K-ATP opener-mediated attenuation of spontaneous bladder contractions in ligature-intact, partial bladder outlet obstructed rats.
Symptoms of urinary frequency and urgency secondary to benign prostatic obstruction are common in elderly men. In many patients, these symptoms correspond to the urodynamic finding of involuntary detrusor contractions during filling cystometry (i.e., detrusor instability). Spontaneous non-voiding contractions during filling can be modeled in animals by subchronic, partial urethral obstruction. However, many investigators remove the obstructive ligature a few days prior to cystometrical evaluation (which may not be an ideal representation of the clinical situation where obstruction is still present), and all perform cystometry within 3 days post-bladder catheterization surgery (i.e., while considerable wound healing is present). In the current study, we evaluated the effects, after oral dosing, of three structurally diverse ATP-sensitive potassium channel openers (KCOs) on spontaneous contractions secondary to obstruction in rats with an intact obstructive ligature at the time of testing and 2 weeks post-bladder catheterization. ZD6169, WAY-133537 and a novel dihydropyridine KCO, A-278637, all significantly decreased spontaneous bladder contractions at 30 min post-dosing (p.o.). However, only ZD6169 (10 micromol/kg) and A-278637 (3 micromol/kg) attenuated such bladder contractions at doses that did not concurrently, significantly affect mean arterial blood pressure and heart rate. These data confirm the efficacy of KCOs to inhibit unstable contractions in obstructed rats, and they further demonstrate the positive effect of a novel, bladder-selective KCO, A-278637, in an animal model with potentially less artifact than in previous such models.
Lynch
James J
JJ
Neuroscience Research, Global Pharmaceutical Research and Development, Department R4N5, Bldg. AP9A-LL, Abbott Laboratories, 100 Abbott Park Road, IL 60064-6115, USA. james.j.lynch@abbott.com
Brune
Michael E
ME
Lubbers
Nathan L
NL
Coghlan
Michael J
MJ
Cox
Bryan F
BF
Polakowski
James S
JS
King
Linda L
LL
Sullivan
James P
JP
Brioni
Jorge D
JD
D018528:ATP-Binding Cassette Transporters; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000494:pharmacology; D003503:Cyclobutanes / Q000494:pharmacology; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D054086:KATP Channels; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D009570:Nitriles / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010949:Plasma / Q000378:metabolism; D015221:Potassium Channels / Q000819:agonists*; D024661:Potassium Channels, Inwardly Rectifying; D015363:Quinolones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013686:Telemetry; D001743:Urinary Bladder / Q000187:drug effects*; D001748:Urinary Bladder Neck Obstruction / Q000503:physiopathology*
C466801:9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno(3,2-b)quinolin-8(4H)-one 1,1-dioxide; D018528:ATP-Binding Cassette Transporters; D000577:Amides; D001577:Benzophenones; D003499:Cyclic S-Oxides; D003503:Cyclobutanes; D054086:KATP Channels; D009570:Nitriles; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D015363:Quinolones; C119323:WAY 133537; C095007:Zeneca ZD 6169; C092520:uK-ATP-1 potassium channel