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  • In the current study although EP agonist was the most


    In the current study, although EP4 agonist was the most effective in relaxing corpus cavernosum, it did not affect the neuronally-mediated relaxation. On the other hand, both alprostadil and iloprost, which were less effective as direct relaxants, potentiated EFS-induced relaxation of rat corpus cavernosum. EFS is reported to activate mainly NO/cGMP pathway to induce corpus cavernosal relaxation [34]. The neurogenic origin of EFS-induced response using parameters similar to those used in the current study was previously confirmed [35]. So, it could be suggested that the mechanisms of action of both alprostadil and iloprost but not EP4 agonist may interact with NO/cGMP pathway. These findings are consistent with those reported by Sato and Kawatani (2004) who revealed that EP4-mediated relaxation of rabbit corpus cavernosum is independent on NO/cGMP pathway, as they showed that neither NO synthase inhibitor nor sGC inhibitor affect the relaxant effect of EP4 agonist [30]. Such proposed interaction was confirmed in the current study as sildenafil- the selective phosphodiesterase (PDE)-5 inhibitor- significantly potentiated the relaxant effect of alprostadil on rat corpus cavernosum. A similar potentiation but to a lesser extent was observed with iloprost. In combination with sildenafil, the Emax values of alprostadil was increased from 24.30 ± 2.39% to 56.75 ± 3.01% and for iloprost from 34.19 ± 4.98% to 48.39 ± 3.00% respectively. Inline, clinical reports show that the use of sildenafil in combination with alprostadil led to a synergistic improvement of erectile dysfunction [36,37]. On the other hand, the relaxant effect of selective EP4 agonist was not potentiated when combined with sildenafil; the Emax value for L902688 was 57.52 ± 3.74% and 52.72 ± 5.57% in absence and presence of sildenafil respectively. These findings are in line with the suggestion that PGE1 and PGI2 pathways but not EP4 receptors pathway may involve a cross talking with NO/cGMP pathway, as discussed earlier. Future studies are required to measure the 4-iodo-SAHA sale of EP4 receptors as well as the level of various prostanoids synthesized in rat corpus cavernosum. At the cellular level, EP2, EP4 and IP receptors- the major PG receptors involved in the relaxant effect of alprostadil and iloprost in rat corpus cavernosum- are Gs-coupled which activates AC/cAMP pathway and subsequently activates cAMP-dependent protein kinase (PKA) leading to relaxation of the smooth muscles [33]. On the other hand, sildenafil- via inhibition of PDE-5- inhibits the breakdown of cGMP which in turn inhibits PDE-3 and increases the intracellular cAMP level resulting in further activation of PKA involved in the relaxant pathways of both alprostadil and iloprost [38]. Some reports have also suggested that there is a cross talk between PKA and PKG in vascular smooth muscles, as they activate each other [39,40], as shown in Fig. 4. Since this potentiatory effect was not observed in case of EP4 agonist and since alprostadil activates both EP2 and EP4 receptors, small intestine seems that this interaction with NO/cGMP may be limited to EP2 receptors in the corpus cavernosal tissues. The modest potentiation of iloprost effect by sildenafil may be also mediated by interaction between NO/cGMP pathway and EP2 receptors. However, since EP4 receptors are also Gs-coupled, it was expected that the relaxant effect of EP4 agonist would be also potentiated upon its combination with sildenafil. However, it was not altered, indicating the possible involvement of another mechanism that would mask the potentiatory effect of sildenafil. In fact, Yokoyama et al. reported that EP4 receptors activation may involve stimulation of Gi which leads to contractile effect rather than relaxation [41], and so it may limit the potentiatory effect of sildenafil in the specific case of the EP4 agonist. These observations give more evidence that the use of combination of sildenafil and alprostadil could be indeed beneficial for the management of erectile dysfunction, after proving the same results in human tissues. The advantage will be to reduce the oral dose of sildenafil and hence to decrease the side effects. The combination of alprostadil/sildenafil and iloprost/sildenafil showed similar relaxant effect as they attained almost the same Emax. Therefore, combination of iloprost and sildenafil seems also to be of potential therapeutic value and worth to be clinically investigated.