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MINI REVIEW
Year : 2014  |  Volume : 1  |  Issue : 1  |  Page : 11-13

Elevated uric acid levels as another cause of erectile dysfunction: Hypothesis and rationale?


Department of Internal Medicine, Division of Nephrology, Konya Numune State Hospital, Konya 42690, Turkey

Date of Web Publication25-Jul-2014

Correspondence Address:
Baris Afsar
Department of Nephrology, Konya Numune State Hospital, Ferhuniye Mahallesi, Hastane Caddeleri, Konya 42690
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2225-1243.137543

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  Abstract 

Elevated uric acid (UA) levels has been shown to be associated with cardiovascular disease such as hypertension, coronary heart disease, heart failure, renal failure, peripheral vascular disease, metabolic syndrome, and stroke. In addition, in recent years various novel pathological entities such as endothelial dysfunction, oxidative stress, inflammation, activation of the renin angiotensin system (RAS) has been found to be associated with increased UA levels. Erectile dysfunction (ED) on the other hand has also been associated with cardiovascular risk. Besides, similar mechanisms such as endothelial dysfunction, oxidative stress and RAS have been found to be related with ED. Thus, the current hypothesis tried to explain why UA may be associated with ED.

Keywords: Endothelial dysfunction, erectile dysfunction, oxidative stress, renin angiotensin system, uric acid


How to cite this article:
Afsar B. Elevated uric acid levels as another cause of erectile dysfunction: Hypothesis and rationale?. J Integr Nephrol Androl 2014;1:11-3

How to cite this URL:
Afsar B. Elevated uric acid levels as another cause of erectile dysfunction: Hypothesis and rationale?. J Integr Nephrol Androl [serial online] 2014 [cited 2018 Dec 14];1:11-3. Available from: http://www.journal-ina.com/text.asp?2014/1/1/11/137543


  Introduction Top


Erectile dysfunction (ED), is defined as the persistent inability to achieve or maintain a penile erection sufficient for satisfactory sexual performance. [1] Besides, ED has been found to be associated with various chronic disease and pathophysiologic states including coronary artery disease, [1] diabetes, [2] oxidative stress, [3] endothelial dysfunction, [4] and renin angiotensin system (RAS). [5]

In humans, uric acid (UA) is the end product of purine metabolism due to the nonfunctioning uricase gene leading to elevated serum UA levels. Recent studies showed that hyperuricemia was frequently noted in patients either with cardiovascular disease or at a high-risk of cardiovascular disease such as hypertension, coronary heart disease, renal failure, peripheral vascular disease, heart failure, metabolic syndrome, and stroke. [6] In addition, in recent years various novel pathological entities such as endothelial dysfunction oxidative stress, inflammation, activation of RAS has been found to be associated with increased UA levels. By the light of aforementioned data the hypothesis arises as follows: Elevated UA levels were associated with endothelial dysfunction, oxidative stress and activation of RAS which in turn associated with ED [Figure 1].
Figure 1: Possible mechanisms for increased uric acid causing erectile dysfunction

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  Mechanisms Top


Endothelial dysfunction

In patients with ED, impaired nitric oxide (NO) release by nonadrenergic, noncholinergic fibers and the endothelium of the corpus cavernosum, which are considered central to the initiation and maintenance of erection has been demonstrated. [7],[8] NO stimulates the formation of cyclic GMP in the smooth muscle component of arteries, arterioles and the corpus cavernosum, which then elicits relaxation through resequestration of calcium. [7],[9]

It was recently demonstrated that higher levels of UA induces increased generation of mitochondrial free oxygen radicals leading to ED. [10] It was also suggested that UA increases arginase activity and reduces endothelial NO synthase phosphorylation thus decreasing NO bioavailability. [11] Last but not the least, it was also suggested that UA causes ED by diminishing mitochondrial mass and adenosine triphosphate production. [12] Thus, all these suggested mechanisms may play a role for the development of ED with elevated UA levels. On the other hand, various studies have shown that elevated UA levels were associated with endothelial dysfunction. [13],[14],[15] More importantly it was demonstrated that allopurinol treatment improved endothelial dysfunction. [16] Thus by the light all aforementioned data it will be interesting to investigate whether UA lowering agents have a beneficial role in ED.

