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The promise of inhibition of smooth muscle tone as a treatment for erectile dysfunction: where are we now?

International Journal of Impotence Research volume 24, pages 49–60 (2012)Cite this article

Abstract

Ten years ago, the inhibition of Rho kinase by intracavernosal injection of Y-27632 was found to induce an erectile response. This effect did not require activation of nitric oxide-mediated signaling, introducing a novel target pathway for the treatment of erectile dysfunction (ED), with potential added benefit in cases where nitric oxide bioavailability is attenuated (and thus phosphodiesterase type 5 (PDE5) inhibitors are less efficacious). Rho-kinase antagonists are currently being developed and tested for a wide range of potential uses. The inhibition of this calcium-sensitizing pathway results in blood vessel relaxation. It is also possible that blockade of additional smooth muscle contractile signaling mechanisms may have the same effect. In this review, we conducted an extensive search of pertinent literature using PUBMED. We have outlined the various pathways involved in the maintenance of penile smooth muscle tone and discussed the current potential benefit for the pharmacological inhibition of these targets for the treatment of ED.

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References

  1. NIH releases consensus statement on impotence. Am Fam Physician 1993; 48: 147–150.

  2. Andersson KE . Erectile physiological and pathophysiological pathways involved in erectile dysfunction. J Urol 2003; 170: S6–13.

    PubMed  Google Scholar 

  3. Chitaley K . Type 1 and type 2 diabetic-erectile dysfunction: same diagnosis (ICD-9), different disease? J Sex Med 2009; 6 (Suppl 3): 262–268.

    PubMed  Google Scholar 

  4. Chang S, Hypolite JA, Changolkar A, Wein AJ, Chacko S, Disanto ME . Increased contractility of diabetic rabbit corpora smooth muscle in response to endothelin is mediated via Rho-kinase beta. Int J Impot Res 2003; 15: 53–62.

    CAS  PubMed  Google Scholar 

  5. Blum MD, Bahnson RR, Porter TN, Carter MF . Effect of local alpha-adrenergic blockade on human penile erection. J Urol 1985; 134: 479–481.

    CAS  PubMed  Google Scholar 

  6. Kim NN, Dhir V, Azadzoi KM, Traish AM, Flaherty E, Goldstein I . Pilot study of the endothelin-A receptor selective antagonist BMS-193884 for the treatment of erectile dysfunction. J Androl 2002; 23: 76–83.

    CAS  PubMed  Google Scholar 

  7. Chitaley K, Wingard CJ, Clinton WR, Branam H, Stopper VS, Lewis RW et al. Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. Nat Med 2001; 7: 119–122.

    CAS  PubMed  Google Scholar 

  8. Saenz DTI, Blanco R, Goldstein I, Azadzoi K, De Las MA, Krane RJ et al. Cholinergic neurotransmission in human corpus cavernosum. I. Responses of isolated tissue. Am J Physiol 1988; 254: H459–H467.

    Google Scholar 

  9. Saenz DTI, Moroukian P, Tessier J, Kim JJ, Goldstein I, Frohrib D . Trabecular smooth muscle modulates the capacitor function of the penis. Studies on a rabbit model. Am J Physiol 1991; 260: H1590–H1595.

    Google Scholar 

  10. Chitaley K, Webb RC, Mills TM . Rhoa/Rho-kinase: a novel player in the regulation of penile erection. Int J Impot Res 2001; 13: 67–72.

    CAS  PubMed  Google Scholar 

  11. Takahashi R, Nishimura J, Hirano K, Naito S, Kanaide H . Modulation of Ca2+ sensitivity regulates contractility of rabbit corpus cavernosum smooth muscle. J Urol 2003; 169: 2412–2416.

    CAS  PubMed  Google Scholar 

  12. Sato M, Kawatani M . Effects of noradrenaline on cytosolic concentrations of Ca(2+) in cultured corpus cavernosum smooth muscle cells of the rabbit. Neurosci Lett 2002; 324: 89–92.

    CAS  PubMed  Google Scholar 

  13. Holmquist F, Persson K, Garcia-Pascual A, Andersson KE . Phospholipase C activation by endothelin-1 and noradrenaline in isolated penile erectile tissue from rabbit. J Urol 1992; 147: 1632–1635.

    CAS  PubMed  Google Scholar 

  14. Murat N, Soner BC, Demir O, Esen A, Gidener S . Contractility of diabetic human corpus cavernosum smooth muscle in response to serotonin mediated via Rho-kinase. Pharmacology 2009; 84: 24–28.

    CAS  PubMed  Google Scholar 

  15. Rodat-Despoix L, Aires V, Ducret T, Marthan R, Savineau JP, Rousseau E et al. Signalling pathways involved in the contractile response to 5-HT in the human pulmonary artery. Eur Respir J 2009; 34: 1338–1347.

    CAS  PubMed  Google Scholar 

  16. Traish AM, Netsuwan N, Daley J, Padman-Nathan H, Goldstein I, Saenz DTI . A heterogeneous population of alpha 1 adrenergic receptors mediates contraction of human corpus cavernosum smooth muscle to norepinephrine. J Urol 1995; 153: 222–227.

    CAS  PubMed  Google Scholar 

  17. Saenz DTI, Kim N, Lagan I, Krane RJ, Goldstein I . Regulation of adrenergic activity in penile corpus cavernosum. J Urol 1989; 142: 1117–1121.

