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

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.

Figure 1

(a) A typical trace showing the increase in intracavernous pressure (ICP) followed by urotensin-II (U-II) intracavernous injection (0.1–1 nmol). The arrows indicate the corresponding time to each intracavernous injection (b). Intracavernous injection of U-II (0.03–1 nmol) causes an increase in ICP expressed as area under the curve(mmHg × s). ***P < 0.001 versus vehicle, ^°°°P < 0.001 versus U-II 0.03 nmol, ^§§§P < 0.001 versus U-II 0.1 nmol, ^###P < 0.001 versus U-II 0.3 nmol or (c) Delta of increase (mmHg) ***P < 0.001 and **P < 0.01 versus vehicle, ^°°°P < 0.001 versus U-II 0.03 nmol; ^§§§P < 0.001 versus U-II 0.1 nmol. Data are calculated as mean ± standard error of mean of n = 5 experiments and analyzed by ANOVA followed by Bonferroni as posttest.

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.

Figure 3

(a) Intracavernous injection of UPG84 (0.03–1 nmol) causes an increase in intracavernous pressure expressed as area under the curve (mmHg × s). *P < 0.05 and **P < 0.01 versus vehicle, °P < 0.05 versus UPG84 0.03 nmol, ^§§§P < 0.001 versus UPG84 0.1 nmol or (b) Delta of increase *P < 0.05 and **P < 0.01 versus vehicle, °P < 0.05 and °°P < 0.01 versus UPG84 0.03 nmol. Data are calculated as mean ± standard error of mean of n = 7 experiments and analyzed by ANOVA followed by Bonferroni as posttest.

Figure 4

(a) Intracavernous injection of urotensin-II (0.03–1 nmol), (b) P5U (0.03–1 nmol) or (c) UPG84 (0.03–1 nmol) did not modify systemic blood pressure. Data are calculated as mean ± standard error of mean of n = 5–7 and analyzed by ANOVA followed by Bonferroni as posttest.