Facilitatory and inhibitory effects of selective norepinephrine reuptake inhibitors on hypogastric nerve-evoked urethral contractions in the cat: a prominent role of urethral beta-adrenergic receptors.

Tricyclic antidepressants (TCA), such as imipramine, are well-accepted for the treatment of urinary incontinence and enuresis, but their mechanism of action remains undefined due to their multiple pharmacological actions. To explore only the contribution imparted by sympathomimetic effects on the urethra by norepinephrine (NE) reuptake inhibition, two selective NE reuptake inhibitors (nisoxetine and tomoxetine) that possess no antimuscarinic or serotonergic properties were examined for their effects on sympathetic hypogastric nerve (HgN) evoked urethral contractions in chloralose anesthetized cats. Under control conditions, HgN stimulation produced a biphasic response composed of a consistent initial contraction that was prazosin- (alpha adrenergic antagonist) sensitive, followed by a more variable relaxation that was propranolol- (beta adrenergic antagonist) sensitive. Unexpectedly, nisoxetine (0.03 to 1.0 mg./kg. intravenously, n = 6) and tomoxetine (0.3 to 3 mg./kg. intravenously, n = 3) produced decreases (about 50% to 60% of control) in HgN-evoked contractions. These inhibitory effects of the reuptake inhibitors were reversed by propranolol. In cats that were pretreated with propranolol, nisoxetine produced a significant increase in HgN-evoked contractions. In conclusion, these results indicate that inhibition of NE reuptake into the sympathetic nerve terminal produces a relative increase in the activation of beta adrenergic receptors compared with alpha adrenergic receptors in the urethra. This increased beta receptor stimulation might be due to a greater diffusion of NE away from the neuro-effector junction to extrajunctional sites following blockade of junctional reuptake. These findings should highlight the importance of urethral beta adrenergic receptors, which is not well-recognized in the literature.