Effect of combination endothelial nitric oxide synthase gene therapy and sildenafil on erectile function in diabetic rats

Bivalacqua, Trinity J.; Usta, Murat; Champion, Hunter C.; Leungwattanakij, Somboon; Dabisch, Paul A.; McNamara, Dennis B.; Kadowitz, Philip J.; Hellstrom, Wayne J.G.

doi:10.1038/sj.ijir.3901054

Cited by 63 publications

(70 citation statements)

References 44 publications

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“…The overall erectile response was greater in diabetic rats receiving eNOS gene therapy and sildenafil than rats receiving sildenafil or eNOS gene alone. [77][78][79] Another in vivo study used adenovirally mediated transfer of eNOS gene with or without cGMP PDE, showing promising results as a future treatment for ED. 80 Myoblast-mediated gene therapy was tested in vivo and was more superior in delivering inducible NOS into the corpus cavernosum than direct adenovirus or a plasmid transfection method.…”

Section: Gene Therapymentioning

confidence: 99%

Linking erectile dysfunction and coronary artery disease

2005

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Coronary artery disease (CAD) and erectile dysfunction (ED) are both highly prevalent conditions that frequently coexist. Additionally, they share mutual vascular risk factors, suggesting that they are both manifestations of systemic vascular disease. The role of endothelial dysfunction in CAD is well established. Normal erectile function is primarily a vascular event that relies heavily on endothelially derived, nitric oxide-induced vasodilation. Accordingly, endothelial dysfunction appears to be a common pathological etiology and mechanism of disease progression between CAD and ED. The risk factors of diabetes mellitus, hypertension, hyperlipidemia, obesity and tobacco abuse contribute to endothelial dysfunction. This article reviews the role of vascular endothelium in health, the abnormalities resulting from vascular risk factors, and clinical trials evaluating the role of endothelial dysfunction in ED.

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Section: Gene Therapymentioning

confidence: 99%

Linking erectile dysfunction and coronary artery disease

2005

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“…The authors concluded that vitamin E enhanced the therapeutic effect of sildenafil, which indicated a potential means of salvaging erectile function among men who are refractory to sildenafil. 8 Similarly, Bivalacqua et al 12 reported the effect of combination of sildenafil and NO synthase gene therapy on erectile function in STZ diabetic rats. The authors clearly showed that overexpression of eNOS and cGMP in combination with sildenafil significantly increased both the ICP and total ICP to CNS in the STZ diabetic rats, which was similar to the response observed in control rats.…”

Section: Discussionmentioning

confidence: 99%

“…In several cohorts, it has been shown that sildenafil is an effective and well-tolerated treatment for ED in men with diabetes. 7,12,15 However, the results of those studies showed that sildenafil does not have the same efficacy in improving erectile function in diabetic men when compared with other ED etiologies. The decreased efficacy of sildenafil in men with diabetes-related ED lead several authors to investigate several other treatment options such as combination treatments and chronic use of PDE5 inhibitors for the treatment of erectile function in that 'hard to treat' population.…”

Section: Discussionmentioning

confidence: 99%

“…For the determination of cGMP levels, cavernosal samples were assayed by using an enzyme-linked immunoassay kit (Cayman Chemical Company, Ann Arbor, MI, USA) based on the competition between free-cGMP and a cGMP-acetylcholinesterase conjugate for a limited amount of cGMPspecific rabbit antibody-binding sites, as previously described. 12 Immunoblot analysis of iNOS and eNOS in cavernosal tissue Cavernosal tissues from control, STZ diabetic rats, and both therapeutic groups that are sildenafil alone and combine with ALT-711-treated STZ diabetic rats (n ¼ 3 samples from each group) were homogenized with a Brinkmann Polytron (Brinkmann Instruments, Westbury, NY, USA) in lyses buffer with 1 mM phenylmethanesulfonylfluoride and sonicated for 30 s followed by a incubation period of 30 min on ice. iNOS protein expression IHC localization of NFjB-p65 and MAP kinase-p38…”

