Among the other mediators which have been reported to

Among the other mediators which have been reported to play a role in erection are prostaglandins (PGs). Several studies have reported that alprostadil- synthetic PGE1- showed high efficacy in management of erectile dysfunction as it induces corpus cavernosal relaxation. Alprostadil has been first demonstrated by Ishii et al. (1986) for treatment of erectile dysfunction as intracavernous injection [9]. Sildenafil is administrated by oral route as it allows rapid n-acetyl-l-cysteine and high bioavailability. However, it may cause systemic side effects including visual disturbance, facial flushing and headache [10]. Alprostadil, on the other hand, is administrated by intracavernous injection which allows satisfactory response and limits its systemic side effects except some local pain. It is used in mild to severe organic cases, and in combination in those cases unresponsive to sildenafil alone [11]. Several other PGs have been also reported to contribute to the control of corpus cavernosal tone. The major PGs produced in human corpus cavernosum are PGE2, PGD2, PGF2α, PGI2 and thromboxane A2 (TXA2). Arachidonic acid is the main precursor of prostanoids synthesis in mammalian cells. It is a substrate for cyclooxygenase enzymes (COX-1 and COX-2) which are responsible for the synthesis of prostanoids [[12], [13], [14]]. Some of them are involved in contraction of penile tissue including PGF2α and more importantly TXA2 which in turn result in inhibition of penile erection. Others are involved in relaxation such as PGE1 and PGE2 which in turn cause stimulation of penile erection [15]. In this regard, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with erectile dysfunction has been always questionable as they inhibit the COX enzymes and in turn inhibit the synthesis of PGs. Determining the potential effect of COX inhibitors with varying selectivities on corpus cavernosal relaxation may help to reduce the incidence of NSAIDs untoward effects and help prescribing the appropriate COX inhibitor as anti-inflammatory agent for patients with erectile dysfunction. However, controversial data has been reported, for instance, a clinical study reported that the use of NSAIDs increases the risk of erectile dysfunction [16]. In line, an in-vivo animal study by Cabral et al. reported that indomethacin inhibits rat corpus cavernosal relaxation [17]. However, Ghasemi et al. showed that indomethacin does not affect nonadrenergic noncholinergic relaxation of rat corpus cavernosum [18]. On the other hand, in rabbit corpus cavernosum, indomethacin was reported to inhibit electric field stimulation (EFS)-induced contractile response [19]. Similarly, in case of acetylcholine (ACh)-induced relaxation which is endothelial-dependent, the effect of COX inhibitors was variable as some studies reported that indomethacin shows no effect on ACh-induced relaxation in rabbit corpus cavernosum [20], while others reported that it enhances the same response in both human and rabbit corpora cavernosa [21]. Senbel showed that both indomethacin and diclofenac significantly inhibit erectile response in rats, while celecoxib shows no significant effect [22]. Gleason et al. reported that the regular use of NSAIDs increases the prevalence of erectile dysfunction [23]. In contrast, another study showed that uncontrolled inflammatory conditions are associated with risk of moderate to severe erectile dysfunction and such prevalence was decreased after controlling the underlying conditions using NSAIDs [24].
Materials and methods
Results
Discussion In the present study, alprostadil, iloprost and L902688 (selective EP4 agonist) caused concentration-dependent relaxation of rat corpus cavernosum. The most effective as relaxant was the EP4 agonist followed by iloprost then alprostadil, suggesting that EP4 receptors may be among the main receptors involved in rat corpus cavernosal relaxation. These findings are consistent with those previously reported by Khan et al. who stated that PGE1 is among the main PGs involved in corpus cavernosal relaxation and that EP4 receptors may have a major role in this process [15]. Furthermore, high expression of EP4 receptors in human corpus cavernosum relative to the other PGs receptors of the E-series was reported by Komuro et al. [29]. Also, EP4 receptors are reported to be more involved in relaxation than EP2 in rabbit corpus cavernosum [30]. At the cellular level, the intracellular signaling pathways of the tested PGs in corpus cavernosum involve activation of EP2 and EP4 receptors by alprostadil [31], IP receptors by iloprost [32], and EP4 receptors by L902688. They all are Gs-coupled which activates adenyl cyclase (AC)/cAMP pathway in corpus cavernosal smooth muscles resulting in lowering the intracellular Ca2+ level which in turn results in corpus cavernosal relaxation [33].