A new therapeutic approach to erectile dysfunction: urotensin-II receptor high affinity agonist ligands |
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Authors: | Roberta d’Emmanuele di Villa Bianca Emma Mitidieri Erminia Donnarumma Ferdinando Fusco Nicola Longo Giuseppe De Rosa Ettore Novellino Paolo Grieco Vincenzo Mirone Giuseppe Cirino Raffaella Sorrentino |
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Institution: | 1.Department of Pharmacy, University of Naples, Federico II, Via D. Montesano 49, Naples, Italy;2.Interdepartmental Centre for Sexual Medicine, University of Naples, Federico II, Via S. Pansini 5, Naples, Italy;3.Department of Neurosciences, Human Reproduction and Odontostomatology, University of Naples Federico II, Via S. Pansini 5, Naples, Italy |
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Abstract: | Urotensin-II (U-II) is a cyclic peptide that acts through a G protein-coupled receptor (urotensin-II receptor UTR]) mainly involved in cardiovascular function in humans. The urotensinergic system is also implicated in the urogenital tract. Indeed, U-II relaxes human corpus cavernosum strips and causes an increase in intracavernous pressure (ICP) in rats. In light of this, the U-II/UTR pathway can be considered a new target for the treatment of erectile dysfunction. On this hypothesis, herein we report on two new UTR high affinity-agonists, P5U (H-Asp-cPen-Phe-Trp-Lys-Tyr-Cys]-Val-OH) and UPG84(H-Asp-cPen-Phe-DTrp-Orn-(pNH2) Phe-Cys]-Val-OH). The effects of P5U and UPG84 were each compared separately with U-II by monitoring the ICP in anesthetized rats. Intracavernous injection of U-II (0.03–1 nmol), P5U (0.03–1 nmol) or UPG84 (0.03–1 nmol) caused an increase in ICP. P5U, in particular, elicited a significant increase in ICP as compared to U-II. The observed effect by using P5U at a dose of 0.1 nmol per rat was comparable to the effect elicited by U-II at a dose of 0.3 nmol. Moreover, UPG84 at the lowest dose (0.03 nmol) showed an effect similar to the highest dose of U-II (1 nmol). Furthermore, UPG84 was found to be more effective than P5U. Indeed, while the lowest dose of P5U (0.03 nmol) did not affect the ICP, UPG84, at the same dose, induced a prominent penile erection in rat. These compounds did not modify the blood pressure, which indicates a good safety profile. In conclusion, UPG84 and P5U may open new perspectives for the management of erectile dysfunction. |
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Keywords: | erectile dysfunction intracavernous pressure rat urotensin-II urotensin-II ligands |
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