Modulation of ATP-sensitive and large-conductance Ca++-activated K+ channels by Zeneca ZD6169 in guinea pig bladder smooth muscle cells.

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 KATP-sensitive K+ channel (KATP). In this study, the effects of ZD6169 and its racemic mixture on the whole-cell KATP and large-conductance CA+2-activated K+ (BKCa) 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 KATP current. With a threshold effective concentration of 0.5 microM, it produced a glyburide-sensitive activation that reached a maximum between 5 and 10 microM. ZD6169 at concentrations greater than 20 microM markedly inhibited KATP channel, which resulted in a bell-shaped concentration-response relationship. Over a similar concentration range, ZD6169 caused a sizable stimulation of the BKCa current. All effects were readily reversible. Consistent with the data in whole-cell recordings, ZD6169 activated single BKCa channel in inside-out patches by increasing its open-state probability. Several lines of evidence showed that the opening of BKCa channel was Ca+2 independent. The activity profile of the racemic ZD6169 on KATP and BKCa 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 KATP channel activation and the presence of BKCa channel stimulation by ZD6169 at higher concentrations may be responsible, in part, for its reported weaker cardiovascular side effects than cromakalim.