, et al. Effect of inducible nitric oxide synthase and heme oxygenase inducers or inhibitors on molecular signaling of erectile function. J Clin Biochem Nutr. 2005;37:103–11.

  38. 38.

    Yu W, Wan Z, Qiu XF, Chen Y, Dai YT. Resveratrol, an activator of SIRT1, restores erectile function in streptozotocin-induced diabetic rats. Asian J Androl. 2013;15:646–51.

  39. 39.

    Yetik-Anacak G, Xia T, Dimitropoulou C, Venema RC, Catravas JD. Effects of hsp90 binding inhibitors on sGC-mediated vascular relaxation. Am J Physiol Heart Circ Physiol. 2006;291:H260–68.

  40. 40.

    Yang Z, Yang C, Xiao L, Liao X, Lan A, Wang X, et al. Novel insights into the role of HSP90 in cytoprotection of H2S against chemical hypoxia-induced injury in H9c2 cardiac myocytes. Int J Mol Med. 2011;28:397–403.

  41. 41.

    Neves D. Advanced glycation end-products: a common pathway in diabetes and age-related erectile dysfunction. Free Radic Res. 2013;47(Suppl 1):49–69.

  42. 42.

    Zhang Y, Yang J, Wang T, Wang SG, Liu JH, Yin CP, et al. Decreased endogenous hydrogen sulfide generation in penile tissues of diabetic rats with erectile dysfunction. J Sex Med. 2016;13:350–60.

  43. 43.

    Mostafa T, Rashed LA, Kotb K. Testosterone and chronic sildenafil/tadalafil anti-apoptotic role in aged diabetic rats. Int J Impot Res. 2010;22:255–61.

  44. 44.

    Mostafa T, Rashed L, Kotb K, Taymour M. Effect of testosterone and frequent low-dose sildenafil/tadalafil on cavernous tissue oxidative stress of aged diabetic rats. Andrologia. 2012;44:411–5.

  45. 45.

    Podlasek CA, Mulhall J, Davies K, Wingard CJ, Hannan JL, Bivalacqua TJ, et al. Translational perspective on the role of testosterone in sexual function and dysfunction. J Sex Med. 2016;13:1183–98.

  46. 46.

    Bucci M, Mirone V, Di Lorenzo A, Vellecco V, Roviezzo F, Brancaleone V, et al. Hydrogen sulphide is involved in testosterone vascular effect. Eur Urol. 2009;56:378–83.

  47. 47.

    Srilatha B, Muthulakshmi P, Adaikan PG, Moore PK. Endogenous hydrogen sulfide insufficiency as a predictor of sexual dysfunction in aging rats. Aging Male. 2012;15:153–8.

  48. 48.

    Zuo C, Huang YM, Jiang R, Yang HF, Cheng B, et al. Endogenous hydrogen sulfide and androgen deficiency-induced erectile dysfunction in rats. Zhonghua Nan Ke Xue. 2014;20:605–12.

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Correspondence to Taymour Mostafa.

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Mostafa, T., Rashed, L., Nabil, N. et al. Cavernosal hydrogen sulfide levels are associated with nitric oxide and hemeoxygenase levels in diabetic rats. Int J Impot Res 31, 105–110 (2019) doi:10.1038/s41443-018-0084-9

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