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Nitric oxide synthase and the lower urinary tract: possible implications for physiology and pathophysiology.

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Department of Clinical Pharmacology, Lund University Hospital, Sweden.


Inhibitory, relaxation-mediating, non-adrenergic, non-cholinergic (NANC) nerves and neurotransmission have been demonstrated in lower urinary tract smooth muscles, and evidence has accumulated that L-arginine-derived nitric oxide (NO) is responsible for the main part of this response. The NO-synthetizing enzyme, nitric oxide synthase (NOS), has been shown to be localized in nerve fibres of the detrusor, trigone, and urethra, but preferably in the outflow region. NOS seems to be colocalized with acetylcholine esterase, vasoactive intestinal peptide, and neuropeptide Y, which 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. It has been speculated that 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 the cyclic GMP system, which makes it less likely that NO has a role as a relaxant neurotransmitter in this tissue. This does not exclude that NO may modulate the effects on the detrusor of other transmitters, or that it has an afferent function. In contrast, NO effectively relaxes isolated smooth muscle preparations from the outflow region, suggesting that it may be involved in the decrease in intraurethral pressure observed at the start of 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. However, the functional importance of the L-arginine/NO system in the central and peripheral pathways controlling micturition remains to be established.

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