Effects of ATP-sensitive K+ channel openers and tolterodine on involuntary bladder contractions in a pig model of partial bladder outlet obstruction.
OBJECTIVE
To compare in vivo the efficacy, potency, and bladder-vascular selectivity of ATP-sensitive potassium channel openers (KCOs), YM934 and (-)-cromakalim to a muscarinic antagonist, tolterodine in a novel partial outlet obstructed pig model.


METHODS
Partially obstructed female Landrace pigs were implanted with telemetry transmitters to allow the continuous measurement of intravesical, abdominal and arterial pressures. A subcutaneous port catheter was used to adjust bladder volume. Bladder and arterial pressure were simultaneously monitored under isoflurane anesthesia before and after increasing i.v. doses of test compounds.


RESULTS
Under anesthesia, voiding was completely inhibited, but spontaneous, nonvoiding bladder contractions were observed with mean amplitude of 16 +/- 1 cm H(2)O, duration of 35 +/- 2 seconds, and intercontraction interval of 43 +/- 4 seconds (n = 25). YM934 and (-)-cromakalim both caused dose-dependent decreases in bladder contraction area under the curve (AUC) with effective doses to inhibit AUC by 35% of 3.6 and 14.9 nmol/kg, i.v., respectively. However, concomitant reductions in mean arterial pressure of 12 and 13% were also observed. Tolterodine did not inhibit spontaneous bladder contractions at doses up to 100 nmol/kg, i.v. corresponding to plasma concentrations up to 41 ng/mL.


CONCLUSIONS
The superior efficacy of KCOs to inhibit spontaneous bladder contractions relative to tolterodine support the hypothesis that KCOs may provide an alternate therapeutic mechanism to treat symptoms of overactive bladder if bladder-vascular selectivity can be sufficiently improved. The minimally invasive model described herein appears useful in the preclinical evaluation of potential therapeutics targeted to treat the overactive bladder.
Fey
Thomas A
TA
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064-6118, USA. tom.a.fey@abbott.com
Gopalakrishnan
Murali
M
Strake
James G
JG
King
Linda L
LL
Brioni
Jorge D
JD
Sullivan
James P
JP
Coghlan
Michael J
MJ
Brune
Michael E
ME
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D048588:Benzoxazines; D003408:Cresols / Q000494:pharmacology*; D019806:Cromakalim / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D015640:Ion Channel Gating / Q000187:drug effects; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D010078:Oxazines / Q000494:pharmacology*; D010276:Parasympatholytics / Q000494:pharmacology; D010665:Phenylpropanolamine; D015221:Potassium Channels / Q000378:metabolism*; D034421:Sus scrofa; D000068737:Tolterodine Tartrate; D001743:Urinary Bladder / Q000502:physiology; D001748:Urinary Bladder Neck Obstruction / Q000188:drug therapy* / Q000503:physiopathology; D014563:Urodynamics / Q000187:drug effects
D001559:Benzhydryl Compounds; D048588:Benzoxazines; D003408:Cresols; D003497:Cyclic N-Oxides; D018727:Muscarinic Antagonists; D010078:Oxazines; D010276:Parasympatholytics; D015221:Potassium Channels; D019806:Cromakalim; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; D000255:Adenosine Triphosphate; C084963:2H-1,4-benzoxazine, 3,4-dihydro-2,2-dimethyl-6-nitro-4-(2-pyridinyl)-, N-oxide