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Recently, the effect of phosphodiesterase inhibitors PDE5i in the lower urinary tract symptoms LUTS associated to benign prostatic hyperplasia have been studied thoroughly. Int J Impot Res. J Am Geriatr Soc. L-NAME, 3 3. Eur Urol. Neurourol Urodyn. All animals underwent to anesthetized cystometograms.
The chronic and systemic administration of L-NAME markedly increased the number of non voiding contractions 2. Sildenafil infusion decreased the number of micturition cycles significantly from the baseline to end point Systemic reduction of nitric oxide causes detrusor overactivity and acute infusion of sildenafil reduces the number of micturition cycles in chronic NO-deficient rats.
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Initially, the rationale for the use of phosphodiesterase inhibitors PDE5i in the treatment of lower urinary tract symptoms LUTS was based on demographic data showing the frequent occurrence of both erectile dysfunction ED and LUTS in men as they age 1 1. By inhibiting the degradation of phosphodiesterase type-5, vascular smooth muscle relaxation is augmented, thus improving corpora cavernosa blood flow.
Phosphodiesterase type-5 has been found throughout the urinary tract, including the corpus cavernosum, clitoris, tunica albuginea, bladder, urethra, prostate, ureter and vagina 3 3. In addition, the inhibition of arginases, which degrade L-arginine into L-ornithine, decreased neurogenic DO in chronic spinal cord-injured SCI rats 5 5.
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Br J Pharmacol. Male Wistar rats g were used. A new model of arterial hypertension. Rats were anesthetized with an intraperitoneal injection of urethane 1. A 1-cm incision was made along the midline of the rat abdomen.
The bladder was exposed and a butterfly needle 19G was inserted into the bladder dome and connected to a pressure transducer and to an infusion pump. Before starting the cystometry, the bladder was emptied.
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The urodynamic variables evaluated and the methodology used in the cystometry match those described in the literature 8 8. J Pharmacol Sci. Statistical significance of the differences was studied by analysis of variance ANOVA and posteriorly by Bonferroni method.
The chronic and systemic administration of L-NAME G2 resulted in a significant increase in total number of non voiding contractions 2.
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No significant difference was observed in the threshold pressure, peak pressure and basal bladder pressure comparing L-NAME group with control Table Comparing the baseline BP before sildenafil with endpoint BP after sildenafil infusion in the G4 group, it was not observed significant change in the arterial blood pressure Figure Therefore, a higher volume threshold becomes necessary to initiate micturition.
There are two theories that could explain this observation: increased urethral resistance or detrusor impairment.
However, as micturition of the L-NAME rats had detrusor pressure similar to control, it suggests an increased urethral resistance. This hypothesis is corroborated by in vitro pharmacological studies, which report that nitric oxide provides relaxation of the urethral smooth muscles 9 9. Parlani M, Conte B, Manzini S: Nonadrenergic, noncholinergic inhibitory control of the rat external urethral sphincter: involvement of nitric oxide.
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J Pharmacol Exp Ther. Acta Physiol Scand. These results suggest that NO has an inhibitory effect in muscular relaxation both in the bladder and in the urethra of animals with chronic deficiency of NO. As demonstrated in a previous experimental study, the systemic reduction of NO causes detrusor overactivity with a decrease in the functional relaxation of the urethra 4 4.
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Chronic L-NAME treatment also increased the number of micturition cycles in comparison with control animals. In this study, acute administration of sildenafil during the voiding phase decreased amplitude and number of micturition cycles in the rats with chronic deficiency of NO; however, it did not alter these variables in the control group G3 , with normal NO level.
Dmochowski R, Roehrborn C, Klise S, Xu L, Kaminetsky J, Kraus S: Urodynamic effects of once daily tadalafil in men with lower urinary tract symptoms secondary to clinical benign prostatic hyperplasia: a randomized, placebo controlled week clinical trial.
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J Urol. Also, the pathophysiological relationship between ED and LUTS is not clear yet, but there are several theories to explain it. The candidate mechanisms include pelvic atherosclerosis, autonomic hyperactivity, the calcium-independent Rho-kinase activation pathway and reduced NO levels. It is likely that there is an overlap between the roles of each of these candidate mechanisms, and an ultimate effect leading to smooth muscle relaxation in prostatic, bladder neck, or erectile tissues appears to be crucial.
Probably the hypothesis of the reduction of NO is the best explanation.
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Increased smooth muscle tension plays a central role in LUTS pathophysiology. Nitric oxide can activate guanylate cyclase, the enzyme that produces cGMP. The accumulation of intracellular cGMP triggers a cascade, leading to decreased intracellular calcium level and subsequent relaxation of smooth muscle cells SMCs.
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And the amount of cGMP results from the balance between production NO and degradation made by phosphodiesterase are enzymes that can hydrolyze and inactivate cyclic nucleotides. It is known that NO is involved in relaxation of the detrusor, bladder neck, urethra and prostate 6 6.
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Clinical trials consistently demonstrated that PDE5i significantly improve IPSS, most studies failed to observe significant improvement in uroflowmetry parameters 13 Stief CG, Porst H, Neuser D, Beneke M, Ulbrich E: A randomised, placebo-controlled study to assess the efficacy of twice-daily vardenafil in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia.
A randomized, double-blind and placebo controlled clinical trial showed that tadalafil, a phosphodiesterase type 5 inhibitor, when administrated in association with tamsulosin improves significantly more the storage symptoms compared with isolated use of alfa-blocker 16 Int Urol Nephrol.
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In consequence, the reduction demonstrated in the number per minute of micturition cycles after acute infusion of sildenafil in NO-deficient rats reinforces the hypothesis that PDE5 inhibitors may exert their effects probably via bladder. This study has some limitations. It has been previously known that L-NAME is a non specific NOS inhibitor that when administered systemically could affect various levels of neuronal or endothelia. In consequence, it has the potential to alter physiology of lower urinary tract throughout these mechanisms.
Additionally, we did not evaluate the pharmacological effects on molecular or morphological grounds of lower urinary tract. Open menu Brazil. International braz j urol.
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Text EN Text English. Purpose Recently, the effect of phosphodiesterase inhibitors PDE5i in the lower urinary tract symptoms LUTS associated to benign prostatic hyperplasia have been studied thoroughly. Results The chronic and systemic administration of L-NAME markedly increased the number of non voiding contractions 2. Conclusion Systemic reduction of nitric oxide causes detrusor overactivity and acute infusion of sildenafil reduces the number of micturition cycles in chronic NO-deficient rats.
Cystometry in Anesthetized Rats Rats were anesthetized with an intraperitoneal injection of urethane 1.
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Figure 4 Representative traces showing no change in the amplitude mmHg and number of micturition cycles MC after sildenafil infusion in a animal of G3 A , and decrease in amplitude and number of MC after sildenafil infusion in a rat of G4 B. The y-axis scale was stadardized to 5 mmHg and the x-axis for intervals of 4 minutes. Table 2 - Change of number and amplitude of micturition cycles from baseline before sildenafil to end point after sildenafil. It was also observed decrease in amplitude and number of MC after sildenafil infusion in the same animal.
Publication Dates Publication in this collection Mar-Apr History Received 10 Sept Accepted 20 Feb This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Ricardo Reges.
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Correspondence address: Dr. Ricardo Reges M. Figures 5 Tables 2. Stay informed of issues for this journal through your RSS reader. PDF English. Google Google Scholar. Effect of acute administration of sildenafil to rats with detrusor overactivity induced by chronic deficiency of nitric oxide.
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