Elsevier

Urology

Volume 74, Issue 1, July 2009, Pages 216-221
Urology

Basic and Translational Science
Comparative Relaxing Effects of Sildenafil, Vardenafil, and Tadalafil in Human Corpus Cavernosum: Contribution of Endogenous Nitric Oxide Release

https://doi.org/10.1016/j.urology.2008.12.056Get rights and content

Objectives

To compare the direct relaxant activity of sildenafil, vardenafil, and tadalafil in the human corpus cavernosum (HCC) and to investigate their modulatory effects on nitric oxide (NO)-mediated responses. Phosphodiesterase (PDE)-5 inhibitors cause cavernosal smooth muscle relaxation and penile erection.

Methods

HCC strips were mounted in 10-mL organ baths containing Krebs solution and connected to force-displacement transducers. The changes in isometric force were recorded using the Powerlab 400 data acquisition system. Corporeal smooth muscle was precontracted submaximally with phenylephrine (10 μmol/L).

Results

All PDE-5 inhibitors tested (0.001-10 μmol/L) relaxed phenylephrine-precontracted HCC with similar values of potency in a concentration-dependent manner. However, the maximal relaxations induced by tadalafil (83% ± 4%) were significantly lower compared with sildenafil (107% ± 5%) and vardenafil (111% ± 3%). The NO synthesis inhibitor N-nitro-l-arginine methyl ester (100 μmol/L) caused significant rightward shifts in the concentration-response curves for sildenafil (4.0-fold), vardenafil (4.6-fold), and tadalafil (3.2-fold) in HCC tissue. The guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (10 μmol/L) also produced similar rightward shifts for these PDE-5 inhibitors. The cavernosal relaxations evoked by either acetylcholine or the NO donor glyceryl trinitrate were markedly potentiated by sildenafil, vardenafil, and tadalafil (0.1 μmol/L each). All PDE-5 inhibitors significantly increased the duration of electrical field stimulation-induced relaxations (8 Hz).

Conclusions

Our findings have shown that sildenafil, vardenafil, and tadalafil relax HCC tissues in a concentration-dependent manner, but the maximal relaxation obtained with tadalafil was significantly lower than that obtained with sildenafil and vardenafil. Moreover, the PDE-5 inhibitors interacted with endogenous and exogenous NO, amplifying its HCC relaxation.

Section snippets

Material and Methods

HCC tissue from 16 individuals (14-65 years old) obtained from patients who had undergone penile prosthesis implantation or multiple organ donation was used after informed consent was obtained from the appropriate person. The University Hospital Ethics Committee approved the protocol.

Relaxant Response Elicited by PDE-5 Inhibitors in HCC

PE (10 μmol/L) caused submaximal HCC contractions of 56.4 ± 8.2 mN (n = 78). Figure 1 shows that the cumulative addition of sildenafil, vardenafil, and tadalafil (0.001-10 μmol/L; n = 4 each) to the bathing medium produced long-lasting and concentration-dependent relaxations in PE-precontracted tissues, with a negative logarithm of the median effective concentration (pEC50) value of 6.67 ± 0.14, 6.71 ± 0.11, and 6.78 ± 0.12 for sildenafil, vardenafil, and tadalafil, respectively. The maximal

Comment

The results of the present study have shown that sildenafil, vardenafil, and tadalafil relax HCC strips in a concentration-dependent manner, but the maximal relaxing response for tadalafil was significantly lower than that with the 2 other PDE-5 inhibitors. In addition, all PDE-5 inhibitors potentiated both endogenous and exogenous NO-mediated HCC relaxation.

The PDE-5 isoform is abundantly expressed in the corpora cavernosal of the penis, where it is thought to be responsible for penile

Conclusions

Our results have shown that sildenafil, vardenafil, and tadalafil potently relax HCC tissues in vitro, and interact with endogenous and exogenous NO, amplifying their relaxing effects. The maximal HCC relaxation obtained with tadalafil was significantly lower than those obtained with sildenafil and vardenafil. However, considering that vardenafil presents with a lower bioavailability and larger volume of distribution compared with tadalafil, our data suggest that the functional differences

References (29)

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