    Google Scholar 

  18. Bonkowsky HL, Bloomer JR, Ebert PS, Mahoney MJ . Heme synthetase deficiency in human protoporphyria. demonstration of the defect in liver and cultured skin fibroblasts. J Clin Invest 1975; 56: 1139–1148.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Saenz DTI, Carson MP, De Las MA, Goldstein I, Traish AM . Endothelin: localization, synthesis, activity, and receptor types in human penile corpus cavernosum. Am J Physiol 1991; 261: H1078–H1085.

    Google Scholar 

  20. Ortega MA, De Artinano AA . Highlights on endothelins: a review. Pharmacol Res 1997; 36: 339–351.

    Google Scholar 

  21. Dai Y, Pollock DM, Lewis RL, Wingard CJ, Stopper VS, Mills TM . Receptor-specific influence of endothelin-1 in the erectile response of the rat. Am J Physiol Regul Integr Comp Physiol 2000; 279: R25–R30.

    CAS  PubMed  Google Scholar 

  22. Mumtaz FH, Lau DH, Siddiqui EJ, Thompson CS, Morgan RJ, Mikhailidis DP . Pharmacological properties of endothelin-1 in the rabbit corpus cavernosum. In Vivo 2006; 20: 243–246.

    CAS  PubMed  Google Scholar 

  23. Parkkisenniemi UM, Klinge E . Functional characterization of endothelin receptors in the bovine retractor penis muscle and penile artery. Pharmacol Toxicol 1996; 79: 73–79.

    CAS  PubMed  Google Scholar 

  24. Abeysinghe HR, Clancy J, Qiu Y . Comparison of endothelin-1-mediated tissue tension and calcium mobilization effects in isolated rabbit corpus cavernosum. Urology 2002; 60: 925–930.

    PubMed  Google Scholar 

  25. Sullivan ME, Dashwood MR, Thompson CS, Mikhailidis DP, Morgan RJ . Down-regulation of endothelin-B receptor sites in cavernosal tissue of hypercholesterolaemic rabbits. Br J Urol 1998; 81: 128–134.

    CAS  PubMed  Google Scholar 

  26. Sullivan ME, Dashwood MR, Thompson CS, Muddle JR, Mikhailidis DP, Morgan RJ . Alterations in endothelin B receptor sites in cavernosal tissue of diabetic rabbits: potential relevance to the pathogenesis of erectile dysfunction. J Urol 1997; 158: 1966–1972.

    CAS  PubMed  Google Scholar 

  27. Uckert S, Fuhlenriede MH, Becker AJ, Stief CG, Scheller F, Knapp WH et al. Is serotonin significant for the control of penile flaccidity and detumescence in the human male? Urol Res 2003; 31: 55–60.

    PubMed  Google Scholar 

  28. Lau DH, Thompson CS, Bellringer JF, Thomas PJ, Mumtaz FH, Morgan RJ et al. Doxazosin and serotonin (5-HT) receptor (1A, 2A, and 4) antagonists inhibit 5-HT-mediated human cavernosal contraction. J Androl 2006; 27: 679–685.

    CAS  PubMed  Google Scholar 

  29. Furukawa K, Nagao K, Ishii N, Uchiyama T . Responses to serotonin (5HT) in isolated corpus cavernosum penis of rabbit. Int J Impot Res 2003; 15: 267–271.

    CAS  PubMed  Google Scholar 

  30. Iversen BM, Arendshorst WJ . Ang Ii and vasopressin stimulate calcium entry in dispersed smooth muscle cells of preglomerular arterioles. Am J Physiol 1998; 274: F498–F508.

    CAS  PubMed  Google Scholar 

  31. Jin L, Ying Z, Hilgers RH, Yin J, Zhao X, Imig JD et al. Increased RhoA/Rho-kinase signaling mediates spontaneous tone in aorta from angiotensin Ii-induced hypertensive rats. J Pharmacol Exp Ther 2006; 318: 288–295.

    CAS  PubMed  Google Scholar 

  32. Becker AJ, Uckert S, Stief CG, Scheller F, Knapp WH, Hartmann U et al. Plasma levels of angiotensin II during different penile conditions in the cavernous and systemic blood of healthy men and patients with erectile dysfunction. Urology 2001; 58: 805–810.

    CAS  PubMed  Google Scholar 

  33. Becker AJ, Uckert S, Stief CG, Truss MC, Machtens S, Scheller F et al. Possible role of bradykinin and angiotensin Ii in the regulation of penile erection and detumescence. Urology 2001; 57: 193–198.

    CAS  PubMed  Google Scholar 

  34. Iwamoto Y, Song K, Takai S, Yamada M, Jin D, Sakaguchi M et al. Multiple pathways of angiotensin I conversion and their functional role in the canine penile corpus cavernosum. J Pharmacol Exp Ther 2001; 298: 43–48.

    CAS  PubMed  Google Scholar 

  35. Yousif MH, Kehinde EO, Benter IF . Different responses to angiotensin-(1–7) in young, aged and diabetic rabbit corpus cavernosum. Pharmacol Res 2007; 56: 209–216.

    CAS  PubMed  Google Scholar 

  36. Kifor I, Williams GH, Vickers MA, Sullivan MP, Jodbert P, Dluhy RG . Tissue angiotensin II as a modulator of erectile function. I. Angiotensin peptide content, secretion and effects in the corpus cavernosum. J Urol 1997; 157: 1920–1925.

    CAS  PubMed  Google Scholar 

  37. Berridge MJ . Smooth muscle cell calcium activation mechanisms. J Physiol 2008; 586: 5047–5061.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Bolton TB . Calcium events in smooth muscles and their interstitial cells; physiological roles of sparks. J Physiol 2006; 570: 5–11.

