Pathophysiologic basis of erectile dysfunction. What can we learn from animal models?

Melman, Arnold

doi:10.1038/sj.ijir.3900679

Cited by 11 publications

(10 citation statements)

References 31 publications

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“…Both in human and rat, decreased smooth muscle content and a corresponding decreased ratio of smooth muscle/collagen in the corpus cavernosum, are associated with age-related ED 52021. The aging process in the penis leading to defective CCSMC relaxation, which is considered the most important factor in age-related ED, causes veno-occlusive dysfunction and increases the severity of ED 22.…”

Section: Discussionmentioning

confidence: 99%

Reduced corporal fibrosis to protect erectile function by inhibiting the Rho-kinase/LIM-kinase/cofilin pathway in the aged transgenic rat harboring human tissue kallikrein 1

et al. 2017

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Our previous studies have demonstrated that erectile function was preserved in aged transgenic rats (TGR) harboring the human tissue kallikrein 1 (hKLK1), while the molecular level of hKLK1 on corporal fibrosis to inhibit age-related erectile dysfunction (ED) is poorly understood. Male wild-type Sprague-Dawley rats (WTR) and TGR harboring the hKLK1 gene were fed to 4- or 18-month-old and divided into three groups: young WTR (yWTR) as the control, aged WTR (aWTR), and aged TGR (aTGR). Erectile function of all rats was assessed by cavernous nerve electrostimulation method. Masson's trichrome staining was used to evaluate corporal fibrosis in the corpus cavernosum. We found that the erectile function of rats in the aWTR group was significantly lower than that of other two groups. Masson's trichrome staining revealed that compared with those of the yWTR and aTGR groups, the ratio of smooth muscle cell (SMC)/collagen (C) was significantly lower in the aWTR group. Immunohistochemistry and Western blotting analysis were performed, and results demonstrated that expression of α-SMA was lower, while expressions of transforming growth factor-β 1 (TGF-β1), RhoA, ROCK1, p-MYPT1, p-LIMK2, and p-cofilin were higher in the aWTR group compared with those in other two groups. However, LIMK2 and cofilin expressions did not differ among three groups. Taken together, these results indicated that the RhoA/ROCK1/LIMK/cofilin pathway may be involved in the corporal fibrosis caused by advanced age, and hKLK1 may reduce this corporal fibrosis by inhibiting the activation of this pathway to ameliorate age-related ED.

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Section: Discussionmentioning

confidence: 99%

Reduced corporal fibrosis to protect erectile function by inhibiting the Rho-kinase/LIM-kinase/cofilin pathway in the aged transgenic rat harboring human tissue kallikrein 1

et al. 2017

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“…In penile cells, hyperglycemia per se promotes activation of this pathway [29]. Conversely, NOS activity is decreased by MetS [13] and type 1 diabetes [28,29,43–49], which also increases penile fibrosis by altering the smooth muscle/fiber ratio [28,50].…”

Section: Discussionmentioning

confidence: 99%

Farnesoid X Receptor Activation Improves Erectile Function in Animal Models of Metabolic Syndrome and Diabetes

Vignozzi

Morelli

Filippi

et al. 2011

The Journal of Sexual Medicine

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Introduction The farnesoid X receptor (FXR) is critically involved in the regulation of the hepato-biliary system. Recent data suggest a role for FXR in modulating other metabolic pathways and vascular function. Aim To investigate whether long-term administration of the selective FXR agonist INT-747 ameliorates erectile function, we tested it in two animal models of metabolic derangements: a rabbit model of high-fat diet (HFD)-induced metabolic syndrome (MetS) and a rat model of streptozotocin (STZ)-induced type 1 diabetes. Methods HFD rabbit or STZ rats with or without chronic INT-747 dosing (10 mg/kg/day for 12 weeks). INT-747 addition to rabbit penile smooth muscle cells (rpSMCs). Main Outcome Measure Effects of INT-747 on metabolic features and erectile function in animal models and clarification of mechanism of action in isolated cells. Results INT-747 dosing normalized visceral adiposity and glucose intolerance in HFD rabbits. INT-747 increased penile FXR expression and partially restored endothelial nitric oxide synthase and dimethylarginine dimethylaminohydrolase 1 expression as well as impaired nitric oxide (NO)-dependent relaxation (improved responsiveness to acetylcholine and electrical field stimulation). INT-747 was also effective in regulating NO downstream events, as shown by increased sodium nitroprusside-induced relaxation. Because phosphodiesterase type 5 and protein kinase G (PKG) were unaltered by INT-747, we analyzed the calcium-sensitizing RhoA/ROCK pathway. HFD increased, and INT-747 normalized, RhoA membrane translocation/activation. RhoA/ROCK signaling inhibition by INT-747 was confirmed in rpSMCs by confocal microscopy, MYPT1-phosphorylation, cytoskeleton remodeling, cell migration, and smooth muscle-related genes expression. In STZ rats, FXR penile expression was not altered but was significantly upregulated by INT-747 dosing. In this model, INT-747 improved penile erection induced by electrical stimulation of cavernous nerve and hypersensitivity to intracavernous injection of a ROCK-inhibitor, Y-27632, without improving hyperglycemia. Conclusion In HFD rabbits, INT-747 dosing improved glucose sensitivity and MetS-associated erectile dysfunction, via upregulation of NO transmission and inhibition of RhoA/ROCK pathway. In STZ rats, INT-747 restored in vivo penile erection and sensitivity to ROCK inhibition, independently of effects on glycemia.

