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

Toque, Haroldo A.; Priviero, Fernanda; Teixeira, Cleber E.; Claudino, Mário A.; Baracat, Juliana S.; Fregonesi, Adriano; Nucci, Gilberto De; Antunes, Edson

doi:10.1016/j.urology.2008.12.056

Cited by 16 publications

(19 citation statements)

References 28 publications

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“…Thus, in a study on human corpus cavernosum, tadalafil was found to have a relaxant effect even in nanomolar concentrations, with the maximal relaxant effect occurring at a concentration of 10 μM. [25] In comparison, in the current study tadalafil significantly relaxed the nonpregnant human myometrium only at 40 and 63 μM concentrations. A possible reason for this difference is the variation in tissue distribution of PDE-5, with greater concentrations being present in the corpus cavernosum than in the myometrium.…”

Section: Discussionmentioning

confidence: 55%

Inhibition by tadalafil of contractility of isolated nonpregnant human myometrium

Sen

Thomas

Das

et al. 2016

Journal of Pharmacology and Pharmacotherapeutics

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Objective:To investigate the inhibitory effect of tadalafil on the contractility of isolated nonpregnant human myometrium.Materials and Methods:The ability of tadalafil (25, 40, and 63 μM) to inhibit 55 mM KCl-induced contractility of isolated nonpregnant human myometrium was studied. The ability of the ATP-sensitive potassium channel blocker glibenclamide (10 μM) and the calcium-sensitive potassium channel (BKCa) blocker iberiotoxin (100 nM) to reverse the inhibitory effect of 40 μM tadalafil on 55 mM KCl-induced myometrial contractility was also studied.Results:Tadalafil produced a concentration-dependent inhibition of myometrial contractility that was statistically significant at 40 and 63 μM concentrations of tadalafil. The inhibition by tadalafil of myometrial contractility was statistically significantly reversed by the concurrent administration of glibenclamide and iberiotoxin.Conclusions:These results suggest that tadalafil inhibits human myometrial contractility by opening ATP-sensitive potassium channels and BKCa channels. The opening of these channels could have been due to the action of raised intracellular levels of cGMP due to inhibition of PDE-5 by tadalafil. The results suggest that tadalafil could be investigated for use in clinical conditions requiring relaxation of the myometrium.

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Section: Discussionmentioning

confidence: 55%

Inhibition by tadalafil of contractility of isolated nonpregnant human myometrium

Sen

Thomas

Das

et al. 2016

Journal of Pharmacology and Pharmacotherapeutics

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“…Interestingly, the endothelium‐dependent cholinergic response to ACh (100 μ m ) was potentiated in the presence of avanafil in HCC, but not in rat CC. These responses in HCC are consistent with previous studies showing that the maximal response to ACh was significantly enhanced in the presence of PDE‐5 inhibitors (Toque et al ., ). Similarly, lodenafil, another new PDE‐5 inhibitor, markedly potentiated ACh responses in HCC tissue (Toque et al ., ).…”

Section: Discussionmentioning

confidence: 97%

Effect of avanafil on rat and human corpus cavernosum

et al. 2014

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We compared the activity of a new phosphodiesterase-5 inhibitor (PDE5i) avanafil with sildenafil and tadalafil in human and rat corpus cavernosum (CC) tissues. The effect of avanafil with several inhibitors and electrical field stimulation (EFS) was evaluated on CC after pre-contraction with phenylephrine. With the PDE5i, sildenafil and tadalafil, concentration-response curves were obtained and cyclic guanosine monophosphate (cGMP) levels were measured in tissues. Avanafil induced relaxation with maximum response of 74 ± 5% in human CC. This response was attenuated by NOS inhibitor and soluble guanylate cyclase (sGC) inhibitor. Avanafil potentiated relaxation responses to acetylcholine and EFS in human CC and enhanced SNP-induced relaxation and showed 3-fold increase in cGMP levels. When compared with sildenafil, avanafil and tadalafil were effective at lower concentrations in human CC. In addition, Sprague-Dawley rats underwent in vivo intracavernosal pressure (ICP) and mean arterial pressure (MAP) measurements. Avanafil increased ICP/MAP that was enhanced by SNP and cavernous nerve (CN) stimulation in rat CC tissues. Also avanafil showed maximum relaxation response of 83 ± 7% in rat CC with 3-fold increase in cGMP concentration. Taken together, these results of our in vivo and in vitro studies in human and rat suggest that avanafil promotes the CC relaxation and penile erection via NO-cGMP pathway.

