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  • The current study showed that the tested nonselective COX

    2019-11-07

    The current study showed that the tested nonselective COX inhibitors potentiated the neuronal (EFS) and endothelial (ACh)-dependent relaxation of rat corpus cavernosum. Indomethacin was the most effective among them in potentiating EFS-induced relaxation. Diclofenac was the most effective in potentiating ACh-induced relaxation, while ketoprofen was the least effective on both responses. On the other hand, diclofenac was the only one among them to potentiate SNP (neuronal and endothelial-independent)-induced relaxation, suggesting that the potentiatory effect of diclofenac may involve interaction with cGMP beyond the level of NO synthesis as reported by Ortiz et al. [42]. On the other hand, the highly selective COX-2 inhibitor (DFU) showed no significant effect on either the neuronal, endothelial and SNP-dependent relaxation of rat corpus cavernosum, indicating that COX-2 isoenzyme may not be involved in the relaxation of corpus cavernosal smooth muscles which may be COX-1 dependent. TXA2 is reported to be one of the major contractile prostanoids in corpus cavernosal smooth muscles [43]. The current study showed that blocking TXA2 receptors by GR32191B significantly potentiated the neuronally-mediated relaxation induced by EFS. These results are in accordance with the findings of Jeremy et al. and Koupparis et al. who reported that TXA2 may increase the expression of reduced nicotinamide either dinucleotide phosphate (NADPH) oxidase which in turn decreases the availability of NO [44,45]. This effect is reported to be mediated via TP receptors [46]. Moreover, TP receptors activation is reported to inhibit endothelial NO production in vascular tissues [47]. In the present work, and in response to EFS (4–16 Hz), the percentage relaxation of rat corpus cavernosum induced by indomethacin in presence of TP receptor antagonist was not significantly different neither from the effect of indomethacin alone nor from the effect of the antagonist, i.e. the potentiatory effect of indomethacin was significantly inhibited/masked in presence of TP receptor blocker. This indicates that this potentiatory effect may be partially due to the inhibition of the synthesis of the contractile prostanoid TXA2, leading to increasing the availability and/or synthesis of NO and also giving the upper hand to the relaxant prostanoids. The slight potentiatory effect of indomethacin on EFS (2 Hz)-induced relaxation that remained after blocking TXA2 receptors may be attributed to inhibiting the synthesis of other contractile PGs such as PGF2α. These findings suggest that nonselective COX inhibitors may not be of harm concerning cavernosal tissue relaxation. This data remains to be confirmed using isolated human cavernosal tissues. Measuring the expression of EP2, EP4 and IP receptors in rat corpus cavernousm and the level of contractile and relaxant PGs synthesized in rats treated with COX inhibitors remains a limitation of the current study. The promising results of this in-vitro study remain to be verified using human corpus cavernosum, in-vivo, as well as in clinical practice.
    Conclusion The current study highlights the importance of EP4 receptor agonist in rat corpus cavernosal relaxation ; activation of EP4 receptors could be implicated in mediating the important relaxant effect of PGs in corpus cavernosum. When compared to alprostadil that is already used alone and in combination for the management of erectile dysfunction, EP4 agonist and iloprost as well as the combination of iloprost with sildenafil could be promising in this respect and worth further investigation. A cross-talk between NO/cGMP pathway and PGE1 and PGI2 pathways but not EP4 agonist pathway may exist in rat corpus cavernosum. Nonselective COX inhibitors potentiated both the neuronal and endothelial-mediated relaxation, part of this effect may be attributed to inhibition of TXA2 synthesis. In contrast, selective COX-2 inhibitor may have no significant effect on corpus cavernosal relaxation. So, the use of COX inhibitors may be safe in patients suffering from erectile dysfunction, which needs further clinical investigation.