1 We evaluated a potential role for proteinase-activated receptor 4 (PAR 4 ) in a rodent paw inflammation model, with a focus on two main features of inflammation: (1) oedema and (2) granulocyte recruitment. 2 A PAR 4 antagonist (Pepducin P4pal-10; palmitoyl-SGRRYGHALR-NH 2 ) reduced both the oedema and granulocyte recruitment induced by a localized administration of carrageenan in the rat hind paw, pointing to a key role for PAR 4 in this inflammation model. 3 Further, intraplantar injection in the mouse hind paw of a PAR 4 agonist (AYPGKF-NH 2 ), but not its standard PAR 4 -inactive peptide control (YAPGKF-NH 2 ), caused an inflammatory reaction characterized by oedema (increased paw thickness) and granulocyte recruitment (increased paw myeloperoxidase activity). The PAR 4 agonist-induced effects were inhibited in mice pretreated with pepducin P4pal10. 4 These PAR 4 agonist-mediated effects were not affected by pretreatment with inhibitors of either NO production or prostaglandin release (L-NAME and indomethacin, respectively). 5 However, selective immuno-depletion of neutrophils significantly reduced PAR 4 agonist-induced oedema formation. 6 Moreover, AYPGKF-NH 2 -induced oedema was also reduced by pretreatment with either a kinin B 2 receptor antagonist (icatibant) or a tissue or plasma kallikrein inhibitor (FE999024 and FE999026, respectively), but not with a kinin B 1 receptor antagonist (SSR240612). 7 We conclude: (1) that PAR 4 plays an important role in the inflammatory response as it mediates some of the hallmarks of inflammation and (2) that PAR 4 -mediated oedema is dependent on the recruitment of neutrophils and components of the kallikrein-kinin system.

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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.

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