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“…In human CC, the relaxation induced by PDE‐5 inhibitors, sildenafil, tadalafil and vardenafil was greatly reduced in the presence of sGC and NOS inhibitors, suggesting that the heme in its reduced (Fe 2+ ) form and endogenous NO contribute to PDE‐5 inhibitors‐induced relaxation in CC . Yet, patients with ED and high cardiovascular risk do not respond to PDE‐5 inhibitor treatment.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological characterisation of the relaxation induced by the soluble guanylate cyclase activator, BAY 60‐2770 in rabbit corpus cavernosum

et al. 2015

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ObjectiveTo characterise the relaxation induced by the soluble guanylate cyclase (sGC) activator, BAY 60-2770 (4-({(4-carboxybutyl) [2-(5-fluoro-2-{[4 0 -(trifluoromethyl) biphenyl-4-yl]methoxy}phenyl)ethyl] amino}methyl)benzoic acid) in rabbit corpus cavernosum (CC). Material and MethodsThe penis from male New Zealand rabbits was removed and fours strips of CC were obtained. Concentration-response curves to BAY 60-2770 were constructed in the absence and presence of inhibitors of nitric oxide synthase, N (G)-nitro-Larginine methyl ester (L-NAME, 100 lM), sGC, 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 lM) and phosphodiesterase type 5 (PDE-5), tadalafil (0.1 lM). The potency (pEC 50 ) and maximal response (E max ) values were determined. Then, electrical-field stimulation (EFS)-induced contraction or relaxation was tested in the absence and presence of BAY 60-2770 (0.1 or 1 lM) alone or combined with ODQ (10 lM). For EFS-induced relaxation two protocols were used: (i) ODQ (10 lM) was first incubated for 20 min and then BAY 60-2770 (1 lM) was added for another 20 min (ODQ + BAY 60-2770); (ii) in different CC strips, BAY 60-2770 was incubated for 20 min followed by another 20 min with ODQ (BAY 60-2770 + ODQ). The intracellular levels of cyclic guanosine monophosphate (cGMP) were also determined. ResultsBAY 60-2770 potently relaxed rabbit CC with mean (SEM) pEC 50 and E max values of 7.58 (0.19) and 81 (4)%, respectively. The inhibitors ODQ (n = 7) or tadalafil (n = 7) produced 4.2-and 6.3-leftward shifts, respectively in BAY 60-2770-induced relaxation without interfering with the E max values. The intracellular levels of cGMP were augmented after stimulation with BAY 60-2770 (1 lM) alone, whereas its coincubation with ODQ produced even higher levels of cGMP. The EFS-induced contraction was reduced in the presence of BAY 60-2770 (1 lM) and this inhibition was even greater when BAY 60-2770 was co-incubated with ODQ. The nitrergic stimulation induced CC relaxation, which was abolished in the presence of ODQ. BAY 60-2770 alone increased the amplitude of relaxation. Co-incubation of ODQ and BAY 60-2770 did not alter the relaxation in comparison with ODQ alone. Interestingly, when BAY 60-2770 was incubated before ODQ, EFS-induced relaxation was partly restored in comparison with ODQ alone or ODQ + BAY 60-2770. ConclusionsThe relaxation induced by the sGC activator, BAY 60-2770 was increased after sGC oxidation and unaltered in the absence of nitric oxide. Thus, this class of substances may have advantages over sGC stimulators or PDE-5 inhibitors for treating patients with erectile dysfunction and extensive endothelial damage.

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

Cited by 16 publications

References 28 publications

Inhibition by tadalafil of contractility of isolated nonpregnant human myometrium

Inhibition by tadalafil of contractility of isolated nonpregnant human myometrium

Effect of avanafil on rat and human corpus cavernosum

Pharmacological characterisation of the relaxation induced by the soluble guanylate cyclase activator, BAY 60‐2770 in rabbit corpus cavernosum

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