Oxidative stress

It has been suggested that increased oxidative stress may be one of the causes of ED (3). One study showed that, homocysteine inhibits endothelium-dependent relaxation of the corpus cavernosum through the generation of superoxide formation. [17] Superoxide inhibits the formation of prostacyclin, which release was impaired in ED. [18],[19] It was also demonstrated that UA by reaction with peroxynitrite may lead to various pro-oxidative effects mediated by the formation of reactive intermediates. [20]

It has been suggested that under some conditions, UA behave as a pro-oxidant under certain conditions. UA mediates the production of aminocarbonyl radicals, which have pro-oxidant effects on several molecules including low-density lipoprotein cholesterol. [21] UA also exerts prooxidative effects once inside the cell. [22] More evidence come from the studies, which showed that allopurinol directly scavenges free radicals and reduce oxidative system. [23] Apart from actions on xanthine oxidase, allopurinol also decreases oxidative stress by copper chelation. [24]

Renin angiotensin system

Recently, it was hypothesized that, local RAS system in the erectile tissue is important. Indeed, it was shown that corpus cavernosum produces and secretes physiologically relevant amounts of Ang II which contribute to the development of detumescence. [25] In addition, local Ang II formation in the vasculature, as well as in erectile tissue is supposed to play a major role in promoting oxidative stress and inflammatory processes, independent of angiotensin converting enzyme functionality. [26] Besides, it was demonstrated that angiotensin receptor blockage has been shown to improve ED. [27] Recently, the inter reaction between UA and RAS system were recognized. In the renal tissue direct correlation of UA with the percentage of renin positive juxtaglomerular cells has been reported. [28] Besides, these data hyperuricemia is also associated with the activation of intrarenal renin angiotension system. [29]


  Consequences and prospect of the hypothesis Top


If the current hypothesis pans out to have merit, it would stimulate the research regarding to explain the connections between elevated UA levels and ED. In addition, subsequent analysis of these potential mechanism regarding elevated UA in causing ED may lead to potential therapeutic options for treatment of ED.

 
  References Top

1.Ewane KA, Lin HC, Wang R. Should patients with erectile dysfunction be evaluated for cardiovascular disease? Asian J Androl 2012;14:138-44.  Back to cited text no. 1
    
2.Schiavi RC, Stimmel BB, Mandeli J, Rayfield EJ. Diabetes mellitus and male sexual function: A controlled study. Diabetologia 1993;36:745-51.  Back to cited text no. 2
    
3.Jeremy JY, Angelini GD, Khan M, Mikhailidis DP, Morgan RJ, Thompson CS, et al. Platelets, oxidant stress and erectile dysfunction: An hypothesis. Cardiovasc Res 2000;46:50-4.  Back to cited text no. 3
    
4.Kaiser DR, Billups K, Mason C, Wetterling R, Lundberg JL, Bank AJ. Impaired brachial artery endothelium-dependent and-independent vasodilation in men with erectile dysfunction and no other clinical cardiovascular disease. J Am Coll Cardiol 2004;43:179-84.  Back to cited text no. 4
    
5.Jin LM. Angiotensin II signaling and its implication in erectile dysfunction. J Sex Med 2009;6 Suppl 3:302-10.  Back to cited text no. 5
[PUBMED]    
6.Nakagawa T, Kang DH, Feig D, Sanchez-Lozada LG, Srinivas TR, Sautin Y, et al. Unearthing uric acid: An ancient factor with recently found significance in renal and cardiovascular disease. Kidney Int 2006;69:1722-5.  Back to cited text no. 6
    
7.Sullivan ME, Thompson CS, Dashwood MR, Khan MA, Jeremy JY, Morgan RJ, et al. Nitric oxide and penile erection: Is erectile dysfunction another manifestation of vascular disease? Cardiovasc Res 1999;43:658-65.  Back to cited text no. 7
    
8.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;88:112-8.  Back to cited text no. 8
    
9.Bredt DS, Snyder SH. Nitric oxide: A physiologic messenger molecule. Annu Rev Biochem 1994;63:175-95.  Back to cited text no. 9
    
10.Hong Q, Qi K, Feng Z, Huang Z, Cui S, Wang L, et al. Hyperuricemia induces endothelial dysfunction via mitochondrial Na+/Ca2+ exchanger-mediated mitochondrial calcium overload. Cell Calcium 2012;51:402-10.  Back to cited text no. 10
    
11.Papežíková I, Pekarová M, Kolárová H, Klinke A, Lau D, Baldus S, et al. Uric acid modulates vascular endothelial function through the down regulation of nitric oxide production. Free Radic Res 2013;47:82-8.  Back to cited text no. 11
    
12.Sánchez-Lozada LG, Lanaspa MA, Cristóbal-García M, García-Arroyo F, Soto V, Cruz-Robles D, et al. Uric acid-induced endothelial dysfunction is associated with mitochondrial alterations and decreased intracellular ATP concentrations. Nephron Exp Nephrol 2012;121:e71-8.  Back to cited text no. 12
    
