title: Comparison of the potassium channel openers, WAY-133537, ZD6169, and celikalim on isolated bladder tissue and In vivo bladder instability in rat.
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 (IC50 values = 0.93, 0.03, and 0.09 microM, respectively for ZD6169, celikalim, and WAY-133537. Contractile inhibition by all three compounds was fully reversed by 6 microM 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 microM, n = 4-5) produced a significant hyperpolarization of 21 and 26 mV, respectively. Hyperpolarization was reversed by the addition of 5 microM glyburide. In patch voltage-clamp studies, WAY-133537 (0.3 microM, 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.
authors.affiliation: Cardiac Diseases, Wyeth-Ayerst Research, Princeton, New Jersey, USA.
authors.forename: A
authors.initials: A
authors.lastname: Wojdan
authors.forename: C
authors.initials: C
authors.lastname: Freeden
authors.forename: M
authors.initials: M
authors.lastname: Woods
authors.forename: G
authors.initials: G
authors.lastname: Oshiro
authors.forename: W
authors.initials: W
authors.lastname: Spinelli
authors.forename: T J
authors.initials: TJ
authors.lastname: Colatsky
authors.forename: J H
authors.initials: JH
authors.lastname: Sheldon
authors.forename: N W
authors.initials: NW
authors.lastname: Norton
authors.forename: D
authors.initials: D
authors.lastname: Warga
authors.forename: M M
authors.initials: MM
authors.lastname: Antane
authors.forename: S A
authors.initials: SA
authors.lastname: Antane
authors.forename: J A
authors.initials: JA
authors.lastname: Butera
authors.forename: T M
authors.initials: TM
authors.lastname: Argentieri
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003503:Cyclobutanes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006984:Hypertrophy; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology*; D009570:Nitriles / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000187:drug effects / Q000473:pathology / Q000502:physiology*
chemical_list: D000577:Amides; D001577:Benzophenones; D001578:Benzopyrans; D003503:Cyclobutanes; D007211:Indoles; D009570:Nitriles; D015221:Potassium Channels; C119323:WAY 133537; C095007:Zeneca ZD 6169; C067406:WAY 120491