    CAS  PubMed  Google Scholar 

  39. House SJ, Potier M, Bisaillon J, Singer HA, Trebak M . The non-excitable smooth muscle: calcium signaling and phenotypic switching during vascular disease. Pflugers Arch 2008; 456: 769–785.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Gomez MF, Stevenson AS, Bonev AD, Hill-Eubanks DC, Nelson MT . Opposing actions of inositol 1,4,5-trisphosphate and ryanodine receptors on nuclear factor of activated T-cells regulation in smooth muscle. J Biol Chem 2002; 277: 37756–37764.

    CAS  PubMed  Google Scholar 

  41. Dreja K, Hellstrand P . Differential modulation of caffeine- and IP3-induced calcium release in cultured arterial tissue. Am J Physiol 1999; 276: C1115–C1120.

    CAS  PubMed  Google Scholar 

  42. Zhou H, Nakamura T, Matsumoto N, Hisatsune C, Mizutani A, Iesaki T et al. Predominant role of type 1 IP3 receptor in aortic vascular muscle contraction. Biochem Biophys Res Commun 2008; 369: 213–219.

    CAS  PubMed  Google Scholar 

  43. Liu X, Farley JM . Acetylcholine-induced Ca++-dependent chloride current oscillations are mediated by inositol 1,4,5-trisphosphate in tracheal myocytes. J Pharmacol Exp Ther 1996; 277: 796–804.

    CAS  PubMed  Google Scholar 

  44. Essin K, Gollasch M . Role of ryanodine receptor subtypes in initiation and formation of calcium sparks in arterial smooth muscle: comparison with striated muscle. J Biomed Biotechnol 2009; 2009: 135249.

    PubMed  PubMed Central  Google Scholar 

  45. Williams BA, Sims SM . Calcium sparks activate calcium-dependent Cl− current in rat corpus cavernosum smooth muscle cells. Am J Physiol Cell Physiol 2007; 293: C1239–C1251.

    CAS  PubMed  Google Scholar 

  46. Nelson MT, Cheng H, Rubart M, Santana LF, Bonev AD, Knot HJ et al. Relaxation of arterial smooth muscle by calcium sparks. Science 1995; 270: 633–637.

    CAS  PubMed  Google Scholar 

  47. Mccloskey C, Cagney V, Large R, Hollywood M, Sergeant G, Mchale N et al. Voltage-dependent Ca2+ currents contribute to spontaneous Ca2+ waves in rabbit corpus cavernosum myocytes. J Sex Med 2009; 6: 3019–3031.

    CAS  PubMed  Google Scholar 

  48. Kerfoot WW, Park HY, Schwartz LB, Hagen PO, Carson III CC . Characterization of calcium channel blocker induced smooth muscle relaxation using a model of isolated corpus cavernosum. J Urol 1993; 150: 249–252.

    CAS  PubMed  Google Scholar 

  49. Craven M, Sergeant GP, Hollywood MA, Mchale NG, Thornbury KD . Modulation of spontaneous Ca2+-activated Cl− currents in the rabbit corpus cavernosum by the nitric oxide-cGMP pathway. J Physiol 2004; 556: 495–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Yanai Y, Hashitani H, Kubota Y, Sasaki S, Kohri K, Suzuki H . The role of Ni(2+)-sensitive T-type Ca(2+) channels in the regulation of spontaneous excitation in detrusor smooth muscles of the guinea-pig bladder. BJU Int 2006; 97: 182–189.

    CAS  PubMed  Google Scholar 

  51. Zhong J, Hume JR, Keef KD . Beta-adrenergic receptor stimulation of L-type Ca2+ channels in rabbit portal vein myocytes involves both alphas and betagamma G protein subunits. J Physiol 2001; 531: 105–115.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Bray JG, Mynlieff M . Involvement of protein kinase C and protein kinase A in the enhancement of L-type calcium current by GABAB receptor activation in neonatal hippocampus. Neuroscience 2011; 179: 62–72.

    CAS  PubMed  Google Scholar 

  53. Mcneish AJ, Altayo FJ, Garland CJ . Evidence both L-type and non-L-type voltage-dependent calcium channels contribute to cerebral artery vasospasm following loss of no in the rat. Vascul Pharmacol 2010; 53: 151–159.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Yuill KH, Mcneish AJ, Kansui Y, Garland CJ, Dora KA . Nitric oxide suppresses cerebral vasomotion by sGC-independent effects on ryanodine receptors and voltage-gated calcium channels. J Vasc Res 2010; 47: 93–107.

    CAS  PubMed  Google Scholar 

  55. Pritchard TJ, Bowman PS, Jefferson A, Tosun M, Lynch RM, Paul RJ . Na(+)–K(+)-atpase and Ca(2+) clearance proteins in smooth muscle: a functional unit. Am J Physiol Heart Circ Physiol 2010; 299: H548–H556.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Cohen RA, Weisbrod RM, Gericke M, Yaghoubi M, Bierl C, Bolotina VM . Mechanism of nitric oxide-induced vasodilatation: refilling of intracellular stores by sarcoplasmic reticulum Ca2+ ATPase and inhibition of store-operated Ca2+ influx. Circ Res 1999; 84: 210–219.

    CAS  PubMed  Google Scholar 

  57. Furukawa K, Ohshima N, Tawada-Iwata Y, Shigekawa M . Cyclic GMP stimulates Na+/Ca2+ exchange in vascular smooth muscle cells in primary culture. J Biol Chem 1991; 266: 12337–12341.

