| Autor: |
Wojdan, Alexandra, Freeden, Chris, Woods, Morgan, Oshiro, George, Spinelli, Walter, Colatsky, Thomas J., Sheldon, Jeffrey H., Norton, N. Wesley, Warga, Dawn, Antane, Madelene M., Antane, Schuyler A., Butera, John A., Argentieri, Thomas M. |
| Zdroj: |
The Journal of Pharmacology and Experimental Therapeutics; June 1999, Vol. 289 Issue: 3 p1410-1418, 9p |
| Abstrakt: |
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. |
| Databáze: |
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