Alterations in K(+)-evoked release of 3H-norepinephrine and contractile responses in urethral and bladder tissues induced by norepinephrine reuptake inhibition.

The effects of norepinephrine (NE) reuptake inhibition on NE release and contractile responses in lower urinary tract tissues were evaluated using tomoxetine, a selective NE reuptake inhibitor, and imipramine, a nonselective reuptake inhibitor. Although both compounds significantly increased K(+)-evoked release of NE from urethral fragments obtained from rabbits, tomoxetine was at least 10X more potent than imipramine. Tomoxetine significantly enhanced the effects of NE to contract rabbit urethral fragments and to relax carbachol contracted rabbit bladder smooth muscle. Imipramine suppressed the effects of NE on urethral tissue and was less potent than tomoxetine in enhancing bladder responses to NE. These presynaptic and postsynaptic effects of NE reuptake inhibition in lower urinary tract tissues may contribute to the efficacy of imipramine in treating incontinence and represent a new clinical utility for selective and more potent reuptake inhibitors, such as tomoxetine.