Evidence of a peripheral role of neurokinins in detrusor hyperreflexia: a further study of selective tachykinin antagonists in chronic spinal injured rats.
OBJECTIVE
Spinal cord injury above the sacral micturition center usually leads to detrusor hyperreflexia, increased intravesical pressure and post-void residual urine. Detrusor hyperreflexia is believed to be mediated by afferent C fibers with tachykinins as neurotransmitters. We investigated the selective peptide tachykinin antagonists MEN 11420 and GR 82334 of NK-2 and NK-1 receptors, respectively, in a chronic rat model of detrusor hyperreflexia after suprasacral spinal cord injury.


METHODS
Adult female Sprague-Dawley rats weighing 200 to 250 gm. were used. The spinal cord was transected at the T10 level. The bladder was evacuated by the Credé maneuver 3 times daily. After 6 weeks the rats were implanted with femoral vein and bladder dome catheters 2 days before filling cystometry. The 5 rats in group 1 received 100 nmol./kg. of the NK-2 antagonist MEN 11420 intravenously. The 5 rats in group 2 received 100 nmol./kg. of the NK-1 antagonist GR 82334 intravenously. The 5 rats in group 3 received a combination of the same dose of each antagonist. Three repetitive micturition cycles were recorded before injection. Three micturition cycles were done 20 minutes after the injection of each antagonist. Mean cystometric parameters were reported, including bladder capacity, micturition pressure, baseline pressure, post-void residual urine and micturition volume, and the number and amplitude of hyperreflexic contractions greater than 15 cm. water.


RESULTS
MEN 11420 significantly reduced the frequency of hyperreflexic contractions and baseline bladder pressure (p <0.05). There was no statistically significant effect on the other cystometric parameters. GR 82334 reduced the amplitude of hyperreflexic contractions but not statistically significant. A combination of MEN 11420 and GR 82334 significantly reduced the frequency and amplitude of hyperreflexic contractions (p <0.05) with no significant effects on other cystometric parameters, although there was a tendency toward increased micturition volume and bladder capacity.


CONCLUSIONS
These results suggest that at the peripheral level there is an efferent role of tachykinins in detrusor hyperreflexia after spinal cord injury. NK-1 and NK-2 receptor selective antagonists reduced the frequency and amplitude of hyperreflexic contractions as well as baseline bladder pressure. This finding may lead to potential new therapeutic modalities using selective tachykinins antagonists with other pharmacological agents to combat detrusor hyperreflexia.
Abdel-Gawad
M
M
Neurourology Research Laboratories, Lady Davis Institute For Medical Research, Jewish General Hospital, McGill University, Montréal, Quebec, Canada.
Dion
S B
SB
Elhilali
M M
MM
D000818:Animals; D005260:Female; D009119:Muscle Contraction / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010803:Physalaemin / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D012021:Reflex, Abnormal / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000150:complications* / Q000503:physiopathology; D015320:Tachykinins / Q000502:physiology*; D001743:Urinary Bladder / Q000187:drug effects / Q000503:physiopathology*; D001750:Urinary Bladder, Neurogenic / Q000209:etiology / Q000503:physiopathology*; D014563:Urodynamics
C107754:MEN 11420; D064729:Neurokinin-1 Receptor Antagonists; D010456:Peptides, Cyclic; D018041:Receptors, Neurokinin-2; D015320:Tachykinins; C079014:GR 82334; D010803:Physalaemin