Therapeutic effect of combination of alagebrium (ALT-711) and sildenafil on erectile function in diabetic rats

Gürbüz, Nilgün; Sağdıç, Gamze; Şanlı, Ahmet Metin; Çiftçioğlu, Akif; Başsorgun, İbrahim; Baykal, Aslı; Usta, Murat

doi:10.1038/ijir.2011.54

Cited by 15 publications

(7 citation statements)

References 27 publications

(32 reference statements)

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“…Gurbuz et al. showed that combination of ALT‐711 and sildenafil could increase both the peak ICP and total ICP in STZ‐induced diabetic rats, similar to levels in normal rats [24].…”

Section: Discussionmentioning

confidence: 83%

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AGE-Breaker ALT-711 Plus Insulin Could Restore Erectile Function in Streptozocin-Induced Type 1 Diabetic Rats

Wang

Tian

Uwais

et al. 2014

The Journal of Sexual Medicine

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Introduction The interaction between advanced glycation end-products (AGEs) and its receptors for AGEs (RAGEs) elicits oxidative stress and mediates the development of erectile dysfunction (ED). ALT-711, an AGE cross-link breaker, has the therapeutic potential for ED but has been less intensively investigated. Aim The aim of this study was to investigate the effects of an AGEs breaker 3-phenacyl-4,5-dimethylthiazolium chloride (ALT-711) plus insulin on erectile function in streptozocin (STZ)-induced type 1 diabetic rats. Methods Fifty 8-week-old Sprague-Dawley rats were randomly distributed into five groups: normal control (C), diabetic (D), insulin-treated diabetic (D + I), ALT-711-treated diabetic (D + ALT-711) and insulin plus ALT-711-treated diabetic (D + I + ALT-711) rats. Diabetes was induced by a single intraperitoneal injection of STZ. Eight weeks after induction of diabetes, ALT-711 was administered by intraperitoneal injection. Two to six units of intermediate-acting insulin were utilized to achieve normal levels of glycemic control. After treatment for 6 weeks, erectile function was determined via measurement of intracavernous pressures (ICPs) following electrostimulation of the cavernous nerve. The deposition of AGEs, expression of RAGEs, superoxide dismutase activity, and lipid peroxidation were measured. We also evaluated penile histological changes such as smooth muscle contents, endothelial cells contents, and apoptotic activity. Main Outcome Measures The main outcome measures were the ratio of ICP/mean arterial pressure (MAP), penile endothelial cells, smooth muscle cells, neuronal nitric oxide synthase, AGE and RAGE expression, malondialdehyde concentration, SOD activity, and apoptosis index. Results Diabetic rats demonstrated significantly reduced ICP/MAP ratio, penile endothelial cells, smooth muscles cells, increased AGEs and RAGE expression, and increased apoptosis. Insulin and ALT-711 monotherapy partially restored erectile function and histological changes. However, the combination therapy group showed erectile parameters and components similar to those in C. ALT-711-treated group demonstrated less deposition of AGEs and lower expression of RAGE than those in insulin-treated group. Conclusion These results suggest that although insulin can effectively control glycemic levels, it does not completely alter the pathological changes in erectile tissues. Better efficacy could be expected with tight glycemic control plus ALT-711, an AGEs cross-link breaker. The combination therapy might have the potential to eliminate metabolic memory by down-regulating the AGEs–RAGE oxidative stress axis.

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“…Gurbuz et al. showed that combination of ALT‐711 and sildenafil could increase both the peak ICP and total ICP in STZ‐induced diabetic rats, similar to levels in normal rats [24].…”

Section: Discussionmentioning

confidence: 83%

“…Freidja et al showed that ALT-711 restores high blood flow-dependent remodeling in mesenteric resistance arteries in a rat model of type 2 diabetes [23]. Gurbuz et al showed that combination of ALT-711 and sildenafil could increase both the peak ICP and total ICP in STZ-induced diabetic rats, similar to levels in normal rats [24].…”

Section: Discussionmentioning

confidence: 98%

AGE-Breaker ALT-711 Plus Insulin Could Restore Erectile Function in Streptozocin-Induced Type 1 Diabetic Rats

Wang

Tian

Uwais

et al. 2014

The Journal of Sexual Medicine

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“…Recently, we have shown that while AGEs, MDA, iNOS, NF-κB, MAP kinase and apoptosis levels were significantly increased in diabetic penises, the chronic use of sildenafil was able to decrease the content of all of those parameters, which led to improved erectile capacity. 15 On the other hand, in recent literature there are several papers suggesting the contributing effect of iNOS on erectile function in the presence of an inflammatory environment. 23 To our knowledge, the study revealed for the first time the protective effect of chronic sildenafil use on erectile function in CRF-induced rats.…”

