The effects of ZD6169 on the ATP-dependent K(+) current (I(K)(ATP)) in isolated cat ventricular myocytes.
The effect of the K(ATP) channel opener ZD6169 [(S)-N-(4-benzoyl-phenyl)-3,3, 3-trifluoro-2-hydroxy-2-methyl-propionamide] currently under development for the treatment of urinary incontinence was explored in acutely isolated adult feline ventricular myocytes. ZD6169 activated a current over a wide range of concentrations (0.1-100 microM) that is completely blocked by 10 microM glyburide thereby identifying it as I(K(ATP)). The maximum activation of K(ATP) current was observed at 10 microM; higher concentrations decreased current activation. In contrast, the standard K(ATP) channel opener cromakalim showed a more usual concentration-response relationship, with increasing current for increased concentrations and no signs of saturation or reversal. The bell-shaped dose-response relationship for ZD6169 activation of I(K(ATP)) has also been seen in bladder myocytes, albeit at a lower concentration, and it has been proposed to contribute to the reported lack of in vivo cardiovascular side effects. We compared the effects of ZD6169 to cromakalim and showed that both compounds dramatically shorten cardiac myocyte action potential duration and that ZD6169 does so in spite of the bell-shaped concentration-response relationship for activation of K(ATP) current.
Jow
B
B
Wyeth-Ayerst Research, Cardiac Diseases, CN-8000, Princeton, NJ 08543, USA. jowb@war.wyeth.com
Numann
R
R
D018528:ATP-Binding Cassette Transporters; D000200:Action Potentials / Q000187:drug effects; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001577:Benzophenones / Q000494:pharmacology*; D002415:Cats; D002469:Cell Separation; D019806:Cromakalim / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D054086:KATP Channels; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000819:agonists*; D024661:Potassium Channels, Inwardly Rectifying
D018528:ATP-Binding Cassette Transporters; D000577:Amides; D000959:Antihypertensive Agents; D001577:Benzophenones; D007004:Hypoglycemic Agents; D054086:KATP Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C095007:Zeneca ZD 6169; C092520:uK-ATP-1 potassium channel; D019806:Cromakalim; D005905:Glyburide