Effect of the ATP-sensitive potassium channel opener ZM226600 on cystometric parameters in rats with ligature-intact, partial urethral obstruction.
The activity of a recent K(ATP) channel opener, the N-(4-Phenylsulfonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide (ZM226600) was investigated on a female rat model of overactive bladder with outlet obstruction. Both ZM226600 and pinacidil instilled into the bladder (10(-7) M, 30 min) or following systemic administration (10, 100 nmol/kg e.v.) almost completely abolished bladder overactivity and improved residual volume and frequency of micturition. However, pinacidil affected arterial pressure. Oxybutynin instilled into the bladder (10(-7), 10(-6), 10(-5) M, 30 min) decreased detrusor overactivity by about 16%, 25% and 46% respectively, but also blocked micturition reflexes at highest doses tested. Oxybutynin reduced detrusor overactivity by about 50% and 80%, after systemic administration (10, 100 nmol/kg e.v.), but also blocked micturition reflexes at the highest dose tested. In conclusion, ZM226600 is more active than oxybutynin in reducing bladder overactivity, and it is devoid of vascular side effects observed with pinacidil. Its short duration of action (about 1 h) is probably the main problem to solve, in order to consider this compound a valid alternative to antimuscarinics in the therapy of bladder overactivity.
Pinna
Christian
C
Department of Pharmacological Sciences, University of Milan, Italy. christian.pinna@unimi.it
Sanvito
Paola
P
Bolego
Chiara
C
Cignarella
Andrea
A
Puglisi
Lina
L
D000255:Adenosine Triphosphate / Q000378:metabolism; D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001577:Benzophenones / Q000737:chemistry / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002217:Carbachol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D020110:Pinacidil / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014524:Urethral Obstruction / Q000503:physiopathology*; D001743:Urinary Bladder / Q000187:drug effects* / Q000503:physiopathology
D000577:Amides; D001577:Benzophenones; D015221:Potassium Channels; C503138:ZM226600; C095007:Zeneca ZD 6169; D020110:Pinacidil; D000255:Adenosine Triphosphate; D002217:Carbachol