    CAS  PubMed  Google Scholar 

  58. Cartwright EJ, Oceandy D, Neyses L . Plasma membrane calcium ATPase and its relationship to nitric oxide signaling in the heart. Ann NY Acad Sci 2007; 1099: 247–253.

    CAS  PubMed  Google Scholar 

  59. Juan YS, Onal B, Broadaway S, Cosgrove J, Leggett RE, Whitbeck C et al. Effect of castration on male rabbit lower urinary tract tissue enzymes. Mol Cell Biochem 2007; 301: 227–233.

    CAS  PubMed  Google Scholar 

  60. Disanto ME, Wang Z, Menon C, Zheng Y, Chacko T, Hypolite J et al. Expression of myosin isoforms in smooth muscle cells in the corpus cavernosum penis. Am J Physiol 1998; 275: C976–C987.

    CAS  PubMed  Google Scholar 

  61. Zhang XH, Melman A, Disanto ME . Update on corpus cavernosum smooth muscle contractile pathways in erectile function: a role for testosterone? J Sex Med 2011; 8: 1865–1879.

    CAS  PubMed  Google Scholar 

  62. Kitazawa T, Masuo M, Somlyo AP . G protein-mediated inhibition of myosin light-chain phosphatase in vascular smooth muscle. Proc Natl Acad Sci USA 1991; 88: 9307–9310.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Chuang AT, Strauss JD, Murphy RA, Steers WD . Sildenafil, a type-5 cGMP phosphodiesterase inhibitor, specifically amplifies endogenous cGMP-dependent relaxation in rabbit corpus cavernosum smooth muscle in vitro. J Urol 1998; 160: 257–261.

    CAS  PubMed  Google Scholar 

  64. Wu X, Somlyo AV, Somlyo AP . Cyclic GMP-dependent stimulation reverses G-protein-coupled inhibition of smooth muscle myosin light chain phosphate. Biochem Biophys Res Commun 1996; 220: 658–663.

    CAS  PubMed  Google Scholar 

  65. Pfitzer G, Arner A . Involvement of small GTPases in the regulation of smooth muscle contraction. Acta Physiol Scand 1998; 164: 449–456.

    CAS  PubMed  Google Scholar 

  66. Taggart MJ, Lee YH, Morgan KG . Cellular redistribution of PKCalpha, rhoA, and ROKalpha following smooth muscle agonist stimulation. Exp Cell Res 1999; 251: 92–101.

    CAS  PubMed  Google Scholar 

  67. Ohkawara H, Ishibashi T, Sakamoto T, Sugimoto K, Nagata K, Yokoyama K et al. Thrombin-induced rapid geranylgeranylation of RhoA as an essential process for RhoA activation in endothelial cells. J Biol Chem 2005; 280: 10182–10188.

    CAS  PubMed  Google Scholar 

  68. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M et al. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 1996; 273: 245–248.

    CAS  PubMed  Google Scholar 

  69. Somlyo AP, Somlyo AV . Signal transduction through the RhoA/Rho-kinase pathway in smooth muscle. J Muscle Res Cell Motil 2004; 25: 613–615.

    PubMed  Google Scholar 

  70. Amano M, Ito M, Kimura K, Fukata Y, Chihara K, Nakano T et al. Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J Biol Chem 1996; 271: 20246–20249.

    CAS  PubMed  Google Scholar 

  71. Teixeira CE, Jin L, Ying Z, Palmer T, Priviero FB, Webb RC . Expression and functional role of the RhoA/Rho-kinase pathway in rat coeliac artery. Clin Exp Pharmacol Physiol 2005; 32: 817–824.

    CAS  PubMed  Google Scholar 

  72. Ark M, Ozveren E, Yazici G, Korkmaz B, Buyukafsar K, Arikan O et al. Effects of HA-1077 and Y-27632, two Rho-kinase inhibitors, in the human umbilical artery. Cell Biochem Biophys 2004; 41: 331–342.

    CAS  PubMed  Google Scholar 

  73. Nakamura K, Nishimura J, Hirano K, Ibayashi S, Fujishima M, Kanaide H . Hydroxyfasudil, an active metabolite of fasudil hydrochloride, relaxes the rabbit basilar artery by disinhibition of myosin light chain phosphatase. J Cereb Blood Flow Metab 2001; 21: 876–885.

    CAS  PubMed  Google Scholar 

  74. Li WJ, Park K, Paick JS, Kim SW . Chronic treatment with an oral Rho-kinase inhibitor restores erectile function by suppressing corporal apoptosis in diabetic rats. J Sex Med 2011; 8: 400–410.

    CAS  PubMed  Google Scholar 

  75. Ishizaki T, Maekawa M, Fujisawa K, Okawa K, Iwamatsu A, Fujita A et al. The small GTP-binding protein Rho binds to and activates a 160 kDA Ser/Thr protein kinase homologous to myotonic dystrophy kinase. EMBO J 1996; 15: 1885–1893.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Takahashi N, Tuiki H, Saya H, Kaibuchi K . Localization of the gene coding for ROCK II/Rho kinase on human chromosome 2p24. Genomics 1999; 55: 235–237.

    CAS  PubMed  Google Scholar 

  77. Satoh KMD, Fukumoto Y, Shimokawa H . Rho-kinase: important new therapeutic target in cardiovascular diseases. Am J Physiol Heart Circ Physiol 2011; 301: H287–H296.

