Comparison of the potassium channel openers, WAY-133537, ZD6169, and celikalim on isolated bladder tissue and in vivo bladder instability in rat

The effects of the ATP-dependent potassium channel agonists ZD6169, celikal im, and WAY-133537 on bladder contractile function were examined in vitro o n isolated bladder strips and in vivo on spontaneous bladder contractions. All three compounds produced a concentration-dependent relaxation of isolat ed rat detrusor strips (IC50 values = 0.93, 0.03, and 0.09 mu M, respective ly for ZD6169, celikalim, and WAY-133537. Contractile inhibition by all thr ee compounds was fully reversed by 6 mu M glyburide. These compounds also e ffectively inhibited spontaneous bladder contractions in the rat hypertroph ied bladder model of detrusor instability. We also examined the electrophys iological properiies of WAY-133537 on isolated rat bladder detrusor myocyte s. Myocytes had an average resting membrane potential of -40 mV. Under patc h current-clamp conditions, WAY-133537 (0.3 and 1.0 mu M, n = 4-5) produced a significant hyperpolarization of 21 and 26 mV, respectively. Hyperpolari zation was reversed by the addition of 5 mu M glyburide. In patch voltage-c lamp studies, WAY-133537 (0.3 mu M, n = 3) significantly increased outward current in response to both voltage step and ramp protocols consistent with activation of the ATP-dependent potassium channel. In the detrusor instabi lity model, WAY-133537 and celikalim had similar oral potencies (ED50 = 0.1 3 and 0.3 mg/kg, respectively), whereas ZD6169 was less potent (ED50 = 2.4 mg/kg). The antihypertensive agent celikalim exerted effects on the bladder at doses that significantly reduced systemic blood pressure. In contrast, both WAY-133537 and ZD6169 inhibited bladder hyperactivity at doses that pr oduced minimal changes in both mean arterial blood pressure and heart rate. These data suggest that both WAY-133537 and ZD6169 may be useful in the tr eatment of bladder instability at doses associated with minimal hemodynamic side effects.