In vivo evaluation of the potency and bladder-vascular selectivity of the ATP-sensitive potassium channel openers (-)-cromakalim, ZD6169 and WAY-133537 in rats.
OBJECTIVE
To compare in vivo the potency and bladder-vascular selectivity of ATP-sensitive potassium channel openers (KCOs) (-)-cromakalim, WAY-133537 and ZD6169 and a muscarinic antagonist, tolterodine in rats.


METHODS
Bladder and arterial pressures were monitored simultaneously, before and after increasing intravenous doses of compounds, in each of two urethane-anaesthetized rat bladder hyperactivity models: spontaneous non-voiding myogenic contractions secondary to partial outlet obstruction and volume-induced neurogenic contractions.


RESULTS
(-)-Cromakalim, WAY-133537 and ZD6169 caused a dose-dependent suppression of spontaneous contractions in the obstructed model, with a 50% inhibition of the contraction area under the curve at doses of 0.06, 0.14 and 2.4 micro mol/kg (intravenous), respectively. Corresponding decreases in mean arterial pressure at these effective doses were 24%, 15% and 15%, respectively. The KCO potency rank order was the same and their relative potency highly comparable in the neurogenic model. There was complete inhibition of spontaneous contractions in obstructed rats at doses corresponding to approximately 50% inhibition of the neurogenic contractions. While tolterodine caused a dose-dependent inhibition of contractions in the neurogenic model, it was ineffective at inhibiting non-voiding contractions in obstructed rats.


CONCLUSIONS
All KCOs tested caused significant decreases in arterial pressure at doses effective on the bladder in the model of obstructive instability, suggesting a lack of bladder-vascular selectivity. Similar KCO potency in both assays suggests no appreciable changes in KATP channel function as a result of partial outlet obstruction.
Fabiyi
A C
AC
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL, USA.
Gopalakrishnan
M
M
Lynch
J J
JJ
Brioni
J D
JD
Coghlan
M J
MJ
Brune
M E
ME
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects*; D019806:Cromakalim / Q000494:pharmacology*; D003503:Cyclobutanes / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D008297:Male; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009570:Nitriles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012021:Reflex, Abnormal / Q000187:drug effects; D001743:Urinary Bladder / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D001748:Urinary Bladder Neck Obstruction / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D001750:Urinary Bladder, Neurogenic / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D014665:Vasodilator Agents / Q000494:pharmacology*
D000577:Amides; D001577:Benzophenones; D015220:Calcium Channels; D003503:Cyclobutanes; D018727:Muscarinic Antagonists; D009570:Nitriles; D014665:Vasodilator Agents; C119323:WAY 133537; C095007:Zeneca ZD 6169; D019806:Cromakalim