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“…Other chronic illnesses such as hypertension, alcoholism, and renal failure have also been studied and reported in animal models of ED [57]. Hypertension, alcoholism, and chronic renal failure (CRF) are closely associated with the development of ED.…”

Section: Experimental Animal Modelsmentioning

confidence: 99%

“…Studies have shown that the increase in oxidative stress in free radical scavengers of NO such as reactive oxygen species (ROS) contributed to the mechanism of type 1 DM‐induced model [56]. The other distinct pharmacological induced animal model is the alloxan‐induced rabbit model [57]. Both drugs resulted in similar changes with alterations in the integrity of endothelial and smooth muscle cells, increased advanced glycation products and oxidative stresses, reduced NOS activity, and development of ED in animals.…”

mentioning

confidence: 99%

Investigative Models in Erectile Dysfunction: A State-of-the-Art Review of Current Animal Models

Chung

Young

Brock

2011

The Journal of Sexual Medicine

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Introduction Erectile dysfunction (ED) is a common male sexual disorder producing a significant negative impact on the physical and psychosocial health of men and their partners. The development of ED is frequently attributable to both psychogenic factors as well as physiological alterations in neural, vascular, hormonal, and endothelial function. While the complex nature of human sexual function cannot possibly be replicated fully, the use of animal models provides a valid alternative to the investigation and evaluation of sexual dysfunction. Aim To review the existing English literature pertaining to the use of experimental models (predominantly rodent models) for the evaluation of ED. Main Outcome Measures Summary of relevant animal models of ED and the advantages and disadvantages of each animal model. Methods A Medline search using the key words “animal models of erectile dysfunction” was carried out and all relevant peer-reviewed English language was evaluated. Results While larger animals such as dogs, monkeys, cats, and rabbits were used in the early period of investigation (1960–1990), in recent times, rodents have largely replaced other animals as the predominant animal model for investigating erectile function. The most frequently reported models of ED can be classified as traumatic (cavernous nerve injury and arterial ligation) and metabolic (diabetic, hypercholesterolemia/lipidemia, and castration). Other models that have been studied include organic (smoking, hypertension, and chronic renal failure) and nonorganic (psychological) models. Conclusions The development and utilization of the various rodent models has allowed for significant advances in the field of sexual dysfunction. Neurophysiological studies using the various animal models have provided important insights into human sexual dysfunction. At present, animal models play a significant role in evaluating novel therapeutics and surgical techniques and will likely continue to remain a vital research tool in the future.

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Pathophysiologic basis of erectile dysfunction. What can we learn from animal models?

Abstract: AimThis is an overview concerning nuances of the animal models that are used to study the diseases that cause erectile dysfunction.

Cited by 11 publications

References 31 publications

Reduced corporal fibrosis to protect erectile function by inhibiting the Rho-kinase/LIM-kinase/cofilin pathway in the aged transgenic rat harboring human tissue kallikrein 1

Reduced corporal fibrosis to protect erectile function by inhibiting the Rho-kinase/LIM-kinase/cofilin pathway in the aged transgenic rat harboring human tissue kallikrein 1

Farnesoid X Receptor Activation Improves Erectile Function in Animal Models of Metabolic Syndrome and Diabetes

Investigative Models in Erectile Dysfunction: A State-of-the-Art Review of Current Animal Models

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