K-CHANNEL OPENING ACTIVITY OF ZD6169 AND ITS ANALOGS - EFFECT ON RB-86 EFFLUX AND H-3 P1075 BINDING IN BLADDER SMOOTH-MUSCLE

Zeneca ZD6169, l)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide, is a novel compound which relaxes urinary bladder smooth muscle in vitro. The effect of ZD6169 and two of its analogs on Rb-86 efflux and H-3-P1 075 binding in guinea pig bladder strips was investigated to character ize the K-channel opening properties of this compound. ZD6169 concentr ation dependently increased the rate of Rb-86 efflux from guinea pig b ladder strips. Rb-86 efflux evoked by ZD6169 and its analogs was block ed by glibenclamide (30 mu M) but not by charybdotoxin, apamin or alph a-dendrotoxin, suggesting that this compound activates K-ATP channels in guinea pig bladder. In addition, interaction of ZD6169 with K-ATP c hannels was also confirmed in human bladder smooth muscle cells. Speci fic binding of H-3-P1075, a potent opener of K-ATP channels, to guinea pig urinary bladder strips was observed. H-3-P1075 binding was inhibi ted by known K-ATP openers. ZD6169 inhibited binding of H-3-P1075 to u rinary bladder strips like other structurally different K-ATP openers, e.g. cromakalim and pinacidil. Potencies for inhibition of H-3-P1075 binding by ZD6169 and other potassium channel openers correlate well w ith potencies for increase in Rb-86 efflux and bladder muscle relaxati on studies. It is concluded that Zeneca ZD6169 is a potassium channel opener which activates ATP-sensitive K-channels in guinea pig urinary bladder strips as well as in human bladder cells. Furthermore, binding studies suggest that the effects of ZD6169 and its analogs are mediat ed by binding to the site labeled by H-3-P1075 in guinea pig bladder s trips.