Abstract
Background
Penile corpus cavernosum is an extremely vascularized tissue and cavernosal smooth muscle tone is regulated by the balance between contractile and relaxant factor. We investigated the possible role of arachidonic acid/cyclooxygenase cascade, phosphodiesterase IV (PDEIV) and Rho-kinase in exogenous hydrogen sulfide (H2S)-induced relaxation in mouse corpus cavernosum.
Methods
The relaxant response to H2S (NaHS as exogenous H2S; 1–1000 μM) were obtained in isolated mouse corpus cavernosum tissues which pre-contracted by phenylephrine (5 μM). The effects of 4-(4-octadecylphenyl)-4-oxobutenoic acid (OBAA; 10 μM), a selective phospholipase A2 (PLA2) inhibitor, indomethacin (1 μM), a non-selective cyclooxygenase (COX) inhibitor, baicalein (10 μM), a lipoxygenase (LOX) inhibitor, and proadifen (10 μM), cytochrome P450 inhibitor, on the relaxant responses to H2S were investigated. Furthermore, the effects of theophylline (500 μM) and rolipram (1 μM), a non-selective and selective PDEIV inhibitor, and fasudil (3 μM), a specific Rho-kinase inhibitor, were studied on H2S-induced relaxation.
Results
H2S-induced relaxations were significantly reduced by OBAA, indomethacin and proadifen but not baicalein. Furthermore, theophylline, rolipram and fasudil reduced H2S-induced relaxations.
Conclusion
These results suggest that PLA2, COX, cytochrome P450, PDEIV and Rho-kinase pathway may involve in H2S-induced relaxation in mouse corpus cavernosum tissues.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Abe K, Kimura H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 1996; 16:1066–71.
Li L, Moore PK. Putative biological roles of hydrogen sulfide in health and disease: a breath of not so fresh air. Trends Pharmacol Sci 2008;29:84–90.
Shibuya N, Mikami Y, Kimura Y, Nagahara N, Kimura H. Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide. J Biochem 2009;146:623–6.
Kimura H. Hydrogen sulfide: its production, release and functions. Amino Acids 2011;41:113–21.
Li L, Hsu A, Moore PK. Actions and interactions of nitric oxide, carbon monoxide and hydrogen sulphide in the cardiovascular system and in inflammation-a tale of three gases!. Pharmacol Ther 2009;123:386–400.
Zhao W, Zhang J, Lu Y, Wang R. The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. EMBO J 2001;20:6008–16.
Cheng Y, Ndisang JF, Tang G, Cao K, Wang R. Hydrogen sulfide-induced relaxation of resistance mesenteric artery beds of rats. Am J Physiol Heart Circ Physiol 2004;287:H2316–23.
Webb GD, Lim LH, Oh VM, Yeo SB, Cheong YP, Ali MY, et al. Contractile and vasorelaxant effects of hydrogen sulfide and its biosynthesis in the human internal mammary artery. J Pharmacol Exp Ther 2008;324:876–82.
Dhaese I, Lefebvre RA. Myosin light chain phosphatase activation is involved in the hydrogen sulfide-induced relaxation in mouse gastric fundus. Eur J Pharmacol 2009;606:180–6.
Rashid S, Heer JK, Garle MJ, Alexander SP, Roberts RE. Hydrogen sulphide-induced relaxation of porcine peripheral bronchioles. Br J Pharmacol 2013;168:1902–10.
Aydinoglu F, Ogulener N. Characterization of relaxant mechanism of H2S in mouse corpus cavernosum. Clin Exp Pharmacol Physiol 2016;43:503–11.
Burnett AL. The role of nitric oxide in erectile dysfunction: implications for medical therapy. J Clin Hypertens (Greenwich) 2006;8:53–62.
Andersson KE. Pharmacology of penile erection. Pharmacol Rev 2001;53(3):417–50.
d’Emmanuele di Villa Bianca R, Sorrentino R, Maffia P, Mirone V, Fusco F, De Palma R, et al. Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation. Proc Natl Acad Sci USA 2009;106(11):4513–8.
d’Emmanuele di Villa Bianca R, Sorrentino R, Coletta C, Mitidieri E, Rossi A, Vellecco V, et al. Hydrogen sulfide-induced dual vascular effect involves arachidonic acid cascade in rat mesenteric arterial bed. J Pharmacol Exp Ther 2011;337:59–64.
Bucci M, Papapetropoulos A, Vellecco V, Zhou Z, Pyriochou A, Roussos C, et al. Hydrogen sulfide is an endogenous inhibitor of phosphodiesterase activity. Arterioscler Thromb Vasc Biol 2010;30:1998–2004.
Nalli AD, Rajagopal S, Mahavadi S, Grider JR, Murthy KS. Inhibition of RhoA-dependent pathway and contraction by endogenous hydrogen sulfide in rabbit gastric smooth muscle cells. Am J Physiol Cell Physiol 2015;308(6):C485–95.
Ali MY, Ping CY, Mok YY, Ling L, Whiteman M, Bhatia M, et al. Regulation of vascular nitric oxide in vitro and in vivo; a new role for endogenous hydrogen sulphide? Br J Pharmacol 2006;149:625–34.
Kubo S, Doe I, Kurokawa Y, Nishikawa H, Kawabata A. Direct inhibition of endothelial nitric oxide synthase by hydrogen sulfide: contribution to dual modulation of vascular tension. Toxicology 2007;232(1–2):138–46.
