Comparison of the potassium channel openers, WAY-133537, ZD6169, and celikalim on isolated bladder tissue and In vivo bladder instability in rat
| Autor: | A, Wojdan, C, Freeden, M, Woods, G, Oshiro, W, Spinelli, T J, Colatsky, J H, Sheldon, N W, Norton, D, Warga, M M, Antane, S A, Antane, J A, Butera, T M, Argentieri |
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| Rok vydání: | 1999 |
| Předmět: |
Male
Indoles Patch-Clamp Techniques Potassium Channels Dose-Response Relationship Drug Molecular Structure Urinary Bladder Hemodynamics Blood Pressure Muscle Smooth Hypertrophy In Vitro Techniques Amides Membrane Potentials Rats Rats Sprague-Dawley Benzophenones Heart Rate Nitriles Animals Benzopyrans Female Cyclobutanes Muscle Contraction |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 289(3) |
| ISSN: | 0022-3565 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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