Abstract
The effects of the ATP-dependent potassium channel agonists ZD6169, celikalim, and WAY-133537 on bladder contractile function were examined in vitro on isolated bladder strips and in vivo on spontaneous bladder contractions. All three compounds produced a concentration-dependent relaxation of isolated rat detrusor strips (IC50values = 0.93, 0.03, and 0.09 μM, respectively for ZD6169, celikalim, and WAY-133537. Contractile inhibition by all three compounds was fully reversed by 6 μM glyburide. These compounds also effectively inhibited spontaneous bladder contractions in the rat hypertrophied bladder model of detrusor instability. We also examined the electrophysiological properties of WAY-133537 on isolated rat bladder detrusor myocytes. Myocytes had an average resting membrane potential of −40 mV. Under patch current-clamp conditions, WAY-133537 (0.3 and 1.0 μM, n = 4–5) produced a significant hyperpolarization of 21 and 26 mV, respectively. Hyperpolarization was reversed by the addition of 5 μM glyburide. In patch voltage-clamp studies, WAY-133537 (0.3 μM, 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 instability model, WAY-133537 and celikalim had similar oral potencies (ED50 = 0.13 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 produced 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 treatment of bladder instability at doses associated with minimal hemodynamic side effects.
Footnotes
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Send reprint requests to: Dr. Thomas M. Argentieri, Ph.D., Wyeth-Ayerst Research, CN-8000, Princeton, NJ 08543-8000. E-mail: argentt{at}war.wyeth.com
- Abbreviations:
- UUI
- urge urinary incontinence
- RMP
- resting membrane potential
- KCO
- potassium channel opener
- PSS
- physiological salt solution
- SBC
- spontaneous bladder contraction
- BP
- mean arterial blood pressure
- HR
- heart rate
- PE
- polyethylene
- PEG200
- polyethylene glycol 200
- BKCa
- calcium-dependent potassium channel
- Received July 29, 1998.
- Accepted January 29, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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