Pathophysiological role of the renin-angiotensin system on erectile dysfunction

European Journal of Clinical Investigation

Volumn 43, Issue 9, 2013, Pages 978-985

  Fraga Silva, Rodrigo A ^a   Montecucco, Fabrizio ^b,c   Mach, François ^b   Santos, Robson A S ^d   Stergiopulos, Nikos ^a  

^a EPFL   (Switzerland)

^b GENEVA UNIVERSITY HOSPITALS   (Switzerland)

^c UNIVERSITY OF GENOA   (Italy)

^d FEDERAL UNIVERSITY OF MINAS GERAIS   (Brazil)

Author keywords

Angiotensin II; Angiotensin (1 7); Erectile dysfunction; Mas receptor; Renin angiotensin system

Indexed keywords

ANGIOTENSIN 1 RECEPTOR; ANGIOTENSIN II; ANGIOTENSINOGEN; CAPTOPRIL; CARVEDILOL; G PROTEIN COUPLED RECEPTOR; HEPTAPEPTIDE; IRBESARTAN; LOSARTAN; MAS RECEPTOR; MYOSIN LIGHT CHAIN KINASE; MYOSIN LIGHT CHAIN PHOSPHATASE; NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; RAMIPRIL; RECEPTOR; TADALAFIL; TELMISARTAN; UNCLASSIFIED DRUG; VALSARTAN;

ANGIOTENSIN BLOOD LEVEL; BIOAVAILABILITY; BLOOD VESSEL REACTIVITY; CORPUS CAVERNOSUM; ERECTILE DYSFUNCTION; FIBROSIS; HUMAN; NONHUMAN; OXIDATIVE STRESS; PATHOPHYSIOLOGY; PENIS ERECTION; PRIORITY JOURNAL; REGULATORY MECHANISM; RENIN ANGIOTENSIN ALDOSTERONE SYSTEM; REVIEW; SECOND MESSENGER; SEXUAL BEHAVIOR; SIGNAL TRANSDUCTION; SMOOTH MUSCLE FIBER; SYSTEMIC CIRCULATION; VASOCONSTRICTION; VASODILATATION;

ANGIOTENSIN II; ANGIOTENSIN-(1-7); ERECTILE DYSFUNCTION; MAS RECEPTOR; RENIN-ANGIOTENSIN SYSTEM;

ANGIOTENSIN I; ANGIOTENSIN II; ERECTILE DYSFUNCTION; HUMANS; MALE; PENILE ERECTION; PEPTIDE FRAGMENTS; PROTO-ONCOGENE PROTEINS; RECEPTOR, ANGIOTENSIN, TYPE 1; RECEPTORS, G-PROTEIN-COUPLED; RENIN-ANGIOTENSIN SYSTEM;

EID: 84881660395     PISSN: 00142972     EISSN: 13652362     Source Type: Journal    
DOI: 10.1111/eci.12117     Document Type: Review

References (93)

