Administration of BAY 41-2272 prevents bladder dysfunction in nitric-oxide deficient rats.

Carlos Arturo Levi D'Ancona,David Cohen,Edson Antunes,Ricardo Reges,Gilberto De Nucci,Fabio Henrique Da Silva,Fabíola Zakia Taufic Mónica

doi:10.1590/s1679-45082010ao1789

Carlos Arturo Levi D'Ancona, David Cohen + Show 5 more

Open Access

https://doi.org/10.1590/s1679-45082010ao1789

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Abstract

to evaluate the protective effects of BAY 41-2272, a soluble guanylate cyclase activator, on changes in cystometric parameters in rats deficient in nitric oxide (NO). Rats were divided into the following groups: (a) control; (b) DMSO; (c) L-NAME; (d) BAY 41-2272 alone; (e) L-NAME + BAY 41-2272. The NO synthase blocker L-NAME (20 mg/rat/day) was given in drinking water concomitantly or not with BAY 41-2272 (10 mg/kg/day, given by gavage). Chronic L-NAME treatment markedly increased the mean arterial blood pressure, and co-treatment with BAY 41-2272 nearly reversed L-NAME-induced rise on mean arterial blood pressure. Non-void contractions were significantly increased in L-NAME group (0.90 ± 0.1 number/minute) compared with either DMSO or control group (0.49 ± 0.1 number/minute), which were prevented by co-treatment with BAY 41-2272 (0.56 ± 025 number/minute; p < 0.05). The threshold and peak pressure increased by 70 and 44%, respectively, after chronic L-NAME treatment, while co-treatment with BAY 41-2272 largely attenuated both effects (27 and 22% increase, respectively). The frequency of micturition cycles decreased by about of 50% in L-NAME-treated rats compared with control animals, and co-treatment with BAY 41-2272 normalized this parameter. Our data show that long-term oral administration of BAY 41-2272 counteracts the bladder dysfunction seen in NO-deficient rats, indicating that restoration of the NO-cGMP pathway by this compound may be of beneficial value to treat bladder symptoms.

Highlights

The neural pathways controlling lower urinary tract function are organized as simple on-off switching circuits that maintain a reciprocal relation between urinary bladder and urethral outlet
Co-treatment with BAY 41-2272 nearly normalized (p < 0.001) the elevated threshold pressure (TP) and peak pressure (PP) seen in the L-NAME group
The present study is the first to show that chronic nitric oxide (NO) blockade causes significant increases in NVCs, TP and PP along with reductions in the micturition frequency

Summary

Introduction

The neural pathways controlling lower urinary tract function are organized as simple on-off switching circuits that maintain a reciprocal relation between urinary bladder and urethral outlet. The activity of the urethral sphincter increases enhancing the outlet resistance that contributes to the maintenance of urinary continence[1]. In the lower urinary tract, NO synthase activity has been detected in the urothelium, smooth muscle, striated muscle, nerves and blood vessels[2,3]. Activation of the NO-cGMP signaling pathway generally results in inhibitory responses at the level of urethra and urethral sphincter, as well as of detrusor smooth muscle (DSM)(4-6). Hypertrophic dilated bladders and dysfunctional urinary outlets were found in mice with targeted deletion of the gene for neuronal NO synthase[7]. We showed that four-week treatment with the NO synthase blocker L-NAME caused in vitro DSM hypersensitivity to muscarinic agonists via increases in the levels of [3H]inositol-phosphate, accompanied by reductions of β3adrenoceptor-mediated DSM relaxations[9]

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