In vivo evaluation of the potency and bladder‐vascular selectivity of the ATP‐sensitive potassium channel openers (–)‐cromakalim, ZD6169 and WAY‐133537 in rats

• Published in: BJU international Vol. 91; no. 3; pp. 284 - 290
• Main Authors: Fabiyi, A.C., Gopalakrishnan, M., Lynch, J.J., Brioni, J.D., Coghlan, M.J., Brune, M.E.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-02-2003; Blackwell
• Subjects: Amides - pharmacology; Animals; ATP‐sensitive potassium channel; Benzophenones - pharmacology; Biological and medical sciences; Calcium Channels - drug effects; Cromakalim - pharmacology; Cyclobutanes - pharmacology; detrusor instability; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; glyburide; Male; Medical sciences; Muscarinic Antagonists - pharmacology; Muscle Contraction - drug effects; Nephrology. Urinary tract diseases; Nitriles - pharmacology; overactive bladder; partial outlet obstruction; Rats; Rats, Sprague-Dawley; Reflex, Abnormal - drug effects; smooth muscle; tolterodine; Urinary Bladder - blood supply; Urinary Bladder - drug effects; Urinary Bladder - physiology; Urinary Bladder Neck Obstruction - drug therapy; Urinary Bladder Neck Obstruction - etiology; Urinary Bladder Neck Obstruction - physiopathology; Urinary Bladder, Neurogenic - drug therapy; Urinary Bladder, Neurogenic - etiology; Urinary Bladder, Neurogenic - physiopathology; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Vasodilator Agents - pharmacology; Animal model; Rat; Hyperactivity; glyburide; smooth muscle; Ionic channel; Selectivity; ATP-sensitive potassium channel; Urinary bladder; Cromakalim; Detrusor muscle; Blood vessel; Arterial pressure; Antagonist; Urinary system disease; Rodentia; Tolterodine; Vertebrata; Sensitivity; detrusor instability; Mammalia; Animal; Bladder disease; Muscarinic receptor; ATP; Potassium; overactive bladder; partial outlet obstruction
• ISSN: 1464-4096; 1464-410X
• DOI: 10.1046/j.1464-410X.2003.03069.x

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.
MATERIALS AND 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 µmol/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 ≈ 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.