Section: Measurement Of Cavernosal Age (5-hmf) Levelsmentioning

confidence: 99%

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

et al. 2011

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Recently, the relationship between advanced glycation end products (AGEs) and erectile dysfunction (ED) has been reported. The present study aimed to investigate whether a combination of an AGE cross-link breaker (alagebrium/ALT-711) and sildenafil could enhance the erectile capacity in streptozotocin (STZ) diabetic rats. Additionally, we assessed the effect of that treatment option on some molecules that have been suggested to have crucial roles in AGE-related ED pathways. Four groups of animals were utilized: (1) age-matched control rats, (2) STZ-induced diabetic rats (40 mg kg À1 i.p.), (3) STZ rats þ sildenafil (5 mg kg À1 p.o.), (4) STZ rats treated with a combination of sildenafil (5 mg kg À1 p.o) þ alagebrium/ALT-711 (10 mg kg À1 p.o.) for the final 1 month of the 2 months of diabetes period. At 2 months after i.p. injection of STZ, all animals underwent cavernosal nerve stimulation (CNS) to assess erectile function. Penile tissue AGEs, MDA (malondialdehyde), cyclic guanosine monophosphate (cGMP) (ELISA), endothelial nitric oxide (NO) synthase (eNOS), inducible NO synthase (iNOS) (western blot), nuclear factor (NF)-kB, mitogen-activated protein (MAP) kinase (immunohistochemistry) and apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling) analyses were performed in all groups of rats. STZ diabetic rats had a significant decrease in erectile function as determined by the peak intracavernosal pressure (ICP) and total ICP (area under the erectile curve) after CNS when compared with control rats (Po0.05). The increase in both ICP and area under the erectile curve of STZ diabetic rats treated with a combination of sildenafil þ alagebrium/ALT-711 as well as in STZ diabetic rats treated with sildenafil alone was significantly greater than STZ diabetic rats. Additionally, combination treatment decreased AGE, MDA, iNOS, NF-kB, MAP kinase and apoptosis levels, whereas it preserved cGMP contents in diabetic penile tissue. Decreased AGE, MDA, iNOS, NF-kB, MAP kinase and increased cGMP levels at the combination (sildenafil þ alagebrium/ALT-711) therapy group increased both the peak ICP and total ICP to CNS in the STZ diabetic rats, which was similar to the response observed in control rats. These results may explain the role of AGEs in diabetes-related ED and the effect of an AGE cross-link breaker alagebrium/ ALT-711 þ sildenafil therapy on some critical molecules related to AGE-related ED pathways.

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“…Moreover, the total erectile response in STZ-induced diabetic rats receiving eNOS gene transfer plus sildenafil was greater than STZ-induced diabetic rats receiving eNOS gene transfer or sildenafil alone. 24 …”

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confidence: 99%

Gene and stem cell therapy for erectile dysfunction

2005

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Erectile dysfunction (ED) is defined as the inability to attain and/or maintain penile erection sufficient for satisfactory sexual performance. ED is a highly prevalent health problem with considerable impact on the quality of life of men and their partners. Although the treatment of ED with oral phosphodiesterase type V (PDE5) inhibitors is effective in a wide range of individuals, it is not efficacious in all patients. The failure of PDE5 inhibitors happens mainly in men with diabetes, non-nerve sparing radical prostatectomy, and high disease severity. Therefore, improved therapies based on a better understanding of the fundamental issues in erectile physiology and pathophysiology have recently been proposed. Here, we summarize studies on ED treatment using gene and stem cell therapies. Adenoviral-mediated intracavernosal transfer of therapeutic genes, such as endothelial nitric oxide synthase (eNOS), calcitonin gene-related peptide (CGRP), superoxide dismutase (SOD), and RhoA/Rho kinase and mesenchymal stem cell-based cell and gene therapy strategy for the treatment of age-and diabetes-related ED are the focus of this review. Penile erection, referred to as engorgement of the penis with blood, is the result of the penile arterial dilation which increases blood inflow, the relaxation of smooth muscle of the corpus cavernosum which increases blood storage, and penile venous occlusion which decreases blood outflow. The physiology of penile erection is complicated and this neurovascular event requires the functional integrity of nerves, endothelium, and smooth muscle. 1 Nitric oxide (NO), produced by both neuronal nitric oxide synthase (nNOS) in the nonadrenergic noncholinergic (NANC) nerves and endothelial nitric oxide synthase (eNOS) in the endothelium of penile arteries and cavernosal sinusoids is the principal mediator of penile erection. 2-5 NO formed in nerves or endothelial cells then diffuses to neighboring smooth muscle cells and activates soluble guanylyl cyclase. This activation results in increased cGMP formation, which mediates smooth muscle relaxation. 5 Besides NO, other molecules such as vasoactive intestinal polypeptide (VIP), calcitonin gene-related peptide (CGRP), substance P, and pituitary adenylate cyclase-activating polypeptide (PACAP) are also important for penile erection. 6 Causes contributing to erectile dysfunction (ED) can be broadly classified into two categories: organic and psychological. Aging, vascular diseases, neurological injuries, and diabetes mellitus are the common causes of organic ED. 7 Depressive stress is the common cause of psychological ED. 8,9 Although the treatment of ED with oral phosphodiesterase type V (PDE5) inhibitors (sildenafil, tadalafil, and vardenafil) is effective in a wide range of individuals with ED, it is not efficacious in all patients. For example, the response rate to sildenafil decreased from 72% in men 18-49 y of age to 53% in men 50 y or older. 10 The failure of sildenafil therapy happened mainly in men with diabetes, non-nerve sparing radical pr...

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Effect of combination endothelial nitric oxide synthase gene therapy and sildenafil on erectile function in diabetic rats

Cited by 63 publications

References 44 publications

Linking erectile dysfunction and coronary artery disease

Linking erectile dysfunction and coronary artery disease

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

Gene and stem cell therapy for erectile dysfunction

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