13.Kanbay M, Yilmaz MI, Sonmez A, Solak Y, Saglam M, Cakir E, et al. Serum uric acid independently predicts cardiovascular events in advanced nephropathy. Am J Nephrol 2012;36:324-31.  Back to cited text no. 13
    
14.Ishiro M, Takaya R, Mori Y, Takitani K, Kono Y, Okasora K, et al. Association of uric acid with obesity and endothelial dysfunction in children and early adolescents. Ann Nutr Metab 2013;62:169-76.  Back to cited text no. 14
    
15.Maruhashi T, Nakashima A, Soga J, Fujimura N, Idei N, Mikami S, et al. Hyperuricemia is independently associated with endothelial dysfunction in postmenopausal women but not in premenopausal women. BMJ Open 2013;3:e003659.  Back to cited text no. 15
    
16.Yelken B, Caliskan Y, Gorgulu N, Altun I, Yilmaz A, Yazici H, et al. Reduction of uric acid levels with allopurinol treatment improves endothelial function in patients with chronic kidney disease. Clin Nephrol 2012;77:275-82.  Back to cited text no. 16
    
17.Khan MA, Thompson CS, Emsley AM, Mumtaz FH, Mikhailidis DP, Angelini GD, et al. The interaction of homocysteine and copper markedly inhibits the relaxation of rabbit corpus cavernosum: New risk factors for angiopathic erectile dysfunction? BJU Int 1999;84:720-4.  Back to cited text no. 17
    
18.Jeremy JY, Mikhailidis DP, Dandona P. Muscarinic stimulation of prostacyclin synthesis by the rat penis. Eur J Pharmacol 1986;123:67-71.  Back to cited text no. 18
[PUBMED]    
19.Jeremy JY, Thompson CS, Mikhailidis DP, Dandona P. Experimental diabetes mellitus inhibits prostacyclin synthesis by the rat penis: Pathological implications. Diabetologia 1985;28:365-8.  Back to cited text no. 19
[PUBMED]    
20.Puddu P, Puddu GM, Cravero E, Vizioli L, Muscari A. Relationships among hyperuricemia, endothelial dysfunction and cardiovascular disease: Molecular mechanisms and clinical implications. J Cardiol 2012;59:235-42.  Back to cited text no. 20
    
21.Bagnati M, Perugini C, Cau C, Bordone R, Albano E, Bellomo G. When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced low-density lipoprotein oxidation: A study using uric acid. Biochem J 1999;340:143-52.  Back to cited text no. 21
    
22.Corry DB, Eslami P, Yamamoto K, Nyby MD, Makino H, Tuck ML. Uric acid stimulates vascular smooth muscle cell proliferation and oxidative stress via the vascular renin-angiotensin system. J Hypertens 2008;26:269-75.  Back to cited text no. 22
    
23.Hoey BM, Butler J, Halliwell B. On the specificity of allopurinol and oxypurinol as inhibitors of xanthine oxidase. A pulse radiolysis determination of rate constants for reaction of allopurinol and oxypurinol with hydroxyl radicals. Free Radic Res Commun 1988;4:259-63.  Back to cited text no. 23
    
24.Malkiel S, Har-el R, Schwalb H, Uretzky G, Borman JB, Chevion M. Interaction between allopurinol and copper: Possible role in myocardial protection. Free Radic Res Commun 1993;18:7-15.  Back to cited text no. 24
    
25.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.  Back to cited text no. 25
    
26.Hirono Y, Yoshimoto T, Suzuki N, Sugiyama T, Sakurada M, Takai S, et al. Angiotensin II receptor type 1-mediated vascular oxidative stress and proinflammatory gene expression in aldosterone-induced hypertension: The possible role of local renin-angiotensin system. Endocrinology 2007;148:1688-96.  Back to cited text no. 26
    
27.Böhm M, Baumhäkel M, Probstfield JL, Schmieder R, Yusuf S, Zhao F, et al. Sexual function, satisfaction, and association of erectile dysfunction with cardiovascular disease and risk factors in cardiovascular high-risk patients: Substudy of 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). Am Heart J 2007;154:94-101.  Back to cited text no. 27
    
28.Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension 2001;38:1101-6.  Back to cited text no. 28
    
29.Perlstein TS, Gumieniak O, Hopkins PN, Murphey LJ, Brown NJ, Williams GH, et al. Uric acid and the state of the intrarenal renin-angiotensin system in humans. Kidney Int 2004;66:1465-70.  Back to cited text no. 29
    


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