Abstract
Soluble guanylyl cyclase (sGC) is the major effector molecule for nitric oxide (NO) and as such an interesting therapeutic target for the treatment of erectile dysfunction. To assess the functional importance of the sGCα1β1 isoform in corpus cavernosum (CC) relaxation, CC from male sGCα1−/− and wild-type mice were mounted in organ baths for isometric tension recording. The relaxation to endogenous NO (from acetylcholine, bradykinin and electrical field stimulation) was nearly abolished in the sGCα1−/− CC. In the sGCα1−/− mice, the relaxing influence of exogenous NO (from sodium nitroprusside and NO gas), BAY 41-2272 (NO-independent sGC stimulator) and T-1032 (phosphodiesterase type 5 inhibitor) were also significantly decreased. The remaining exogenous NO-induced relaxation seen in the sGCα1−/− mice was significantly decreased by the sGC-inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. The specificity of the impairment of the sGC-related responses was demonstrated by the unaltered relaxations seen with forskolin (adenylyl cyclase activator) and 8-pCPT-cGMP (cGMP analog). In conclusion, the sGCα1β1 isoform is involved in corporal smooth muscle relaxation in response to NO and NO-independent sGC stimulators. The fact that there is still some effect of exogenous NO in the sGCα1−/− mice suggests the contribution of (an) additional pathway(s).
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References
Andersson KE, Wagner G . Physiology of penile erection. Physiol Rev 1995; 75: 191–236.
Kim N, Azadzoi KM, Goldstein I, Saenz de Tejada I . A nitric oxide-like factor mediates nonadrenergic-noncholinergic neurogenic relaxation of penile corpus cavernosum smooth muscle. J Clin Invest 1991; 88: 112–118.
Hurt KJ, Musicki B, Palese MA, Crone JK, Becker RE, Moriarity JL et al. Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection. Proc Natl Acad Sci USA 2002; 99: 4061–4066.
Toda N, Ayajiki K, Okamura T . Nitric oxide and penile erectile function. Pharmacol Ther 2005; 106: 233–266.
Musicki B, Burnett AL . eNOS function and dysfunction in the penis. Exp Biol Med (Maywood) 2006; 231: 154–165.
Friebe A, Koesling D . Regulation of nitric oxide-sensitive guanylyl cyclase. Circ Res 2003; 93: 96–105.
Lohmann SM, Vaandrager AB, Smolenski A, Walter U, de Jonge HR . Distinct and specific functions of cGMP-dependent protein kinases. Trends Biochem Sci 1997; 22: 307–312.
Hedlund P, Aszodi A, Pfeifer A, Alm P, Hofmann F, Ahmad M et al. Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice. Proc Natl Acad Sci USA 2000; 97: 2349–2354.
Garbers DL . Purification of soluble guanylate cyclase from rat lung. J Biol Chem 1979; 254: 240–243.
Harteneck C, Koesling D, Soling A, Schultz G, Bohme E . Expression of soluble guanylyl cyclase. Catalytic activity requires two enzyme subunits. FEBS Lett 1990; 272: 221–223.
Koesling D, Herz J, Gausepohl H, Niroomand F, Hinsch KD, Mulsch A et al. The primary structure of the 70 kDa subunit of bovine soluble guanylate cyclase. FEBS Lett 1988; 239: 29–34.
Yuen PS, Potter LR, Garbers DL . A new form of guanylyl cyclase is preferentially expressed in rat kidney. Biochemistry 1990; 29: 10872–10878.
Harteneck C, Wedel B, Koesling D, Malkewitz J, Bohme E, Schultz G . Molecular cloning and expression of a new alpha-subunit of soluble guanylyl cyclase. Interchangeability of the alpha-subunits of the enzyme. FEBS Lett 1991; 292: 217–222.
Russwurm M, Behrends S, Harteneck C, Koesling D . Functional properties of a naturally occurring isoform of soluble guanylyl cyclase. Biochem J 1998; 335(Part 1): 125–130.
Mergia E, Russwurm M, Zoidl G, Koesling D . Major occurrence of the new alpha2beta1 isoform of NO-sensitive guanylyl cyclase in brain. Cell Signal 2003; 15: 189–195.
Ushiyama M, Morita T, Kuramochi T, Yagi S, Katayama S . Erectile dysfunction in hypertensive rats results from impairment of the relaxation evoked by neurogenic carbon monoxide and nitric oxide. Hypertens Res 2004; 27: 253–261.
Burnett AL, Johns DG, Kriegsfeld LJ, Klein SL, Calvin DC, Demas GE et al. Ejaculatory abnormalities in mice with targeted disruption of the gene for heme oxygenase-2. Nat Med 1998; 4: 84–87.
Schachter M . Erectile dysfunction and lipid disorders. Curr Med Res Opin 2000; 16(Suppl 1): s9–s12.
