Role of nitric oxide synthase in bladder pathologic remodeling and dysfunction resulting from partial outlet obstruction.

OBJECTIVES

To investigate the relationship between nitric oxide synthase (NOS) and oxidative stress and pathologic remodeling in the partial obstructed bladder of a rat model.

METHODS

We surgically established partial bladder outlet obstruction (PBOO) in 2 groups of rats and allowed it to persist for 3-6 weeks. Normal and sham-operated rats served as the controls. Each group contained 6 rats for a total of 24 rats. Cystometry was used to evaluate the bladder function. The bladders were removed, and histopathologic measurements were performed to evaluate bladder hypertrophy and fibrosis and NOS immunolocalization. Biochemical measurements were used to evaluated NOS mRNA and activity and the oxidative stress level.

RESULTS

The obstructed rats experienced significant increases in bladder weight, muscle hypertrophy, and deposits of collagen fibers compared with the normal and sham-operated groups. PBOO debilitated bladder contractibility, increased the residual urine volume and voiding interval, decreased the voiding volume, and caused poor bladder emptying, with an increased residual urine volume and decompensated bladder in the PBOO rats at 6 weeks. The elevation in malondialdehyde and reduction in superoxide dismutase activity in the PBOO rats suggested that oxidative stress injury occurred in the obstructed bladder. Lower inducible NOS and endothelial NOS (eNOS) mRNA expression was demonstrated through quantitative polymerase chain reaction. In particular, eNOS was significantly downregulated in the PBOO rats compared with the normal and sham-operated rats. The normal and PBOO bladder tissues did not express detectable levels of neuronal NOS mRNA or exhibit neuronal NOS immunoreactivity. The total NOS activity had decreased progressively in the PBOO groups in conjunction with the significantly decreased eNOS activity compared with that in the normal and sham-operated groups.

CONCLUSIONS

These findings suggest that decreases in NOS activity and expression (mainly of eNOS) concomitant with increases in reactive oxygen species generation represent the underlying pathogenic mechanism of obstructed bladder remodeling and dysfunction.