Vol. 280, Issue 1, 38-45, 1997

Modulation of ATP-Sensitive and Large-Conductance Ca⁺⁺-Activated K⁺ Channels by Zeneca ZD6169 in Guinea Pig Bladder Smooth Muscle Cells

Shiling Hu and Helen S. Kim

Research Department, Pharmaceuticals Division, Ciba-Geigy Corp., Summit, New Jersey

ZD6169, the S-enantiomer of the racemic N-(4-benzoylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide, was reported to possess a mechanoinhibitory effect on bladder detrusor smooth muscle through its ability to activate the K_ATP-sensitive K⁺ channel (K_ATP). In this study, the effects of ZD6169 and its racemic mixture on the whole-cell K_ATP and large-conductance Ca⁺⁺-activated K⁺ (BK_Ca) currents in isolated smooth muscle cells from guinea pig bladder detrusor were examined by the patch-clamp technique. ZD6169 produced a multiple stimulatory and inhibitory effect on the K_ATP current. With a threshold effective concentration of 0.5 µM, it produced a glyburide-sensitive activation that reached a maximum between 5 and 10 µM. ZD6169 at concentrations greater than 20 µM markedly inhibited K_ATP channel, which resulted in a bell-shaped concentration-response relationship. Over a similar concentration range, ZD6169 caused a sizable stimulation of the BK_Ca current. All effects were readily reversible. Consistent with the data in whole-cell recordings, ZD6169 activated single BK_Ca channel in inside-out patches by increasing its open-state probability. Several lines of evidence showed that the opening of BK_Ca channel was Ca⁺⁺ independent. The activity profile of the racemic ZD6169 on K_ATP and BK_Ca channels had remarkable resemblance to that of ZD6169. Our results indicate that ZD6169 exerts diverse effects on multiple types of K⁺ channels. A combination of the absence of K_ATP channel activation and the presence of BK_Ca channel stimulation by ZD6169 at higher concentrations may be responsible, in part, for its reported weaker cardiovascular side effects than cromakalim.