    CAS  PubMed  Google Scholar 

  78. Wang Y, Zheng XR, Riddick N, Bryden M, Baur W, Zhang X et al. Rock isoform regulation of myosin phosphatase and contractility in vascular smooth muscle cells. Circ Res 2009; 104: 531–540.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang H, Eto M, Steers WD, Somlyo AP, Somlyo AV . RhoA-mediated Ca2+ sensitization in erectile function. J Biol Chem 2002; 277: 30614–30621.

    CAS  PubMed  Google Scholar 

  80. Chang S, Hypolite JA, Zderic SA, Wein AJ, Chacko S, Disanto ME . Increased corpus cavernosum smooth muscle tone associated with partial bladder outlet obstruction is mediated via Rho-kinase. Am J Physiol Regul Integr Comp Physiol 2005; 289: R1124–R1130.

    CAS  PubMed  Google Scholar 

  81. Zhu PY, Jiang R, Deng QF, Wang XR . Expression of Rho-kinase and heme oxygenase in the corpus cavernosum of spontaneous hypertensive rats. Zhonghua Nan Ke Xue 2008; 14: 215–219.

    CAS  PubMed  Google Scholar 

  82. Gratzke C, Strong TD, Gebska MA, Champion HC, Stief CG, Burnett AL et al. Activated RhoA/Rho kinase impairs erectile function after cavernous nerve injury in rats. J Urol 2010; 184: 2197–2204.

    CAS  PubMed  Google Scholar 

  83. Vignozzi L, Morelli A, Filippi S, Ambrosini S, Mancina R, Luconi M et al. Testosterone regulates RhoA/Rho-kinase signaling in two distinct animal models of chemical diabetes. J Sex Med 2007; 4: 620–630.

    CAS  PubMed  Google Scholar 

  84. Chiou WF, Liu HK, Juan CW . Abnormal protein expression in the corpus cavernosum impairs erectile function in type 2 diabetes. BJU Int 2010; 105: 674–680.

    CAS  PubMed  Google Scholar 

  85. Shcherbakova OV, Serebryanaya DV, Postnikov AB, Schroeter MM, Zittrich S, Noegel AA et al. Kinase-related protein/telokin inhibits Ca2+-independent contraction in Triton-skinned guinea pig Taenia coli. Biochem J 2010; 429: 291–302.

    CAS  PubMed  Google Scholar 

  86. Herring BP, Lyons GE, Hoggatt AM, Gallagher PJ . Telokin expression is restricted to smooth muscle tissues during mouse development. Am J Physiol Cell Physiol 2001; 280: C12–C21.

    CAS  PubMed  Google Scholar 

  87. Sobieszek A, Andruchov OY, Nieznanski K . Kinase-related protein (Telokin) is phosphorylated by smooth-muscle myosin light-chain kinase and modulates the kinase activity. Biochem J 1997; 328 (Part 2): 425–430.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Nieznanski K, Sobieszek A . Telokin (kinase-related protein) modulates the oligomeric state of smooth-muscle myosin light-chain kinase and its interaction with myosin filaments. Biochem J 1997; 322 (Part 1): 65–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Numata T, Katoh T, Yazawa M . Functional role of the C-terminal domain of smooth muscle myosin light chain kinase on the phosphorylation of smooth muscle myosin. J Biochem 2001; 129: 437–444.

    CAS  PubMed  Google Scholar 

  90. Shirinsky VP, Vorotnikov AV, Birukov KG, Nanaev AK, Collinge M, Lukas TJ et al. A kinase-related protein stabilizes unphosphorylated smooth muscle myosin minifilaments in the presence of ATP. J Biol Chem 1993; 268: 16578–16583.

    CAS  PubMed  Google Scholar 

  91. Choudhury N, Khromov AS, Somlyo AP, Somlyo AV . Telokin mediates Ca2+-desensitization through activation of myosin phosphatase in phasic and tonic smooth muscle. J Muscle Res Cell Motil 2004; 25: 657–665.

    CAS  PubMed  Google Scholar 

  92. Walker LA, Macdonald JA, Liu X, Nakamoto RK, Haystead TA, Somlyo AV et al. Site-specific phosphorylation and point mutations of Telokin modulate its Ca2+-desensitizing effect in smooth muscle. J Biol Chem 2001; 276: 24519–24524.

    CAS  PubMed  Google Scholar 

  93. Wu X, Haystead TA, Nakamoto RK, Somlyo AV, Somlyo AP . Acceleration of myosin light chain dephosphorylation and relaxation of smooth muscle by telokin. Synergism with cyclic nucleotide-activated kinase. J Biol Chem 1998; 273: 11362–11369.

    CAS  PubMed  Google Scholar 

  94. Khromov AS, Wang H, Choudhury N, Mcduffie M, Herring BP, Nakamoto R et al. Smooth muscle of telokin-deficient mice exhibits increased sensitivity to Ca2+ and decreased cGMP-induced relaxation. Proc Natl Acad Sci USA 2006; 103: 2440–2445.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Crozatier B . Central role of PKCs in vascular smooth muscle cell ion channel regulation. J Mol Cell Cardiol 2006; 41: 952–955.

    CAS  PubMed  Google Scholar 

  96. Bousquet SM, Monet M, Boulay G . Protein kinase C-dependent phosphorylation of transient receptor potential canonical 6 (TRPC6) on serine 448 causes channel inhibition. J Biol Chem 2010; 285: 40534–40543.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Paffett ML, Riddle MA, Kanagy NL, Resta TC, Walker BR . Altered protein kinase c regulation of pulmonary endothelial store- and receptor-operated Ca2+ entry after chronic hypoxia. J Pharmacol Exp Ther 2010; 334: 753–760.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Kline LW, Ji J, Wang GJ, Sutherland SK, Pang PK, Benishin CG . Protein kinase C masks nitric oxide synthase activity in vascular smooth muscle under basal conditions. J Cardiovasc Pharmacol 2004; 43: 281–287.