1. Dean RC, Lue TF. Physiology of penile erection and pathophysiology of erectile dysfunction. Urol Clin North Am 2005;32:379-95.
2. Ayta IA, McKinlay JB, Krane RJ. The likely worldwide increase in erectile dysfunction between 1995 and 2025 and some possible policy consequences. BJU Int 1999;84:50-6.
3. Feldman HA, Goldstein I, Hatzichristou DG, Krane RJ, McKinlay JB. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994;151:54-61.
4. Rotella DP. Phosphodiesterase 5 inhibitors: current status and potential applications. Nat Rev Drug Discov 2002;1:674-82.
5. 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.
6. Vitezic D. A risk-benefit assessment of sildenafil in the treatment of erectile dysfunction. Drug Saf 2001;24:255-65.
7. Leungwattanakij S, Flynn V Jr, Hellstrom WJ. Intracavernosal injection and intraurethral therapy for erectile dysfunction. Urol Clin North Am 2001;28:343-54.
8. Harding LM, Adeniyi A, Everson R, Barker S, Ralph DJ, Baranowski AP. Comparison of a needle-free high-pressure injection system with needle-tipped injection of intracavernosal alprostadil for erectile dysfunction. Int J Impot Res 2002;14:498-501.
9. Eardley I, Donatucci C, Corbin J, El-Meliegy A, Hatzimouratidis K, McVary K et al. Pharmacotherapy for erectile dysfunction. J Sex Med 2010;7:524-40.
10. Li MK, Lim PH, Wong MY, Fok A, Chia SJ, Consigliere D et al. Transurethral alprostadil for the treatment of erectile dysfunction: results of a multicentre trial. Ann Acad Med Singapore 2000;29:727-31.
11. Schiffrin EL. Vascular and cardiac benefits of angiotensin receptor blockers. Am J Med 2002;113:409-18.
12. Ma TK, Kam KK, Yan BP, Lam YY. Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: current status. Br J Pharmacol 2010;160:1273-92.
13. 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;57:193-8.
14. 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;58:805-10.
15. 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;157:1920-5.
16. da Costa Goncalves AC, Leite R, Fraga-Silva RA, Pinheiro SV, Reis AB, Reis FM et al. Evidence that the vasodilator angiotensin-(1-7)-Mas axis plays an important role in erectile function. Am J Physiol Heart Circ Physiol 2007;293:H2588-96.
17. Yousif MH, Kehinde EO, Benter IF. Different responses to angiotensin-(1-7) in young, aged and diabetic rabbit corpus cavernosum. Pharmacol Res 2007;56:209-16.
18. da Costa-Goncalves AC, Fraga-Silva RA, Leite R, Santos RA. AVE 0991, a non-peptide Mas-receptor agonist, facilitates penile erection. Exp Physiol 2013;98:850-5.
19. Matsusaka T, Ichikawa I. Biological functions of angiotensin and its receptors. Annu Rev Physiol 1997;59:395-412.
20. Fraga-Silva RA, Ferreira AJ, Dos Santos RA. Opportunities for targeting the Angiotensin-converting enzyme 2/angiotensin-(1-7)/mas receptor pathway in hypertension. Curr Hypertens 2013;15:31-8.
21. Ferreira AJ, Murca TM, Fraga-Silva RA, Castro CH, Raizada MK, Santos RA. New cardiovascular and pulmonary therapeutic strategies based on the Angiotensin-converting enzyme 2/angiotensin-(1-7)/mas receptor axis. Int J Hypertens 2012;2012:147825.
22. Bader M. Tissue renin-angiotensin-aldosterone systems: targets for pharmacological therapy. Annu Rev Pharmacol Toxicol 2010;50:439-65.
23. Jin LM. Angiotensin II signaling and its implication in erectile dysfunction. J Sex Med 2009;6(Suppl 3):302-10.
24. Park JK, Kim SZ, Kim SH, Park YK, Cho KW. Renin angiotensin system in rabbit corpus cavernosum: functional characterization of angiotensin II receptors. J Urol 1997;158:653-8.
25. Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I et al. Angiotensin-(1-7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA 2003;100:8258-63.
26. Unger T. The role of the renin-angiotensin system in the development of cardiovascular disease. Am J Cardiol 2002;89:3A-9A.
27. Kokubu T, Ueda E, Joh T, Nishimura K. Purification and properties of angiotensin I-converting enzyme in human lung and its role on the metabolism of vasoactive peptides in pulmonary circulation. Adv Exp Med Biol 1979;120B:467-75.
