Augmentation of nitric oxide to treat detrusor-external sphincter dyssynergia in spinal cord injury

Detrusor-external sphincter dyssynegia (DSD) is a common cause of bladder o utlet obstruction in men with spinal cord injuries, which if left untreated leads ultimately to renal failure. External sphincterotomy is currently th e main treatment for DSD. However, obstruction persists in a substantial pr oportion of cases after this procedure. There is no effective drug treatmen t for DSD. Nitric oxide is an inhibitory neurotransmitter synthesised by ni tric oxide synthase. Both animal and human studies suggest that nitric oxid e mediates urethral sphincter relaxation. Nitric-oxide-synthase staining ne urons have been identified in very high density in the urethral sphincters of a variety of animals and in human beings. Relaxation of the urethral sph incter 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 elec trical stimulation. We hypothesise that augmentation of external sphincter nitric oxide could be an effective pharmacological treatment for DSD. Curre ntly available nitric oxide donors such as glyceryl trinitrate or isosorbid e mononitrate could be used to deliver nitric oxide to the urethral sphinct er. The variable pharmacokinetics of these drugs combined with different mo des of delivery (sublingual, buccal, or oral) could be used to achieve both short-term and long-term increases in concentrations of sphincter nitric o xide, thereby resulting in either acute or chronic lowering of urethral pre ssure. 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 .