Effects of ZD6169 and ZD0947, 2 potassium adenosine triphosphate channel openers, on bladder function of spinalized rats.
OBJECTIVE
The use of K+ channel openers is emerging as an attractive possibility for treating bladder overactivity. We tested the efficacy of the 2 adenosine triphosphate dependent K channel openers ZD6169 and ZD0947 on detrusor hyperreflexia after spinal cord injury in rats.


METHODS
Included in this study were 72 adult Sprague-Dawley rats. Six animals served as normal controls, while 66 underwent spinal cord transection at the 10th thoracic vertebra. Two weeks after spinal cord injury 6 animals underwent filling cystometrography to confirm detrusor hyperreflexia, while another 12 served as control paraplegics. For each drug 24 animals were used and divided into 2 equal groups of 12. Group 1 received the drug in a dose of 3 mg./kg. daily, while group 2 received a dose of 0.3 mg./kg. daily. Each control paraplegic and treatment group was further subdivided into 2 subgroups of 6 rats. In subgroup 1 filling cystometrography was done 3 weeks after spinal cord injury, while in subgroup 2 it was done 4 weeks after spinal cord injury.


RESULTS
Three weeks after spinal cord injury detrusor hyperreflexia developed in all control paraplegic animals with a mean bladder capacity plus or minus standard deviation of 0.7 +/- 0.2 ml. and a mean voiding pressure of 59 +/- 14.2 cm. water. Detrusor hyperreflexia resolved in 66% of the animals that received ZD6169 for 1 week at either dose. For example, mean bladder capacity was 2.5 +/- 1.8 versus 1.8 +/- 1.2 ml. and mean voiding pressure was 42.1 +/- 15.9 versus 43.2 +/- 21.4 cm. water in animals that received 3 versus 0.3 mg./kg. daily, respectively. All animals that received a dose of 3 mg./kg. ZD0947 daily for 1 week showed no detrusor hyperreflexia with a mean bladder capacity of 2.7 +/- 1.8 ml. and mean voiding pressure of 34 +/- 8.5 cm. water, while at 0.3 mg./kg. daily 83% showed no detrusor hyperreflexia with a mean bladder capacity of 2.5 +/- 2.0 ml. and a mean voiding pressure of 41.5 +/- 13.8 cm. water. Each drug produced better urodynamic results when given for 2 weeks.


CONCLUSIONS
ZD6169 and ZD0947 are effective treatment for detrusor hyperreflexia after spinal cord injury and they may provide alternative treatment options for overactive bladder. Each drug has time and dose dependent response effects that reflect their wide range of efficacy. However, ZD0947 shows an efficacy profile that is relatively superior to that of ZD6169.
Urology Research Laboratory, Royal Victoria Hospital, McGill University, Montreal, Quebec, Canada.
Aly M
AM
Abdel-Karim
Russell A
RA
Bialecki
Mostafa M
MM
Elhilali
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D009122:Muscle Hypertonia / Q000503:physiopathology*; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000503:physiopathology*; D001750:Urinary Bladder, Neurogenic / Q000503:physiopathology*; D014563:Urodynamics / Q000187:drug effects* / Q000502:physiology
D000577:Amides; D001577:Benzophenones; D004095:Dihydropyridines; D015221:Potassium Channels; C463119:ZD0947; C095007:Zeneca ZD 6169