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.
Highlights
RhoA-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)
Epidemiological studies indicate that about 50% of men aged between 40 and 70 years have some degree of erectile dysfunction (ED) which is often related to poor health or chronic illnesses such as atherosclerosis, diabetes mellitus, depression and hypogonadism [1,2]
In the present study we examined the effects of SAR407899, a novel selective RhoA/Rho-kinase inhibitor, in vitro on the corpus cavernosum isolated from diabetic, spontaneous hypertensive (SHR) rats, diabetic rabbits, and humans
Summary
RhoA-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). Sildenafil citrate (Viagra®) was rapidly followed by the introduction, on the worldwide market, of two more PDE5 inhibitors: vardenafil (Levitra®) and tadalafil (Cialis®), and others are in advanced stages of development [5] This class of drugs largely contributed to understanding the mechanisms involved in penile erection, which results from a complex interplay of neurotransmitters, neuromodulators, endocrine and intracellular messengers, at both the central and peripheral levels [6,7]. The nitric oxide (NO) transmitter, locally synthesized by NO-synthase (NOS), rapidly diffuses into the muscle cells and, activating the intracellular enzyme guanylate cyclase, induces the synthesis of cyclic-guanylyl-monophosphate (cGMP) This second messenger eventually leads to smooth muscle relaxation by triggering a cascade of phosphorylation reactions and Ca++-dependent processes [8]. The PDE5 inhibitors promote smooth muscle relaxation and penile erection by raising the intracellular cGMP concentration through selectively inhibiting its enzymatic degradation by PDE5 [9]
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