28. Touyz RM, Berry C. Recent advances in angiotensin II signaling. Braz J Med Biol Res 2002;35:1001-15.
29. Nakajima M, Hutchinson HG, Fujinaga M, Hayashida W, Morishita R, Zhang L et al. The angiotensin II type 2 (AT2) receptor antagonizes the growth effects of the AT1 receptor: gain-of-function study using gene transfer. Proc Natl Acad Sci USA 1995;92:10663-7.
30. Suzuki J, Iwai M, Nakagami H, Wu L, Chen R, Sugaya T et al. Role of angiotensin II-regulated apoptosis through distinct AT1 and AT2 receptors in neointimal formation. Circulation 2002;106:847-53.
31. Ferrario CM, Chappell MC, Tallant EA, Brosnihan KB, Diz DI. Counterregulatory actions of angiotensin-(1-7). Hypertension 1997;30:535-41.
32. Lemos VS, Silva DM, Walther T, Alenina N, Bader M, Santos RA. The endothelium-dependent vasodilator effect of the nonpeptide Ang(1-7) mimic AVE 0991 is abolished in the aorta of mas-knockout mice. J Cardiovasc Pharmacol 2005;46:274-9.
33. Sampaio WO, Souza dos Santos RA, Faria-Silva R, da Mata Machado LT, Schiffrin EL, Touyz RM. Angiotensin-(1-7) through receptor Mas mediates endothelial nitric oxide synthase activation via Akt-dependent pathways. Hypertension 2007;49:185-92.
34. Langeveld B, van Gilst WH, Tio RA, Zijlstra F, Roks AJ. Angiotensin-(1-7) attenuates neointimal formation after stent implantation in the rat. Hypertension 2005;45:138-41.
35. Iwata M, Cowling RT, Gurantz D, Moore C, Zhang S, Yuan JX et al. Angiotensin-(1-7) binds to specific receptors on cardiac fibroblasts to initiate antifibrotic and antitrophic effects. Am J Physiol Heart Circ Physiol 2005;289:H2356-63.
36. Katovich MJ, Grobe JL, Raizada MK. Angiotensin-(1-7) as an antihypertensive, antifibrotic target. Curr Hypertens Rep 2008;10:227-32.
37. da Silveira KD, Coelho FM, Vieira AT, Sachs D, Barroso LC, Costa VV et al. Anti-inflammatory effects of the activation of the angiotensin-(1-7) receptor, MAS, in experimental models of arthritis. J Immunol 2010;185:5569-76.
38. Vickers C, Hales P, Kaushik V, Dick L, Gavin J, Tang J et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem 2002;277:14838-43.
39. Zisman LS, Meixell GE, Bristow MR, Canver CC. Angiotensin-(1-7) formation in the intact human heart: in vivo dependence on angiotensin II as substrate. Circulation 2003;108:1679-81.
40. Rice GI, Thomas DA, Grant PJ, Turner AJ, Hooper NM. Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J 2004;383:45-51.
41. Stanziola L, Greene LJ, Santos RA. Effect of chronic angiotensin converting enzyme inhibition on angiotensin I and bradykinin metabolism in rats. Am J Hypertens 1999;12:1021-9.
42. Ferreira AJ, Santos RA. Cardiovascular actions of angiotensin-(1-7). Braz J Med Biol 2005;38:499-507.
43. Ferreira AJ, Santos RA, Bradford CN, Mecca AP, Sumners C, Katovich MJ et al. Therapeutic implications of the vasoprotective axis of the renin-angiotensin system in cardiovascular diseases. Hypertension 2010;55:207-13.
44. Nicholls MG, Richards AM, Agarwal M. The importance of the renin-angiotensin system in cardiovascular disease. J Hum Hypertens 1998;12:295-9.
45. Ryan MJ, Didion SP, Mathur S, Faraci FM, Sigmund CD. Angiotensin II-induced vascular dysfunction is mediated by the AT1A receptor in mice. Hypertension 2004;43:1074-9.
46. Bader M, Ganten D. Update on tissue renin-angiotensin systems. J Mol Med 2008;86:615-21.
47. 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;298:43-8.
48. Kanaide H, Ichiki T, Nishimura J, Hirano K. Cellular mechanism of vasoconstriction induced by angiotensin II: it remains to be determined. Circ Res 2003;93:1015-7.
49. Ying Z, Jin L, Palmer T, Webb RC. Angiotensin II up-regulates the leukemia-associated Rho guanine nucleotide exchange factor (RhoGEF), a regulator of G protein signaling domain-containing RhoGEF, in vascular smooth muscle cells. Mol Pharmacol 2006;69:932-40.
50. Bivalacqua TJ, Usta MF, Champion HC, Kadowitz PJ, Hellstrom WJ. Endothelial dysfunction in erectile dysfunction: role of the endothelium in erectile physiology and disease. J Androl 2003;24:S17-37.