Section: Discussionmentioning

confidence: 99%

“…The erectile capacity was evaluated by intracavernous pressure measurements in control, CRF and sildenafil therapeutic rats after 12 weeks of nephrectomy procedure, as previously described in several studies. 14 15 16 17 18 Of note, sildenafil treatment was given up 3 days before the “erectile response measurement” due to the wash-out issue of the drug.…”

Section: Methodsmentioning

confidence: 99%

Chronic administration of sildenafil improves erectile function in a rat model of chronic renal failure

et al. 2015

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The relationship between erectile dysfunction (ED) and chronic renal failure (CRF) has been reported in several studies. This study aimed to investigate whether the chronic use of sildenafil could enhance the erectile capacity in CRF-induced rats. In addition, we assessed the effect of that treatment on certain molecules, which have been suggested to play crucial roles in erectile physiology and CRF-related ED as well. Three groups of animals were utilized: (1) age-matched control rats, (2) CRF-induced rats, (3) CRF-induced rats treated with chronic administration of sildenafil (5 mg kg−1 p.o. for 6 weeks [treatment started after 6 weeks of CRF induction]). At 3 months, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Penile tissue advanced glycation end products (AGE's)/5-hydroxymethyl-2-furaldehyde, malondialdehyde (MDA), cGMP (ELISA), inducible nitric oxide synthase (iNOS) and neuronal NOS (nNOS) (Western blot) analyses were performed in all rat groups. CRF-induced rats had a significant decrease in erectile function when compared to control rats (P < 0.05). The increase in both intracavernosal pressure (ICP) and area under the curve of CRF-induced rats treated with sildenafil (Group 3) was greater than CRF-induced rats (Group 2). Additionally, sildenafil treatment decreased AGE, MDA and iNOS levels, while it preserved nNOS and cGMP contents in CRF-induced penile tissue. Decreased AGE, MDA, iNOS and increased nNOS, cGMP levels at the sildenafil-treated group increased both ICP and Total ICP to CNS, which led to improve erectile function in CRF-induced rats. The results of the present study revealed the therapeutic effect of chronic sildenafil administration on erectile function in CRF-induced rats.

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“…In general, metabolic diseases are described as having system-wide effects on glucose and oxidative mechanisms. During a state of hyperglycemia, there is an increased generation of advanced glycation end products (AGEs) in erectile tissue, which causes oxidative stress, decreased production of NO, and ultimately the development of ED [22][23][24]. In an animal model of DM, hyperglycemia increased O-GlycNAc modification of endothelial nitric oxide synthase (eNOS) in the penis, which prevented phosphorylation at the enzymatic level.…”

Section: Metabolic Diseases Obesity and High Blood Pressurementioning

confidence: 99%

Metabolic Syndrome and Erectile Dysfunction

Walton¹,

Usta²,

Wong³

et al. 2021

obm icm

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Metabolic syndrome (MetS) is considered a risk factor for erectile dysfunction (ED), and ED is almost three times more prevalent in men with MetS. Vascular pathologies are a significant factor for the development of ED, and many experts suggest endothelial dysfunction (EnD) as a likely explanation for the association between ED and MetS. Studies also show that corporal vascular and trabecular smooth muscle dysfunction leads ultimately to corporal veno-occlusive dysfunction. Different functional system abnormalities, such as nervous degenerations, hormonal insufficiencies, and metabolic factors (e.g., hyperlipidemia, advanced glycation end products), are also likely involved in the pathophysiological pathways. Autonomic neuropathy is also commonly encountered in patients and animal models of MetS. From another perspective, low testosterone levels may be predictive of MetS. Several studies concluded that components of MetS, such as high blood pressure, obesity, hyperinsulinemia, T2DM, hyperglycemia, hypertriglyceridemia, elevated C-Reactive protein, and low HDL levels, were all associated with decreased serum testosterone levels. Lifestyle modification, such as exercise and diet, are the first-line treatment for MetS. Studies have found that a 10% weight loss has been shown to significantly increase IIEF-5 scores. Exercise was also shown to increase endothelial-derived NO and decrease oxidative stress, resulting in a lower risk of developing ED in physically active men. Metformin combined with PDE5 inhibitors is a promising treatment approach, although with limited research.

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Therapeutic effect of combination of alagebrium (ALT-711) and sildenafil on erectile function in diabetic rats

Cited by 15 publications

References 27 publications

AGE-Breaker ALT-711 Plus Insulin Could Restore Erectile Function in Streptozocin-Induced Type 1 Diabetic Rats

AGE-Breaker ALT-711 Plus Insulin Could Restore Erectile Function in Streptozocin-Induced Type 1 Diabetic Rats

Chronic administration of sildenafil improves erectile function in a rat model of chronic renal failure

Metabolic Syndrome and Erectile Dysfunction

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