Effects of nitric oxide inhibitors in mice with bladder outlet obstruction

ABSTRACT Purpose To investigate the lower urinary tract changes in mice treated with L-NAME, a non-selective competitive inhibitor of nitric oxide synthase (NOS), or aminoguanidine, a competitive inhibitor of inducible nitric oxide synthase (iNOS), after 5 weeks of partial bladder outlet obstruction (BOO), in order to evaluate the role of constitutive and non-constitutive NOS in the pathogenesis of this experimental condition. Materials and Methods C57BL6 male mice were partially obstructed and randomly allocated into 6 groups: Sham, Sham + L-NAME, Sham + aminoguanidine, BOO, BOO + L-NAME and BOO + aminoguanidine. After 5 weeks, bladder weight was obtained and cystometry and tissue bath contractile studies were performed. Results BOO animals showed increase of non-voiding contractions (NVC) and bladder capacity, and also less contractile response to Carbachol and Electric Field Stimulation. Inhibition of NOS isoforms improved bladder capacity and compliance in BOO animals. L-NAME caused more NVC, prevented bladder weight gain and leaded to augmented contractile responses at muscarinic and electric stimulation. Aminoguanidine diminished NVC, but did not avoid bladder weight gain in BOO animals and did not improve contractile responses. Conclusion It can be hypothesized that chronic inhibition of three NOS isoforms in BOO animals leaded to worsening of bladder function, while selective inhibition of iNOS did not improve responses, what suggests that, in BOO animals, alterations are related to constitutive NOS.

Administração de BAY 41-2272 previne disfunção vesical em ratos deficientes de oxido nítrico / Administration of BAY 41-2272 prevents bladder dysfunction in nitric-oxide deficient rats

Objective: 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). Methods: 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). Results: 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. Conclusions: 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.

Objetivo: avaliar os efeitos protetores do BAY 41-2272, um ativador solúvel da guanilato ciclase, sobre alteração dos parâmetros citométricos em ratos deficientes de óxido nítrico (NO). Métodos: os ratos foram divididos nos seguintes grupos: (a) controle; (b) DMSO (c) L-NAME; (d) BAY 41-2272 isolado; (e) L-NAME + BAY 41-2272. O bloqueador da NO-sintase L-NAME (20 mg/rato/dia) foi ministrado na água de beber, concomitantemente ou não com o BAY 41-2272 (10 mg/kg/dia, ministrado por gavagem). Resultados: o tratamento crônico com L-NAME aumentou de forma acentuada a pressão arterial média, e o co-tratamento com BAY 41-2272 quase reverteu o aumento na pressão arterial média induzido por L-NAME. Contrações não esvaziadoras da bexiga mostraram-se significativamente aumentadas no grupo L-NAME (0,90 ± 0,1 número/minuto) comparadas com DMSO ou grupo controle (0,49 ± 0,1 número/minuto), que foram evitadas pelo co-tratamento com BAY 41-2272 (0,56 ± 0,25 número/minuto; p < 0,05). O limiar e o pico de pressão aumentaram em 70 e 44%, respectivamente, após o tratamento crônico com L-NAME, enquanto o co-tratamento com BAY 41-2272 atenuou muito ambos os efeitos (27 e 22% de aumento, respectivamente). A frequência de ciclos de micção diminuiu em 50% nos ratos tratados com L-NAME em comparação aos animais controle; o cotratamento com BAY 41-2272 normalizou esse parâmetro. Conclusões: nossos dados mostram que a administração oral a longo prazo de BAY 41-2272 contrapõe-se à disfunção de bexiga vista em ratos deficientes de NO, o que sugere que a restauração da via da NO-cGMP por esse composto pode ter valor benéfico para tratar sintomas vesicais.