Saenz de Tejada I, Goldstein I, Azadzoi K, Krane RJ, Cohen RA . Impaired neurogenic and endothelium-mediated relaxation of penile smooth muscle from diabetic men with impotence. N Engl J Med 1989; 320: 1025–1030.
Abdel-Gawad M, Huynh H, Brock GB . Experimental chronic renal failure-associated erectile dysfunction: molecular alterations in nitric oxide synthase pathway and IGF-I system. Mol Urol 1999; 3: 117–125.
Morales A, Gingell C, Collins M, Wicker PA, Osterloh IH . Clinical safety of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction. Int J Impot Res 1998; 10: 69–73.
Goldenberg MM . Safety and efficacy of sildenafil citrate in the treatment of male erectile dysfunction. Clin Ther 1998; 20: 1033–1048.
Sips P, Buys E, Rogge E, Dewerchin M, Brouckaert P . Functional knockout of the soluble guanylate cyclase alpha 1 subunit leads to gender-specific hypertension while retaining sensitivity to nitric oxide. Circulation 2005; 112: 17–A747, Abstract.
Kelm M, Schrader J . Control of coronary vascular tone by nitric oxide. Circ Res 1990; 66: 1561–1575.
Takagi M, Mochida H, Noto T, Yano K, Inoue H, Ikeo T et al. Pharmacological profile of T-1032, a novel specific phosphodiesterase type 5 inhibitor, in isolated rat aorta and rabbit corpus cavernosum. Eur J Pharmacol 2001; 411: 161–168.
Stasch JP, Becker EM, Alonso-Alija C, Apeler H, Dembowsky K, Feurer A et al. NO-independent regulatory site on soluble guanylate cyclase. Nature 2001; 410: 212–215.
Nakane M, Hsieh G, Miller LN, Chang R, Terranova MA, Moreland RB et al. Activation of soluble guanylate cyclase causes relaxation of corpus cavernosum tissue: synergism of nitric oxide and YC-1. Int J Impot Res 2002; 14: 121–127.
Nimmegeers S, Sips P, Buys E, Brouckaert P, Van de Voorde J . Functional role of the soluble guanylyl cyclase alpha 1 subunit in vascular smooth muscle relaxation. Cardiovasc Res 2007; 76: 149–159.
Wanigasekara Y, Kepper ME, Keast JR . Immunohistochemical characterisation of pelvic autonomic ganglia in male mice. Cell Tissue Res 2003; 311: 175–185.
Ottesen B, Fahrenkrug J . Vasoactive intestinal polypeptide and other preprovasoactive intestinal polypeptide-derived peptides in the female and male genital tract: localization, biosynthesis, and functional and clinical significance. Am J Obstet Gynecol 1995; 172: 1615–1631.
Steers WD, McConnell J, Benson GS . Anatomical localization and some pharmacological effects of vasoactive intestinal polypeptide in human and monkey corpus cavernosum. J Urol 1984; 132: 1048–1053.
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: 261–266.
Gupta S, Moreland RB, Munarriz R, Daley J, Goldstein I, Saenz de Tejada I et al. Possible role of Na(+)-K(+)-ATPase in the regulation of human corpus cavernosum smooth muscle contractility by nitric oxide. Br J Pharmacol 1995; 116: 2201–2206.
Homer KL, Wanstall JC . Cyclic GMP-independent relaxation of rat pulmonary artery by spermine NONOate, a diazeniumdiolate nitric oxide donor. Br J Pharmacol 2000; 131: 673–682.
Masson P, Lambert SM, Brown M, Shabsigh R . PDE-5 inhibitors: current status and future trends. Urol Clin North Am 2005; 32: 511–525, viii.
Koglin M, Stasch JP, Behrends S . BAY 41-2272 activates two isoforms of nitric oxide-sensitive guanylyl cyclase. Biochem Biophys Res Commun 2002; 292: 1057–1062.
Teixeira CE, Priviero FB, Todd Jr J, Webb RC . Vasorelaxing effect of BAY 41-2272 in rat basilar artery: involvement of cGMP-dependent and independent mechanisms. Hypertension 2006; 47: 596–602.
Acknowledgements
We thank the DMBR animal caretakers for maintaining the animal facility and Cyriel Mabilde for the construction of the adapted holders in the myograph. This work was supported by a grant of FWO-Vlaanderen and the Bijzonder Onderzoeksfonds (BOF-GOA) of Ghent University. EB was supported by an award from the Northeast Affiliate Research Committee of the American Heart Association.
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Nimmegeers, S., Sips, P., Buys, E. et al. Role of the soluble guanylyl cyclase α1-subunit in mice corpus cavernosum smooth muscle relaxation. Int J Impot Res 20, 278–284 (2008). https://doi.org/10.1038/sj.ijir.3901627
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DOI: https://doi.org/10.1038/sj.ijir.3901627
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