FACILITATORY AND INHIBITORY EFFECTS OF SELECTIVE NOREPINEPHRINE REUPTAKE INHIBITORS ON HYPOGASTRIC NERVE-EVOKED URETHRAL CONTRACTIONS IN THE GAT - 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 mec hanism of action remains undefined due to their multiple pharmacologic al actions. To explore only the contribution imparted by sympathomimet ic effects on the urethra by norepinephrine (NE) reuptake inhibition, two selective NE reuptake inhibitors (nisoxetine and tomoxetine) that possess no antimuscarininc or serotonergic properties were examined fo r their effects on sympathetic hypogastric nerve (HgN) evoked urethral contractions in chloralose anesthetized cats. Under control condition s, HgN stimulation produced a biphasic response composed of a consiste nt initial contraction that was prazosin- (alpha adrenergic antagonist ) sensitive, followed by a more variable relaxation that was propranol ol- (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 con trol) in HgN-evoked contractions. These inhibitory effects of the reup take inhibitors were reversed by propranolol. In cats that were pretre ated with propranolol, nisoxetine produced a significant increase in H gN-evoked contractions. In conclusion, these results indicate that inh ibition of NE reuptake into the sympathetic nerve terminal produces a relative increase in the activation of beta adrenergic receptors compa red with alpha adrenergic receptors in the urethra. This increased bet a receptor stimulation might be due to a greater diffusion of NE away from the neuro-effector junction to extrajunctional sites following bl ockade of junctional reuptake. These findings should highlight the imp ortance of urethral beta adrenergic receptors, which is not well-recog nized in the literature.