Wibberley, Alexandra; (2001) The pharmacology of the autonomic control of the female rat urethra: Relevance to micturition. Doctoral thesis (Ph.D.), University College London.

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Abstract

The storage and periodic elimination of urine (micturition) is dependent upon a complex co-ordination of activities in the bladder and urethra. Nitric oxide (NO) has been suggested to play a role in the urethral control. The effects of NO are mediated by increases in guanosine 3':5'-cyclic monophosphate (cGMP) formation, which is broken down by a family of phosphodiesterases (PDEs), including PDE 5. However, the exact roles of this transduction system in the urethra are unknown. Therefore, the present experiments examined the effects of this pathway on changes in urethral and bladder pressures caused by bladder distension (micturition reflex) in urethane-anaesthetised female rats. As changes in urethral tone are due to both smooth and striated muscle (external urethral sphincter; EUS) EMG recordings were made to assess changes in EUS tone (EUS-EMG). The roles of NO/cGMP signalling in vitro were examined in the isolated female rat urethra. L-NAME, a NO synthase (NOS) inhibitor significantly attenuated reflex-evoked urethral relaxations and increased EUS-EMG activity and baseline urethral tone. Following neuromuscular blockade with α-Bungarotoxin (α-BT), L- NAME still attenuated urethral relaxations, but did not cause an increase in EUS-EMG or baseline tone. This supports the view that NO mediates urethral smooth muscle relaxations during voiding, and also indicates that there is a tonic release of NO inhibiting EUS-EMG activity. As would be expected, zaprinast, a PDE types 1, 5, 6 and 9 inhibitor, significantly potentiated reflex-evoked urethral relaxations. However, zaprinast also increased background and reflex-evoked EUS-EMG activity. Surprisingly, this ability to potentiate reflex-evoked relaxations was blocked by α-BT indicating that it is due to the ability of zaprinast to increase EUS-EMG activity. It is possible that this ability to increase EUS-EMG is indirect by causing changes in smooth muscle tone. This was investigated by examining the effects of urethral smooth muscle relaxation with intraurethral perfusion of isoprenaline and sodium nitroprusside on EUS-EMG activity. These relaxations were associated with an increase in EUS activity, and were inhibited by the ganglion blocker, chlorisondamine, supporting this view. Further experiments in the isolated female rat urethra demonstrated that L-NAME increased urethral tone and attenuated electrically-evoked (TTX sensitive) urethral relaxations. Nicotinic agonists evoked urethral relaxations, which were attenuated by L-NAME and inhibited by hexamethonium and chlorisondamine, but were TTX resistant. Zaprinast decreased urethral tone, although re-tensioning tissues to pre-drug levels unmasked a potentiation of the duration of electrically-evoked urethral relaxations at low frequencies of stimulation (1-4 Hz). These results indicate that reflex-, electrical- and nicotinic agonist-evoked urethral relaxations are mediated by NO. In vitro, these effects appear to be mediated by increases in cGMP. However, the ability of zaprinast to potentiate urethral relaxations in vivo are due to an ability to increase EUS activity, and conclusive evidence for the involvement of cGMP in the urethra in vivo could not be demonstrated. Further, the data indicates that there is an interaction between urethral smooth and striated muscles, mediated by ganglionic nicotinic receptors. In addition to the complex effects of the NO/cGMP pathway on this musculature, the above interactions complicate investigations regarding the effects of zaprinast in the urethra in vivo.

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