    CAS  PubMed  Google Scholar 

  99. Jiang X, Yang F, Tan H, Liao D, Bryan Jr RM, Randhawa JK et al. Hyperhomocystinemia impairs endothelial function and eNOS activity via PKC activation. Arterioscler Thromb Vasc Biol 2005; 25: 2515–2521.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Muniyappa R, Srinivas PR, Ram JL, Walsh MF, Sowers JR . Calcium and protein kinase C mediate high-glucose-induced inhibition of inducible nitric oxide synthase in vascular smooth muscle cells. Hypertension 1998; 31: 289–295.

    CAS  PubMed  Google Scholar 

  101. Angulo J, Cuevas P, Fernandez A, Allona A, Moncada I, Martin-Morales A et al. Enhanced thromboxane receptor-mediated responses and impaired endothelium-dependent relaxation in human corpus cavernosum from diabetic impotent men: role of protein kinase C activity. J Pharmacol Exp Ther 2006; 319: 783–789.

    CAS  PubMed  Google Scholar 

  102. Jin L, Teixeira CE, Webb RC, Leite R . Comparison of the involvement of protein kinase C in agonist-induced contractions in mouse aorta and corpus cavernosum. Eur J Pharmacol 2008; 590: 363–368.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Eto M, Senba S, Morita F, Yazawa M . Molecular cloning of a novel phosphorylation-dependent inhibitory protein of protein phosphatase-1 (CPI17) in smooth muscle: its specific localization in smooth muscle. FEBS Lett 1997; 410: 356–360.

    CAS  PubMed  Google Scholar 

  104. Kitazawa T, Eto M, Woodsome TP, Khalequzzaman M . Phosphorylation of the myosin phosphatase targeting subunit and CPI-17 during Ca2+ sensitization in rabbit smooth muscle. J Physiol 2003; 546: 879–889.

    CAS  PubMed  Google Scholar 

  105. Koyama M, Ito M, Feng J, Seko T, Shiraki K, Takase K et al. Phosphorylation of CPI-17, an inhibitory phosphoprotein of smooth muscle myosin phosphatase, by Rho-kinase. FEBS Lett 2000; 475: 197–200.

    CAS  PubMed  Google Scholar 

  106. Takizawa N, Koga Y, Ikebe M . Phosphorylation of CPI17 and myosin binding subunit of type 1 protein phosphatase by p21-activated kinase. Biochem Biophys Res Commun 2002; 297: 773–778.

    CAS  PubMed  Google Scholar 

  107. Kolitsi Z, Panayiotakis G, Anastassopoulos V, Scodras A, Pallikarakis N . A multiple projection method for digital tomosynthesis. Med Phys 1992; 19: 1045–1050.

    CAS  PubMed  Google Scholar 

  108. Somlyo AP, Somlyo AV . Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol Rev 2003; 83: 1325–1358.

    CAS  PubMed  Google Scholar 

  109. Chang S, Hypolite JA, Mohanan S, Zderic SA, Wein AJ, Chacko S . Alteration of the PKC-mediated signaling pathway for smooth muscle contraction in obstruction-induced hypertrophy of the urinary bladder. Lab Invest 2009; 89: 823–832.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Morrison JF, Pallot DJ, Sheen R, Dhanasekaran S, Mensah-Brown EP . The effects of age and streptozotocin diabetes on the sympathetic innervation in the rat penis. Mol Cell Biochem 2007; 295: 53–58.

    CAS  PubMed  Google Scholar 

  111. Takahashi K, Ghatei MA, Lam HC, O’halloran DJ, Bloom SR . Elevated plasma endothelin in patients with diabetes mellitus. Diabetologia 1990; 33: 306–310.

    CAS  PubMed  Google Scholar 

  112. Haak T, Jungmann E, Felber A, Hillmann U, Usadel KH . Increased plasma levels of endothelin in diabetic patients with hypertension. Am J Hypertens 1992; 5: 161–166.

    CAS  PubMed  Google Scholar 

  113. Carneiro FS, Giachini FR, Lima VV, Carneiro ZN, Nunes KP, Ergul A et al. DOCA-salt treatment enhances responses to endothelin-1 in murine corpus cavernosum. Can J Physiol Pharmacol 2008; 86: 320–328.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Carneiro FS, Nunes KP, Giachini FR, Lima VV, Carneiro ZN, Nogueira EF et al. Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension. J Sex Med 2008; 5: 2793–2807.

    CAS  PubMed  Google Scholar 

  115. Wilkes N, White S, Stein P, Bernie J, Rajasekaran M . Phosphodiesterase-5 inhibition synergizes Rho-kinase antagonism and enhances erectile response in male hypertensive rats. Int J Impot Res 2004; 16: 187–194.

    CAS  PubMed  Google Scholar 

  116. Behr-Roussel D, Chamiot-Clerc P, Bernabe J, Mevel K, Alexandre L, Safar ME et al. Erectile dysfunction in spontaneously hypertensive rats: pathophysiological mechanisms. Am J Physiol Regul Integr Comp Physiol 2003; 284: R682–R688.

    CAS  PubMed  Google Scholar 

  117. Christ GJ, Stone B, Melman A . Age-dependent alterations in the efficacy of phenylephrine-induced contractions in vascular smooth muscle isolated from the corpus cavernosum of impotent men. Can J Physiol Pharmacol 1991; 69: 909–913.

