K-Channel Opening Activity of ZD6169 and Its Analogs: Effect on ⁸⁶Rb Efflux and ³H-P1075 Binding in Bladder Smooth Muscle

Abstract

Zeneca ZD6169, (S^,)-N--(4-benzoylphenyl)-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 ⁸⁶Rb efflux and ³H-P1075 binding in guinea pig bladder strips was investigated to characterize the K-channel opening properties of this compound. ZD6169 concentration dependently increased the rate of ⁸⁶Rb efflux from guinea pig bladder strips. ⁸⁶Rb efflux evoked by ZD6169 and its analogs was blocked by glibenclamide (30 µM) but not by charybdotoxin, apamin or α-dendrotoxin, suggesting that this compound activates K_Atp channels in guinea pig bladder. In addition, interaction of ZD6169 with K_Atp channels was also confirmed in human bladder smooth muscle cells. Specific binding of ³H-P1075, a potent opener of K_Atp channels, to guinea pig urinary bladder strips was observed. ³H-P1075 binding was inhibited by known K_Atp openers. ZD6169 inhibited binding of ³H-P1075 to urinary bladder strips like other structurally different K_ATp openers, e.g. cromakalim and pinacidil. Potencies for inhibition of ³H-P1075 binding by ZD6169 and other potassium channel openers correlate well with potencies for increase in ⁸⁶Rb efflux and bladder muscle relaxation 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 mediated by binding to the site labeled by ³H-P1075 in guinea pig bladder strips.

Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence

“…The drugs also increase the outflow of 86 Rb or 42 K in preloaded tissues, further supporting the view that they relax bladder tissue by K ATP channel opening, subsequent hyperpolarization, and reduction in Ca 2ϩ influx (Andersson, 1993;Trivedi et al, 1995;Wojdan et al, 1999).…”

“…Newer K ATP channel openers, such as ZD6169 (Howe et al, 1995;Trivedi et al, 1995) have been claimed to be more selective for the bladder than first-generation K ATP openers (cromakalim, pinacidil). Oral administration of ZD6169 reduced voiding frequency in rats and dogs without lowering blood pressure (Howe et al, 1995;Wojdan et al, 1999;Lynch III et al, 2003).…”

Pharmacology of ZM244085: A Novel Bladder‐Selective Dihydropyridine KATP Channel Activator

“…ZM244085 increased [s6Rb']efflux in 25 mM KCI-depolarized guinea pig bladder strips in a concentration-dependent manner in the concentration range of 3 to 100 pM; it also increased [42K+] efflux from cultured human bladder smooth muscle cells (26). At a high concentration of 138 FM, ZM244085 produced an increase in K+ efflux similar in magnitude to that induced by 100 pM cromakalim.…”

Effect of Magnesium on the Contraction of Whole Rabbit Bladder in vitro

“…Drugs that act primarily on ion channels, that is cal cium or potassium channels, have recently been devel oped for treating detrusor instability [5,6], Contraction of smooth muscle, including that of the bladder, depends primarily on changes in the intracellular concentration of free calcium [7][8][9][10][11]. Increased sensitivity to calcium is thought to be one of the factors that induce detrusor hyperactivity in the bladder with neurogenic and/or out flow obstruction [12,13].…”