The potassium (K⁺) channel opening activity of Zeneca ZD6169 and one of its pyridylsulfonyl analogs from the anilide tertiary carbinol series was ascertained. Their mechanoin-hibitory effects on the myogenic activity of the guinea pig bladder detrusor muscle were measured in a set of functional assays. Elevating the K⁺ concentration in the tissue bath from 15 to 80 mmol/l increased the IC50 value of ZD6169 from 1.61 ± 0.22 to 223 ± 37 µmol/l. This result suggests that ZD6169 may act as a K⁺ channel opener. Similar to the prototypic ATP-sensitive K⁺ (K_ATP) channel opener cromakalim, the K⁺ channel openers from the anilide tertiary carbinol series displayed stereoselective mechanoinhibitory activity only in the test protocol in which the detrusor was stimulated with 15 mmol/l KC1. Being the active enantiomer, ZD6169 has an activity more than 30-fold higher than the less active enantiomer. ZD6169 at 10 µmol/l hyperpolarized the guinea pig detrusor membrane potential by 6.1 ± 1.2 mV and increased the whole cell K_Atp current in isolated guinea pig smooth muscle cells by 34.9 ± 7.9 pA. This is comparable to the increase of 26.8 ± 5.0 pA obtained with 10 µmol/l of lemakalim, the active enantiomer of cromakalim. The K⁺ channel opening activity of ZD6169 and the pyridylsulfonyl analog was competitively antagonized by the K_Atp channel blocker glibenclamide in the guinea pig detrusor with a pA2 value of 7.2. This activity, however, was unaffected by blockers of small and large conductance Ca-dependent K⁺ channels, such as apamin and charybdotoxin, respectively. The present study showed that Zeneca ZD6169 and its analog from the anilide tertiary carbinol series are K⁺ channel openers that activate K_ATP channels in vitro to relax bladder detrusors.

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