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A new therapeutic approach to erectile dysfunction: urotensin-II receptor high affinity agonist ligands.

di Villa Bianca Rd, Mitidieri E, Donnarumma E, Fusco F, Longo N, Rosa GD, Novellino E, Grieco P, Mirone V, Cirino G, Sorrentino R - Asian J. Androl. (2015 Jan-Feb)

Bottom Line: P5U, in particular, elicited a significant increase in ICP as compared to U-II.Furthermore, UPG84 was found to be more effective than P5U.These compounds did not modify the blood pressure, which indicates a good safety profile.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Naples, Federico II, Via D. Montesano 49, Naples, Italy.

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-c[Pen-Phe-Trp-Lys-Tyr-Cys]-Val-OH) and UPG84(H-Asp-c[Pen-Phe-DTrp-Orn-(pNH 2 ) 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.

No MeSH data available.


Related in: MedlinePlus

(a) Intracavernous injection of P5U (0.03–1 nmol) causes an increase in intracavernous pressure expressed as area under the curve (mmHg × s). ***P < 0.001 and **P < 0.01 versus vehicle, °P < 0.05 and °°°P < 0.001 versus P5U 0.03 nmol, §§§P < 0.001 versus P5U 0.1 nmol, ###P < 0.001 versus P5U 0.3 nmol or (b) Delta of increase (mmHg) ***P < 0.001 and **P < 0.01 versus vehicle, °P < 0.05 and °°°P < 0.001 versus P5U 0.03 nmol, §§§P < 0.001 versus P5U 0.1 nmol. Data are calculated as mean ± standard error of mean of n = 7 experiments and analyzed by ANOVA followed by Bonferroni as posttest.
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Figure 2: (a) Intracavernous injection of P5U (0.03–1 nmol) causes an increase in intracavernous pressure expressed as area under the curve (mmHg × s). ***P < 0.001 and **P < 0.01 versus vehicle, °P < 0.05 and °°°P < 0.001 versus P5U 0.03 nmol, §§§P < 0.001 versus P5U 0.1 nmol, ###P < 0.001 versus P5U 0.3 nmol or (b) Delta of increase (mmHg) ***P < 0.001 and **P < 0.01 versus vehicle, °P < 0.05 and °°°P < 0.001 versus P5U 0.03 nmol, §§§P < 0.001 versus P5U 0.1 nmol. Data are calculated as mean ± standard error of mean of n = 7 experiments and analyzed by ANOVA followed by Bonferroni as posttest.

Mentions: The intracavernous injection of P5U induces a significant increase in ICP (Figure 2). In particular, P5U significantly raises ICP at doses of 0.1, 0.3 and 1 nmol (Figure 2a). P5U-induced effect, at a dose of 0.1 nmol of (73.95 ± 7.312 mmHg × s, n = 7) is not statistically different from the effect elicited by U-II at a dose of 0.3 nmol per rat (65.78 ± 3.7 mmHg × s, n = 5). In addition, the increase in ICP calculated as delta displays the same profile of the area under the curve (Figure 2b).


A new therapeutic approach to erectile dysfunction: urotensin-II receptor high affinity agonist ligands.

di Villa Bianca Rd, Mitidieri E, Donnarumma E, Fusco F, Longo N, Rosa GD, Novellino E, Grieco P, Mirone V, Cirino G, Sorrentino R - Asian J. Androl. (2015 Jan-Feb)

(a) Intracavernous injection of P5U (0.03–1 nmol) causes an increase in intracavernous pressure expressed as area under the curve (mmHg × s). ***P < 0.001 and **P < 0.01 versus vehicle, °P < 0.05 and °°°P < 0.001 versus P5U 0.03 nmol, §§§P < 0.001 versus P5U 0.1 nmol, ###P < 0.001 versus P5U 0.3 nmol or (b) Delta of increase (mmHg) ***P < 0.001 and **P < 0.01 versus vehicle, °P < 0.05 and °°°P < 0.001 versus P5U 0.03 nmol, §§§P < 0.001 versus P5U 0.1 nmol. Data are calculated as mean ± standard error of mean of n = 7 experiments and analyzed by ANOVA followed by Bonferroni as posttest.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4291883&req=5

Figure 2: (a) Intracavernous injection of P5U (0.03–1 nmol) causes an increase in intracavernous pressure expressed as area under the curve (mmHg × s). ***P < 0.001 and **P < 0.01 versus vehicle, °P < 0.05 and °°°P < 0.001 versus P5U 0.03 nmol, §§§P < 0.001 versus P5U 0.1 nmol, ###P < 0.001 versus P5U 0.3 nmol or (b) Delta of increase (mmHg) ***P < 0.001 and **P < 0.01 versus vehicle, °P < 0.05 and °°°P < 0.001 versus P5U 0.03 nmol, §§§P < 0.001 versus P5U 0.1 nmol. Data are calculated as mean ± standard error of mean of n = 7 experiments and analyzed by ANOVA followed by Bonferroni as posttest.
Mentions: The intracavernous injection of P5U induces a significant increase in ICP (Figure 2). In particular, P5U significantly raises ICP at doses of 0.1, 0.3 and 1 nmol (Figure 2a). P5U-induced effect, at a dose of 0.1 nmol of (73.95 ± 7.312 mmHg × s, n = 7) is not statistically different from the effect elicited by U-II at a dose of 0.3 nmol per rat (65.78 ± 3.7 mmHg × s, n = 5). In addition, the increase in ICP calculated as delta displays the same profile of the area under the curve (Figure 2b).

Bottom Line: P5U, in particular, elicited a significant increase in ICP as compared to U-II.Furthermore, UPG84 was found to be more effective than P5U.These compounds did not modify the blood pressure, which indicates a good safety profile.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, University of Naples, Federico II, Via D. Montesano 49, Naples, Italy.

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-c[Pen-Phe-Trp-Lys-Tyr-Cys]-Val-OH) and UPG84(H-Asp-c[Pen-Phe-DTrp-Orn-(pNH 2 ) 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.

No MeSH data available.


Related in: MedlinePlus