NITRIC-OXIDE SYNTHASE AND NITRIC OXIDE-MEDIATED EFFECTS IN LOWER URINARY-TRACT SMOOTH MUSCLES

In the lower urinary tract smooth muscles, both excitatory and inhibitory non-adrenergic, non-cholinergic (NANC) nerves and neurotransmission can be demonstrated. An inhibitory relaxation meditating system may serve not only the detrusor, the trigone, and the bladder neck/urethra, but may also be of importance for their integrated function. Available data suggest that nitric oxide synthase (NOS) is localized in nerve fibres of the lower urinary tract, preferably in the outflow region, and evidence has accumulated that L-arginine-derived nitric oxide (NO) is responsible for the main part of the inhibitory NANC response. Coinciding localization of NOS positive nerves with nerves expressing acetylcholine esterase, vasoactive intestinal peptide, and neuropeptide Y, suggests that NO may have a role both as a directly acting transmitter and as a modulator of efferent neurotransmission. In addition, NO may be involved in afferent neurotransmission. Theoretically, NO released from nerves in the detrusor, could be one factor keeping the bladder relaxed during filling. However, the detrusor has a low sensitivity to NO and agents acting via cyclic GMP, which makes it less likely that NO has a role as a relaxant neurotransmitter. This does not exclude that NO may modulate the effects of other transmitters, or that it has an afferent function. NO effectively relaxes isolated smooth muscle preparations from the outflow region, suggesting that it may be involved in the decrease in intraurethral pressure associated with normal micturition, and with the excessive urethral pressure variations (''unstable urethra''), which may be associated with certain voiding disturbances in women. The L-arginine/NO system may also control afferent activity in the outlet region, where lack of NO may lower the threshold for afferent firing leading to bladder instability. Another possible site where the L-arginine/NO pathway can have a functional role is in the urethral lamina propria. Here, NO-mediated relaxation may influence the ''inner urethral softness'', and thereby the sealing function of the urethral mucosa. However, it should be stressed that the functional importance of the L-arginine/NO system in the central and peripheral pathways controlling micturition remains to be established.