51. Jin L, Lagoda G, Leite R, Webb RC, Burnett AL. NADPH oxidase activation: a mechanism of hypertension-associated erectile dysfunction. J Sex Med 2008;5:544-51.
52. Horiuchi M, Iwanami J, Mogi M. Regulation of angiotensin II receptors beyond the classical pathway. Clin Sci 2012;123:193-203.
53. Lin CS, Ho HC, Gholami S, Chen KC, Jad A, Lue TF. Gene expression profiling of an arteriogenic impotence model. Biochem Biophys Res Commun 2001;285:565-9.
54. Li SX, Dai YT. Effects of angiotensin II on male rats with diabetic erectile dysfunction. Zhonghua Nan Ke Xue 2005;11:346-9.
55. Toque HA, Romero MJ, Tostes RC, Shatanawi A, Chandra S, Carneiro ZN et al. p38 Mitogen-activated protein kinase (MAPK) increases arginase activity and contributes to endothelial dysfunction in corpora cavernosa from angiotensin-II-treated mice. J Sex Med 2010;7:3857-67.
56. Chen Y, Cui S, Lin H, Xu Z, Zhu W, Shi L et al. Losartan improves erectile dysfunction in diabetic patients: a clinical trial. Int J Impot Res 2012;24:217-20.
57. Dorrance AM, Lewis RW, Mills TM. Captopril treatment reverses erectile dysfunction in male stroke prone spontaneously hypertensive rats. Int J Impot Res 2002;14:494-7.
58. 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.
59. Llisterri JL, Lozano Vidal JV, Aznar Vicente J, Argaya Roca M, Pol Bravo C, Sanchez Zamorano MA et al. Sexual dysfunction in hypertensive patients treated with losartan. Am J Med Sci 2001;321:336-41.
60. Schlimmer N, Kratz M, Bohm M, Baumhakel M. Telmisartan, ramipril and their combination improve endothelial function in different tissues in a murine model of cholesterol-induced atherosclerosis. Br J Pharmacol 2011;163:804-14.
61. Yang R, Yang B, Wen Y, Fang F, Cui S, Lin G et al. Losartan, an Angiotensin type I receptor, restores erectile function by downregulation of cavernous renin-angiotensin system in streptozocin-induced diabetic rats. J Sex Med 2009;6:696-707.
62. Segal RL, Bivalacqua TJ, Burnett AL. Irbesartan promotes erection recovery after nerve-sparing radical retropubic prostatectomy: a retrospective long-term analysis. BJU Int 2012;110:1782-6.
63. Kloner RA, Mullin SH, Shook T, Matthews R, Mayeda G, Burstein S et al. Erectile dysfunction in the cardiac patient: how common and should we treat? J Urol 2003;170:S46-50.
64. Della Chiesa A, Pfiffner D, Meier B, Hess OM. Sexual activity in hypertensive men. J Hum Hypertens 2003;17:515-21.
65. Dusing R. Sexual dysfunction in male patients with hypertension: influence of antihypertensive drugs. Drugs 2005;65:773-86.
66. Ekman E, Hagg S, Sundstrom A, Werkstrom V. Antihypertensive drugs and erectile dysfunction as seen in spontaneous reports, with focus on angiotensin II type 1 receptor blockers. Drug Healthc Patient Saf 2010;2:21-5.
67. Savergnini SQ, Beiman M, Lautner RQ, de Paula-Carvalho V, Allahdadi K, Pessoa DC et al. Vascular relaxation, antihypertensive effect, and cardioprotection of a novel peptide agonist of the MAS receptor. Hypertension 2010;56:112-20.
68. Xu P, Costa-Goncalves AC, Todiras M, Rabelo LA, Sampaio WO, Moura MM et al. Endothelial dysfunction and elevated blood pressure in MAS gene-deleted mice. Hypertension 2008;5:574-80 Epub 2008/01/09.
69. Rabelo LA, Alenina N, Bader M. ACE2-angiotensin-(1-7)-Mas axis and oxidative stress in cardiovascular disease. Hypertens Res 2011;34:154-60.
70. Fraga-Silva RA, Pinheiro SV, Goncalves AC, Alenina N, Bader M, Santos RA. The antithrombotic effect of angiotensin-(1-7) involves mas-mediated NO release from platelets. Mol Med 2008;14:28-35.
71. Fraga-Silva RA, Da Silva DG, Montecucco F, Mach F, Stergiopulos N, da Silva RF et al. The angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor axis: a potential target for treating thrombotic diseases. Thromb Haemost 2012;108:1089-96.
72. Fraga-Silva RA, Costa-Fraga FP, De Sousa FB, Alenina N, Bader M, Sinisterra RD et al. An orally active formulation of angiotensin-(1-7) produces an antithrombotic effect. Clinics 2011;66:837-41.