Lim JJ, Liu YH, Khin ES, Bian JS. Vasoconstrictive effect of hydrogen sulfide involves downregulation of cAMP in vascular smooth muscle cells. Am J Physiol Cell Physiol 2008;295(5):C1261–70.
d’Emmanuele di Villa Bianca R, Mitidieri E, Donnarumma E, Tramontano T, Brancaleone V, Cirino G, et al. Hydrogen sulfide is involved in dexamethasone-induced hypertension in rat. Nitric Oxide 2015;46:80–6.
Sánchez A, Contreras C, Villalba N, Martínez P, Martínez AC, Bríones A, et al. Altered arachidonic acid metabolism via COX-1 and COX-2 contributes to the endothelial dysfunction of penile arteries from obese Zucker rats. Br J Pharmacol 2010;159(3):604–16.
Angulo J, Cuevas P, La Fuente JM, Pomerol JM, Ruiz-Castañé E, Puigvert A, et al. Regulation of human penile smooth muscle tone by prostanoid receptors. Br J Pharmacol 2002; 136(1):23–30.
Lin H, Yuan J, Ruan KH, Yang W, Zhang J, Dai Y, et al. COX-2-10aa-PGIS gene therapy improves erectile function in rats after cavernous nerve injury. J Sex Med 2013;10(6):1476–87.
Fernandes VS, Ribeiro AS, Barahona MV, Orensanz LM, Martínez-Sáenz A, Recio P, et al. Hydrogen sulfide mediated inhibitory neurotransmission to the pig bladder neck: role of KATP channels, sensory nerves and calcium signaling. J Urol 2013;190(2):746–56.
Jin L, Foss CE, Zhao X, Mills TM, Wang MH, McCluskey LP, et al. Cytochrome P450 epoxygenases provide a novel mechanism for penile erection. FASEB J 2006;20(3):539–41.
Yousif MH, Benter IF. Role of cytochrome P450 metabolites of arachidonic acid in regulation of corporal smooth muscle tone in diabetic and older rats. Vascul Pharmacol 2007;47:281–7.
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(5):H835–43.
Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther 2006;109(2):366–98.
Uckert S, Hedlund P, Waldkirch E, Sohn M, Jonas U, Andersson KE, et al. Interactions between cGMP- and cAMP-pathways are involved in the regulation of penile smooth muscle tone. World J Urol 2004;22(4):261–6.
Waldkirch E, Uckert S, Yildirim H, Sohn M, Jonas U, Stief CG, et al. Cyclic AMP-specific and cyclic GMP-specific phosphodiesterase isoenzymes in human cavernous arteries-immunohistochemical distribution and functional significance. World J Urol 2005;23(6):405–10.
Gupta R, Kumar G, Kumar RS. An update on cyclic nucleotide phosphodiesterase (PDE) inhibitors: phosphodiesterases and drug selectivity. Methods Find Exp Clin Pharmacol 2005;27:101–18.
Santos-Silva AJ, Cairrão E, Morgado M, Alvarez E, Verde I. PDE4 and PDE5 regulate cyclic nucleotides relaxing effects in human umbilical arteries. Eur J Pharmacol 2008;582(1–3):102–9.
Matsumoto T, Kobayashi T, Kamata K. Phosphodiesterases in the vascular system. J Smooth Muscle Res 2003;39:67–86.
Srilatha B, Adaikan PG, Li L, Moore PK. Hydrogen sulphide: a novel endogenous gasotransmitter facilitates erectile function. J Sex Med 2007;4:1304–11.
Ghasemi M, Dehpour AR, Moore KP, Mani AR. Role of endogenous hydrogen sulfide in neurogenic relaxation of rat corpus cavernosum. Biochem Pharmacol 2012;83:1261–8.
Bardin PG, Dorward MA, Lampe FC, Franke B, Holgate ST. Effect of selective phosphodiesterase 3 inhibition on the early and late asthmatic responses to inhaled allergen. Br J Clin Pharmacol 1998;45(4):387–91.
Rees RW, Ralph DJ, Royle M, Moncada S, Cellek S. Y-27632, an inhibitor of Rhokinase, antagonizes noradrenergic contractions in the rabbit and human penile corpus cavernosum. Br J Pharmacol 2001;133:455–8.
Teixeira CE, Jin L, Ying Z, Palmer T, Webb RC. Ca2+ sensitization and the regulation of contractility in rat anococcygeus and retractor penis muscle. Biochem Pharmacol 2005;69(10):1483–92.
Waldkirch ES, Ückert S, Sohn M, Kuczyk MA, Hedlund P. Rho kinase (ROK)-related proteins in human cavernous arteries: an immunohistochemical and functional approach. J Sex Med 2012;9(5):1337–43.
Kumcu EK, Aydinoglu F, Astarci E, Ogulener N. The effect of sub-chronic systemic ethanol treatment on corpus cavernosal smooth muscle contraction: the contribution of RhoA/Rho-kinase. Naunyn Schmiedebergs Arch Pharmacol 2016;389(3):249–58.
Hedegaard ER, Gouliaev A, Winther AK, Arcanjo DD, Aalling M, Renaltan NS, et al. Involvement of potassium channels and calcium-independent mechanisms in hydrogen sulfide-induced relaxation of rat mesenteric small arteries. J Pharmacol Exp Ther 2016;356(1):53–63.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Aydinoglu, F., Ogulener, N. The role of arachidonic acid/cyclooxygenase cascade, phosphodiesterase IV and Rho-kinase in H2S-induced relaxation in the mouse corpus cavernosum. Pharmacol. Rep 69, 610–615 (2017). https://doi.org/10.1016/j.pharep.2017.02.018
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1016/j.pharep.2017.02.018