Augmentation of nitric oxide to treat detrusor-external sphincter dyssynergia in spinal cord injury.
Detrusor-external sphincter dyssynergia (DSD) is a common cause of bladder outlet obstruction in men with spinal cord injuries, which if left untreated leads ultimately to renal failure. External sphincterotomy is currently the main treatment for DSD. However, obstruction persists in a substantial proportion of cases after this procedure. There is no effective drug treatment for DSD. Nitric oxide is an inhibitory neurotransmitter synthesised by nitric oxide synthase. Both animal and human studies suggest that nitric oxide mediates urethral sphincter relaxation. Nitric-oxide-synthase staining neurons have been identified in very high density in the urethral sphincters of a variety of animals and in human beings. Relaxation of the urethral sphincter is abolished by inhibitors of nitric oxide synthase and enhanced by nitric oxide donors. Mice with targeted deletion of the gene, for neuronal nitric oxide have urethral sphincters that do not relax in response to electrical stimulation. We hypothesise that augmentation of external sphincter nitric oxide could be an effective pharmacological treatment for DSD. Currently available nitric oxide donors such as glyceryl trinitrate or isosorbide mononitrate could be used to deliver nitric oxide to the urethral sphincter. The variable pharmacokinetics of these drugs combined with different modes of delivery (sublingual, buccal, or oral) could be used to achieve both short-term and long-term increases in concentrations of sphincter nitric oxide, thereby resulting in either acute or chronic lowering of urethral pressure. The safety and efficacy of this potential treatment for DSD needs to be established in clinical trials of men with spinal cord injures with DSD.
Mamas
M A
MA
Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK.
Reynard
J M
JM
Brading
A F
AF
D000818:Animals; D006801:Humans; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology*; D020030:Nitric Oxide Donors / Q000008:administration & dosage* / Q000009:adverse effects; D013119:Spinal Cord Injuries / Q000150:complications* / Q000503:physiopathology; D016896:Treatment Outcome; D001748:Urinary Bladder Neck Obstruction / Q000188:drug therapy* / Q000503:physiopathology; D001750:Urinary Bladder, Neurogenic / Q000188:drug therapy* / Q000503:physiopathology
D020030:Nitric Oxide Donors; D009569:Nitric Oxide