JPET Assistant Professor of Medicine (Clinician-Educator)

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wojdan, A.
Right arrow Articles by Argentieri, T. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wojdan, A.
Right arrow Articles by Argentieri, T. M.

Vol. 289, Issue 3, 1410-1418, June 1999

Comparison of the Potassium Channel Openers, WAY-133537, ZD6169, and Celikalim on Isolated Bladder Tissue and In Vivo Bladder Instability in Rat

Alexandra Wojdan, Chris Freeden, Morgan Woods, George Oshiro, Walter Spinelli, Thomas J. Colatsky, Jeffrey H. Sheldon, N. Wesley Norton, Dawn Warga, Madelene M. Antane, Schuyler A. Antane, John A. Butera and Thomas M. Argentieri

Cardiac Diseases (A.W., C.F., M.W., G.O., W.S., T.J.C.), Chemical Sciences (M.M.A., S.A.A., J.A.B.), and Cardiovascular Women's Health (J.H.S., N.W.N., D.W., T.M.A.), Wyeth-Ayerst Research, Princeton, New Jersey

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 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.

0022-3565/99/2893-1410$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 J. Pharmacol. Exp. Ther.Home page
S. Tertyshnikova, R. J. Knox, M. J. Plym, G. Thalody, C. Griffin, T. Neelands, D. G. Harden, L. Signor, D. Weaver, R. A. Myers, et al.
BL-1249 [(5,6,7,8-Tetrahydro-naphthalen-1-yl)-[2-(1H-tetrazol-5-yl)-phenyl]-amine]: A Putative Potassium Channel Opener with Bladder-Relaxant Properties
J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 250 - 259.
[Abstract] [Full Text] [PDF]

Home page
 Pharmacol. Rev.Home page
K.-E. Andersson and A. J. Wein
Pharmacology of the Lower Urinary Tract: Basis for Current and Future Treatments of Urinary Incontinence
Pharmacol. Rev., December 1, 2004; 56(4): 581 - 631.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. Gopalakrishnan, S. A. Buckner, K. L. Whiteaker, C.-C. Shieh, E. J. Molinari, I. Milicic, A. V. Daza, R. Davis-Taber, V. E. Scott, D. Sellers, et al.
(-)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-Dioxide (A-278637): A Novel ATP-Sensitive Potassium Channel Opener Efficacious in Suppressing Urinary Bladder Contractions. I. In Vitro Characterization
J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 379 - 386.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
M. E. Brune, T. A. Fey, J. D. Brioni, J. P. Sullivan, M. Williams, W. A. Carroll, M. J. Coghlan, and M. Gopalakrishnan
(-)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-Dioxide (A-278637): A Novel ATP-Sensitive Potassium Channel Opener Efficacious in Suppressing Urinary Bladder Contractions. II. In Vivo Characterization
J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 387 - 394.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
S. M. Gopalakrishnan, S. A. Buckner, I. Milicic, D. R. Groebe, K. L. Whiteaker, D. J. Burns, U. Warrior, and M. Gopalakrishnan
Functional Characterization of Adenosine Receptors and Coupling to ATP-Sensitive K+ Channels in Guinea Pig Urinary Bladder Smooth Muscle
J. Pharmacol. Exp. Ther., March 1, 2002; 300(3): 910 - 917.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
G. J. Christ, N. S. Day, M. Day, C. Santizo, W. Zhao, T. Sclafani, J. Zinman, K. Hsieh, K. Venkateswarlu, M. Valcic, et al.
Bladder injection of "naked" hSlo/pcDNA3 ameliorates detrusor hyperactivity in obstructed rats in vivo
Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2001; 281(5): R1699 - R1709.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
G. V. Petkov, T. J. Heppner, A. D. Bonev, G. M. Herrera, and M. T. Nelson
Low levels of KATP channel activation decrease excitability and contractility of urinary bladder
Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2001; 280(5): R1427 - R1433.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
C.-C. Shieh, J. Feng, S. A. Buckner, J. D. Brioni, M. J. Coghlan, J. P. Sullivan, and M. Gopalakrishnan
Functional Implication of Spare ATP-Sensitive K+ Channels in Bladder Smooth Muscle Cells
J. Pharmacol. Exp. Ther., March 1, 2001; 296(3): 669 - 675.
[Abstract] [Full Text]

Home page
 Pharmacol. Rev.Home page
C.-C. Shieh, M. Coghlan, J. P. Sullivan, and M. Gopalakrishnan
Potassium Channels: Molecular Defects, Diseases, and Therapeutic Opportunities
Pharmacol. Rev., December 1, 2000; 52(4): 557 - 594.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 1999 by the American Society for Pharmacology and Experimental Therapeutics.