73. Fraga-Silva RA, Costa-Fraga FPSavergnini SQ, Da Silva DG, Montecucco F, Mach F et al. An orally-active formulation of angiotensin-(1-7) reduces penile fibrosis by attenuation of oxidative stress. In: World Meeting on Sexual Medicine 2012. Chicago, USA. The Journal of Sexual Medicine.
74. Bosnyak S, Jones ES, Christopoulos A, Aguilar MI, Thomas WG, Widdop RE. Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors. Clin Sci (Lond) 2011;121:297-303.
75. Dilauro M, Burns KD. Angiotensin-(1-7) and its effects in the kidney. ScientificWorldJournal 2009;9:522-35.
76. Walters PE, Gaspari TA, Widdop RE. Angiotensin-(1-7) acts as a vasodepressor agent via angiotensin II type 2 receptors in conscious rats. Hypertension 2005;45:960-6.
77. Handa RK, Ferrario CM, Strandhoy JW. Renal actions of angiotensin-(1-7): in vivo and in vitro studies. Am J Physiol 1996;270:F141-7.
78. Hayashi N, Yamamoto K, Ohishi M, Tatara Y, Takeya Y, Shiota A et al. The counterregulating role of ACE2 and ACE2-mediated angiotensin 1-7 signaling against angiotensin II stimulation in vascular cells. Hypertens Res 2010;33:1182-5.
79. Nie W, Yan H, Li S, Zhang Y, Yu F, Zhu W et al. Angiotensin-(1-7) enhances angiotensin II induced phosphorylation of ERK1/2 in mouse bone marrow-derived dendritic cells. Mol Immunol 2009;46:355-61.
80. Castro CH, Santos RA, Ferreira AJ, Bader M, Alenina N, Almeida AP. Evidence for a functional interaction of the angiotensin-(1-7) receptor Mas with AT1 and AT2 receptors in the mouse heart. Hypertension 2005;46:937-42.
81. Stegbauer J, Oberhauser V, Vonend O, Rump LC. Angiotensin-(1-7) modulates vascular resistance and sympathetic neurotransmission in kidneys of spontaneously hypertensive rats. Cardiovasc Res 2004;61:352-9.
82. Clark MA, Tallant EA, Diz DI. Downregulation of the AT1A receptor by pharmacologic concentrations of Angiotensin-(1-7). J Cardiovasc Pharmacol 2001;37:437-48.
83. Neves LA, Santos RA, Khosla MC, Milsted A. Angiotensin-(1-7) regulates the levels of angiotensin II receptor subtype AT1 mRNA differentially in a strain-specific fashion. Regul Pept 2000;95:99-107.
84. Li P, Chappell MC, Ferrario CM, Brosnihan KB. Angiotensin-(1-7) augments bradykinin-induced vasodilation by competing with ACE and releasing nitric oxide. Hypertension 1997;29:394-400.
85. Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, Snyder SH. Nitric oxide: a physiologic mediator of penile erection. Science 1992;257:401-3.
86. Grobe JL, Mecca AP, Mao H, Katovich MJ. Chronic angiotensin-(1-7) prevents cardiac fibrosis in DOCA-salt model of hypertension. Am J Physiol Heart Circ Physiol 2006;290:H2417-23.
87. Deelman L, Sharma K. Mechanisms of kidney fibrosis and the role of antifibrotic therapies. Curr Opin Nephrol Hypertens 2009;18:85-90.
88. Zhang J, Noble NA, Border WA, Huang Y. Infusion of angiotensin-(1-7) reduces glomerulosclerosis through counteracting angiotensin II in experimental glomerulonephritis. Am J Physiol Renal Physiol 2010;298:F579-88.
89. Shenoy V, Ferreira AJ, Qi Y, Fraga-Silva RA, Diez-Freire C, Dooies A et al. The angiotensin-converting enzyme 2/angiogenesis-(1-7)/Mas axis confers cardiopulmonary protection against lung fibrosis and pulmonary hypertension. Am J Respir Crit Care Med 2010;182:1065-72.
90. Pereira RM, Dos Santos RA, Teixeira MM, Leite VH, Costa LP, da Costa Dias FL et al. The renin-angiotensin system in a rat model of hepatic fibrosis: evidence for a protective role of Angiotensin-(1-7). J Hepatol 2007;46:674-81.
91. Ferreira AJ, Shenoy V, Qi Y, Fraga-Silva RA, Santos RA, Katovich MJ et al. Angiotensin-converting enzyme 2 activation protects against hypertension-induced cardiac fibrosis involving extracellular signal-regulated kinases. Exp Physiol 2011;96:287-94.
92. McCollum LT, Gallagher PE, Ann Tallant E. Angiotensin-(1-7) attenuates angiotensin II-induced cardiac remodeling associated with upregulation of dual-specificity phosphatase 1. Am J Physiol Heart Circ Physiol 2012;302:H801-10.
93. Pei Z, Meng R, Li G, Yan G, Xu C, Zhuang Z et al. Angiotensin-(1-7) ameliorates myocardial remodeling and interstitial fibrosis in spontaneous hypertension: role of MMPs/TIMPs. Toxicol Lett 2010;199:173-81.