Type 5 phosphodiesterase regulation of human sperm motility

Cuadra, Deborah L.; Chan, Philip J.; Patton, William C.; Stewart, Steven; King, Alan

doi:10.1067/mob.2000.105435

Cited by 41 publications

(38 citation statements)

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“…cGMP is thought to modulate also sperm motility. Indeed, the cGMP-dependent phosphodiesterase (PDE) inhibitor sildenafil was reported by some authors (Lefievre et al 2000, Cuadra et al 2000, but not by others (Andrade et al 2000, Aversa et al 2000, Burger et al 2000, to increase the velocity and amplitude of lateral head displacement in human spermatozoa. Lefievre et al (2000) observed an inhibition of sperm PDE activity with sildenafil at high concentrations, inhibiting many PDE and causing also an increase in cAMP, whereas Cuadra et al (2000) reported that sildenafil stimulates sperm motility at much lower concentrations, quite close to the IC 50 of sildenafil for the cGMP-dependent PDE.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, the cGMP-dependent phosphodiesterase (PDE) inhibitor sildenafil was reported by some authors (Lefievre et al 2000, Cuadra et al 2000, but not by others (Andrade et al 2000, Aversa et al 2000, Burger et al 2000, to increase the velocity and amplitude of lateral head displacement in human spermatozoa. Lefievre et al (2000) observed an inhibition of sperm PDE activity with sildenafil at high concentrations, inhibiting many PDE and causing also an increase in cAMP, whereas Cuadra et al (2000) reported that sildenafil stimulates sperm motility at much lower concentrations, quite close to the IC 50 of sildenafil for the cGMP-dependent PDE. A recent review of ex vivo studies suggests that sildenafil and tadalafil exert a dosedependent effect on sperm motility, which is enhanced at low doses but may be reduced at high concentrations, but further investigations are required to evaluate the mechanisms by which these PDE selective inhibitors modulate sperm motility (Dimitriadis et al 2008).…”

Section: Introductionmentioning

confidence: 99%

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Nitric oxide stimulates human sperm motility via activation of the cyclic GMP/protein kinase G signaling pathway

Miraglia¹,

Angelis²,

Gazzano³

et al. 2011

Reproduction

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Nitric oxide (NO), a modulator of several physiological processes, is involved in different human sperm functions. We have investigated whether NO may stimulate the motility of human spermatozoa via activation of the soluble guanylate cyclase (sGC)/cGMP pathway. Sperm samples obtained by masturbation from 70 normozoospermic patients were processed by the swim-up technique. The kinetic parameters of the motile sperm-rich fractions were assessed by computer-assisted sperm analysis. After a 30-90 min incubation, the NO donor S-nitrosoglutathione (GSNO) exerted a significant enhancing effect on progressive motility (77, 78, and 78% vs 66, 65, and 62% of the control at the corresponding time), straight linear velocity (44, 49, and 48 mm/s vs 34, 35, and 35.5 mm/s), curvilinear velocity (81, 83, and 84 mm/s vs 68 mm/s), and average path velocity (52, 57, and 54 mm/s vs 40, 42, and 42 mm/s) at 5 mM but not at lower concentrations, and in parallel increased the synthesis of cGMP. A similar effect was obtained with the NO donor spermine NONOate after 30 and 60 min. The GSNO-induced effects on sperm motility were abolished by 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (a specific sGC inhibitor) and mimicked by 8-bromo-cGMP (8-Br-cGMP; a cell-permeating cGMP analog); the treatment with Rp-8-Br-cGMPS (an inhibitor of cGMP-dependent protein kinases) prevented both the GSNO-and the 8-Br-cGMP-induced responses. On the contrary, we did not observe any effect of the cGMP/PRKG1 (PKG) pathway modulators on the onset of hyperactivated sperm motility. Our results suggest that NO stimulates human sperm motility via the activation of sGC, the subsequent synthesis of cGMP, and the activation of cGMP-dependent protein kinases.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nitric oxide stimulates human sperm motility via activation of the cyclic GMP/protein kinase G signaling pathway

Miraglia¹,

Angelis²,

Gazzano³

et al. 2011

Reproduction

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“…Cuadra et al 45 showed that when incubated in different concentrations of sildenafil (0-40 nmol l À1 ), sperm progressive motility and hyperactivation were stimulated to a greater extent than in controls at 4 h, followed by a decrease with a dose-dependent effect. A study by Glenn et al 46 on 57 male patients showed that the number and velocity of progressively motile sperms were significantly increased between 15-135 min when incubated with sildenafil (0.67 mmol) at 37 1C for 3 h. Burger et al 47 demonstrated that sildenafil incubation (125, 250 and 750 ng ml À1 ) did not affect sperm motility and viability of washed human spermatozoa compared with Ham's control, whereas pentoxifylline (3 mM) incubation enhanced both significantly.…”

Section: In Vitro Effectmentioning

confidence: 99%

“…This supports the hypothesis that PDE subtypes affect sperm function by regulating separate pools of cAMP, and that PDE inhibitors result in the buildup of intracellular cyclic nucleotides affecting acrosome reaction. Cuadra et al 45 investigated whether sildenafil has an effect on acrosome parameters in spermatozoa washed by two-layer colloid wash and resuspended in modified human tubal fluid with 5% serum albumin incubated in different concentrations of sildenafil followed for 48 h. Sildenafil stimulated sperm acrosome reaction by 50% above controls, suggesting a role in preventing premature acrosome reaction associated with failed fertilization.…”

Section: Acrosome Reactionmentioning

confidence: 99%

Oral phosphodiesterase-5 inhibitors and sperm functions

Mostafa

2008

Int J Impot Res

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This review aims to elucidate the possible effects of phosphodiesterase-5 (PDE5) inhibitors on sperm functions. PDEs hydrolyze cyclic nucleotides, and together with adenylyl and guanylyl cyclase, which catalyze the formation of cAMP and cGMP, regulate the levels of these second messengers in cells. cGMP-specific PDE5 is one of the PDEs that have been intensively studied because of its fundamental pharmacological relevance, as oral PDE5 inhibitors are used successfully in treating erectile dysfunction. In addition, they have shown diverse beneficial actions in different disease categories. Specific relevance of the cGMP system in reproductive functions has been recently proposed. Its use was shown to be devoid of effects on semen volume, concentration, sperm membrane integrity or sperm penetration assay. Most available studies demonstrated a significant increase in sperm motility and viability both in vivo and in vitro, which seems to be enhanced at low doses and reduced at high concentrations. Also, these molecules showed a role in capacitation and a debated one concerning acrosome reaction. However, due to the relative short period since the launching of oral PDE5 inhibitors, more investigations should be carried out in wider scales to assess their effect(s) on variant sperm function that could be beneficial as potential therapeutic approaches.

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“…The authors have demonstrated that this PDE5 inhibitor stimulates human sperm motility with an increase in intracellular cAMP suggesting an inhibitory action on a PDE that is different to PDE5. Cuadra et al, (2000) evaluated the effect of sildenafil on sperm motility. Spermatozoa were exposed to sildenafil at either 0 nmol/L, 0.4 nmol/L, 4.0 nmol/L, or 40 nmol/L.…”

Section: The Development Of In Vitro Studiesmentioning

confidence: 99%