Erectile properties of the Rho-kinase inhibitor SAR407899 in diabetic animals and human isolated corpora cavernosa

Abstract

BackgroundRhoA-Rho kinase complex contributes to keep the cavernosus smooth muscle contracted and its inhibition is considered a potential strategy for the therapy of erectile dysfunction (ED).MethodsWe compared the effects of SAR407899, the Rho-kinase inhibitor Y-27632 and the PDE5 inhibitor sildenafil for their ability to relax corpus cavernosum strips contracted with phenylephrine in healthy and diabetic animals. Strips were obtained from WKY, spontaneous hypertensive (SHR), control CD, and diabetic CD rats, humans, control and diabetic rabbits. Diabetes was induced by streptozotocin or alloxan injection. In vivo penile erection (length) induced by drugs was measured in conscious rabbits.ResultsSAR407899 dose-dependently relaxed the pre-contracted corpora cavernosa in all species, with similar potency and efficacy in healthy vs diabetic rats, WKY vs SHR rats, healthy vs diabetic rabbits (IC50 range from 0.05 to 0.29 μM, Emax range 89 to 97%). In the presence of the NO-synthase (NOS) inhibitor, L-NAME, the SAR407899 response did not decrease in any of the species or experimental conditions. The effect was confirmed in human strips where sildenafil was significantly less potent and effective, with IC50 respectively 0.13 and 0.51 μM; Emax 92 and 43%. Unlike SAR407899, the potency and efficacy of sildenafil and Y27632 were significantly reduced by diabetes and L-NAME. In vivo, SAR407899 dose-dependently induced rabbit penile erection, with greater potency and longer duration of action than sildenafil. Sildenafil, but not SAR407899, was less effective in alloxan-induced diabetes.ConclusionThe induction of penile erection by SAR407899, unlike that by sildenafil, is largely independent of e-NO activity. This suggests its use in erectile dysfunction for diabetic and hypertensive patients where e-NO activity is impaired.

Understanding and targeting the Rho kinase pathway in erectile dysfunction

“…48 In a similar study, PDE5 levels were similar in diabetic and nondiabetic rats, which could explain the muted erectile response to intracavernosal injections of PDE5 inhibitors in diabetic men with ED. 27,47,51 Additionally, RhoA, ROCK-1 and type A endothelin receptor levels were elevated in diabetic rats, suggesting an enhanced contractile response in addition to impaired relaxation in diabetic ED. 27 …”

“…More recently developed ROCK inhibitors, including azaindole-1 and SAR407899, have shown promise in recovering erections in preclinical rat studies. 45–47 Azaindole-1, a more selective ROCK inhibitor with less secondary kinase inhibition than Y-27632 and fasudil, demonstrated both antihypertensive and proerectile effects. 45,46 …”

“…9,47,51 Studies in myocardium and erectile tissues demonstrate RhoA–ROCK pathway involvement in the upregulation of apoptosis, through increased activation of caspase-3 and PTEN, and decreased PKB activity. 52,53 In a mouse model of heart failure, ROCK-1 was found to be a substrate of activated caspase-3, and cleavage resulted in a 130 kDa ROCK-1 fragment.…”

Targeting of Rho Kinase Ameliorates Impairment of Diabetic Endothelial Function in Intrarenal Artery

“…Recently, the Rho/Rho-kinase pathway has been implicated in diabetes, including erectile dysfunction, cardiomyopathy, retinopathy, cerebro-vascular disease and nephropathy [6–10]. Thus, Rho kinase inhibitors may represent another group of therapeutic agents for diabetic complications [11].…”

Does Accreditation by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC) Ensure Greater Compliance With Animal Welfare Laws?

“…An animal research facility's AAALAC-accredited status is often cited in scientific articles as a form of assurance to editors and readers that relevant regulations were followed and animals were treated humanely (Cooper, Foltin, & Evans, 2013;Guagnini, Ferazzini, Grasso, Blanco, & Croci, 2012). Though AAALAC accreditation is incredibly influential, its effectiveness at identifying superior animal care programs is primarily taken for granted and there have not been any objective third-party evaluations of whether AAALAC accreditation actually accomplishes what it claims to do: guarantee accredited facilities will meet and exceed relevant laws and guidelines.…”