Estradiol increases urethral tone through the local inhibition of neuronal nitric oxide synthase expression

Estrogens are known to modulate lower urinary tract (LUT) trophicity and neuronal nitric oxide synthase (nNOS) expression in several organs. The aim of this study was to explore the effects of endogenous and supraestrus levels of 17[beta]-estradiol ([E.sub.2]) on LUT and urethral nNOS expression and function. LUT function and histology and urethral nNOS expression were studied in adult female mice subjected either to sham surgery, surgical castration, or castration plus chronic [E.sub.2] supplementation (80 [micro]g x [kg.sup.-1] x [day.sup.-1], i.e., pregnancy level). The micturition pattern was profoundly altered by long-term supraestrus levels of [E.sub.2] with decreased frequency paralleled by increased residual volumes higher than those of ovariectomized mice. Urethral resistance was increased twofold in [E.sub.2]-treated mice, with no structural changes in urethra, supporting a pure tonic mechanism. Acute nNOS inhibition by 7-nitroindazole decreased frequency and increased residual volumes in ovariectomized mice but had no additive effect on the micturition pattern of long-term supraestrus mice, showing that longterm supraestrus [E.sub.2] levels and acute inhibition of nNOS activity had similar functional effects. Finally, [E.sub.2] decreased urethral nNOS expression in ovariectomized mice. Long-term supraestrus levels of [E.sub.2] increased urethral tone through inhibition of nNOS expression, whereas physiological levels of [E.sub.2] had no effect. estrogen; neurourology; urethra