    CAS  PubMed  Google Scholar 

  118. Luo Y, Jiang R . Expressions of Cav1.3 and RyR1 in the corpus cavernosum of the penis in aged rats. Zhonghua Nan Ke Xue 2009; 15: 985–989.

    CAS  PubMed  Google Scholar 

  119. Jin L, Liu T, Lagoda GA, Champion HC, Bivalacqua TJ, Burnett AL . Elevated RhoA/Rho-kinase activity in the aged rat penis: mechanism for age-associated erectile dysfunction. FASEB J 2006; 20: 536–538.

    CAS  PubMed  Google Scholar 

  120. Park K, Shin JW, Oh JK, Ryu KS, Kim SW, Paick JS . Restoration of erectile capacity in normotensive aged rats by modulation of angiotensin receptor type 1. J Androl 2005; 26: 123–128.

    CAS  PubMed  Google Scholar 

  121. Rajasekaran M, White S, Baquir A, Wilkes N . Rho-kinase inhibition improves erectile function in aging male Brown–Norway rats. J Androl 2005; 26: 182–188.

    CAS  PubMed  Google Scholar 

  122. Leungwattanakij S, Bivalacqua TJ, Usta MF, Yang DY, Hyun JS, Champion HC et al. Cavernous neurotomy causes hypoxia and fibrosis in rat corpus cavernosum. J Androl 2003; 24: 239–245.

    PubMed  Google Scholar 

  123. Cho MC, Park K, Chai JS, Lee SH, Kim SW, Paick JS . Involvement of sphingosine-1-phosphate/RhoA/Rho-kinase signaling pathway in corporal fibrosis following cavernous nerve injury in male rats. J Sex Med 2010; 8: 712–721.

    PubMed  Google Scholar 

  124. Burnett AL, Nelson RJ, Calvin DC, Liu JX, Demas GE, Klein SL et al. Nitric oxide-dependent penile erection in mice lacking neuronal nitric oxide synthase. Mol Med 1996; 2: 288–296.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Burnett AL . Nitric oxide regulation of penile erection: biology and therapeutic implications. J Androl 2002; 23: S20–S26.

    CAS  PubMed  Google Scholar 

  127. Plane F, Wiley KE, Jeremy JY, Cohen RA, Garland CJ . Evidence that different mechanisms underlie smooth muscle relaxation to nitric oxide and nitric oxide donors in the rabbit isolated carotid artery. Br J Pharmacol 1998; 123: 1351–1358.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Sanders DB, Kelley T, Larson D . The role of nitric oxide synthase/nitric oxide in vascular smooth muscle control. Perfusion 2000; 15: 97–104.

    CAS  PubMed  Google Scholar 

  129. Sauzeau V, Le JH, Cario-Toumaniantz C, Smolenski A, Lohmann SM, Bertoglio J et al. Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle. J Biol Chem 2000; 275: 21722–21729.

    CAS  PubMed  Google Scholar 

  130. Sawada N, Itoh H, Yamashita J, Doi K, Inoue M, Masatsugu K et al. cGMP-dependent protein kinase phosphorylates and inactivates RhoA. Biochem Biophys Res Commun 2001; 280: 798–805.

    CAS  PubMed  Google Scholar 

  131. Kitazawa T, Semba S, Huh YH, Kitazawa K, Eto M . Nitric oxide-induced biphasic mechanism of vascular relaxation via dephosphorylation of CPI-17 and MYPT1. J Physiol 2009; 587: 3587–3603.

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Sidi AA, Cameron JS, Duffy LM, Lange PH . Intracavernous drug-induced erections in the management of male erectile dysfunction: experience with 100 patients. J Urol 1986; 135: 704–706.

    CAS  PubMed  Google Scholar 

  133. Traish A, Gupta S, Gallant C, Huang YH, Goldstein I . Phentolamine mesylate relaxes penile corpus cavernosum tissue by adrenergic and non-adrenergic mechanisms. Int J Impot Res 1998; 10: 215–223.

    CAS  PubMed  Google Scholar 

  134. Bella AJ, Brock GB . Intracavernous pharmacotherapy for erectile dysfunction. Endocrine 2004; 23: 149–155.

    CAS  PubMed  Google Scholar 

  135. Padma-Nathan H, Goldstein I, Klimberg I, Coogan C, Auerbach S, Lammers P . Long-term safety and efficacy of oral phentolamine mesylate (Vasomax) in men with mild to moderate erectile dysfunction. Int J Impot Res 2002; 14: 266–270.

    CAS  PubMed  Google Scholar 

  136. Ugarte F, Hurtado-Coll A . Comparison of the efficacy and safety of sildenafil citrate (Viagra) and oral phentolamine for the treatment of erectile dysfunction. Int J Impot Res 2002; 14 (Suppl 2): S48–S53.

    PubMed  Google Scholar 

  137. Lowe FC . Treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia: sexual function. BJU Int 2005; 95 (Suppl 4): 12–18.

    CAS  PubMed  Google Scholar 

  138. Carson CC . Combination of phosphodiesterase-5 inhibitors and alpha-blockers in patients with benign prostatic hyperplasia: treatments of lower urinary tract symptoms, erectile dysfunction, or both? BJU Int 2006; 97 (Suppl 2): 39–43.

    CAS  PubMed  Google Scholar 

  139. Kaplan SA, Gonzalez RR, Te AE . Combination of alfuzosin and sildenafil is superior to monotherapy in treating lower urinary tract symptoms and erectile dysfunction. Eur Urol 2007; 51: 1717–1723.

    CAS  PubMed  Google Scholar 

  140. Merlin SL, Brock GB, Begin LR, Hiou Tim FF, Macramalla AN, Seyam RM et al. New insights into the role of endothelin-1 in radiation-associated impotence. Int J Impot Res 2001; 13: 104–109.

    CAS  PubMed  Google Scholar 

  141. Jesmin S, Zaedi S, Yamaguchi N, Maeda S, Yamaguchi I, Goto K et al. Effects of dual endothelin receptor antagonist on antiapoptotic marker Bcl-2 expression in streptozotocin-induced diabetic rats. Exp Biol Med (Maywood) 2006; 231: 1034–1039.

    CAS  Google Scholar 

  142. Baumhakel M, Custodis F, Schlimmer N, Laufs U, Bohm M . Improvement of endothelial function of the corpus cavernosum in apolipoprotein E knockout mice treated with irbesartan. J Pharmacol Exp Ther 2008; 327: 692–698.

    PubMed  Google Scholar 

  143. Dorrance AM, Lewis RW, Mills TM . Captopril treatment reverses erectile dysfunction in male stroke prone spontaneously hypertensive rats. Int J Impot Res 2002; 14: 494–497.

    CAS  PubMed  Google Scholar 

  144. Fogari R, Zoppi A, Corradi L, Mugellini A, Poletti L, Lusardi P . Sexual function in hypertensive males treated with lisinopril or atenolol: a cross-over study. Am J Hypertens 1998; 11: 1244–1247.

    CAS  PubMed  Google Scholar 

  145. Fogari R, Zoppi A, Poletti L, Marasi G, Mugellini A, Corradi L . Sexual activity in hypertensive men treated with valsartan or carvedilol: a crossover study. Am J Hypertens 2001; 14: 27–31.

    CAS  PubMed  Google Scholar 

  146. Baumhakel M, Schlimmer N, Bohm M . Effect of irbesartan on erectile function in patients with hypertension and metabolic syndrome. Int J Impot Res 2008; 20: 493–500.

    CAS  PubMed  Google Scholar 

  147. Bohm M, Baumhakel M, Teo K, Sleight P, Probstfield J, Gao P et al. Erectile dysfunction predicts cardiovascular events in high-risk patients receiving telmisartan, ramipril, or both: The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (ONTARGET/TRANSCEND) trials. Circulation 2010; 121: 1439–1446.

    PubMed  Google Scholar 

  148. Fovaeus M, Andersson KE, Hedlund H . Effects of some calcium channel blockers on isolated human penile erectile tissues. J Urol 1987; 138: 1267–1272.

    CAS  PubMed  Google Scholar 

  149. Ma LL, Liu YQ, Tang WH, Zhao LM, Jiang H . Experimental study of verapamil on the relaxation of isolated human corpus cavernosum tissues. Asian J Androl 2006; 8: 195–198.

    CAS  PubMed  Google Scholar 

  150. Sarikaya S, Asci R, Aybek Z, Yilmaz AF, Buyukalpelli R, Yildiz S . Effects of intracavernous calcium channel blockers in dogs. Int Urol Nephrol 1997; 29: 673–680.

    CAS  PubMed  Google Scholar 

  151. Morrissette DL, Skinner MH, Hoffman BB, Levine RE, Davidson JM . Effects of antihypertensive drugs atenolol and nifedipine on sexual function in older men: a placebo-controlled, crossover study. Arch Sex Behav 1993; 22: 99–109.

    CAS  PubMed  Google Scholar 

  152. Fogelman J . Verapamil caused depression, confusion, and impotence. Am J Psychiatry 1988; 145: 380.

    CAS  PubMed  Google Scholar 

  153. Bolayir K, Goksin N . Intracavernous self-injection of papaverine and verapamil: a clinical experience. Acta Chir Hung 1994; 34: 253–256.

    CAS  PubMed  Google Scholar 

  154. Sahin M, Basar MM, Bozdogan O, Atan A . Short-term histopathologic effects of different intracavernosal agents on corpus cavernosum and antifibrotic activity of intracavernosal verapamil: an experimental study. Urology 2001; 58: 487–492.

    CAS  PubMed  Google Scholar 

  155. Shibuya M, Suzuki Y . Treatment of cerebral vasospasm by a protein kinase inhibitor at 877. No To Shinkei 1993; 45: 819–824.

    CAS  PubMed  Google Scholar 

  156. Doggrell SA . Rho-kinase inhibitors show promise in pulmonary hypertension. Expert Opin Invest Drugs 2005; 14: 1157–1159.

    CAS  Google Scholar 

  157. Park K, Kim SW, Rhu KS, Paick JS . Chronic administration of an oral Rho kinase inhibitor prevents the development of vasculogenic erectile dysfunction in a rat model. J Sex Med 2006; 3: 996–1003.

    CAS  PubMed  Google Scholar 

  158. Liao JK, Seto M, Noma K . Rho kinase (ROCK) inhibitors. J Cardiovasc Pharmacol 2007; 50: 17–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Shimokawa H, Rashid M . Development of Rho-kinase inhibitors for cardiovascular medicine. Trends Pharmacol Sci 2007; 28: 296–302.

    CAS  PubMed  Google Scholar 

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  1. Department of Urology, University of Washington, Seattle, WA, USA

    X Jiang & K Chitaley

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Jiang, X., Chitaley, K. The promise of inhibition of smooth muscle tone as a treatment for erectile dysfunction: where are we now?. Int J Impot Res 24, 49–60 (2012). https://doi.org/10.1038/ijir.2011.49

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