Functional characterization of large conductance calcium-activated K+ channel openers in bladder and vascular smooth muscle

  • John Malysz
  • Steven A. Buckner
  • Anthony V. Daza
  • Ivan Milicic
  • Arturo Perez-Medrano
  • Murali Gopalakrishnan
Original Article


Calcium activated K+ channels (KCa channels) are found in a variety of smooth muscle tissues, the most characterized of which are the large conductance KCa channels (BKCa or maxi-K+ channels). Recent medicinal chemistry efforts have identified novel BKCa openers including 2-amino-5-(2-fluoro-phenyl)-4-methyl-1H-pyrrole-3-carbonitrile (NS-8), BMS-204352 and its analog 3-(5-chloro-2-hydroxy-phenyl)-3-hydroxy-6-trifluoromethyl-1,3-dihydro-indol-2-one (compound 1), and 5,7-dichloro-4-(5-chloro-2-hydroxy-phenyl)-3-hydroxy-1H-quinolin-2-one (compound 2). Although these compounds are effective BKCa openers as shown by electrophysiological methods, little is known about their effects on smooth muscle contractility. In this study, the responsiveness of structurally diverse BKCa openers—NS-8, compounds 1 and 2 and the well characterized nonselective NS-1619—was assessed using segments of endothelium denuded rat aorta, rat and guinea pig detrusor precontracted with extracellular K+, and Landrace pig detrusor stimulated by electrical field. In all preparations, the compounds tested inhibited or completely abolished contractions with similar potencies (−logIC50 values: 3.8 to 5.1). In rat aorta, in the presence of 80 mM K+, the compounds significantly shifted the concentration-response curve to the right compared with those obtained in 30 mM K+. These data are consistent with K+ channel (BKCa channel) activation as the underlying mechanism of relaxation by compounds that share the electrophysiological property of BKCa current activation. The similar potencies at detrusor and vascular smooth muscle suggest that the achievement of smooth muscle selectivity in vitro with the representative compounds examined in this study may prove to be a challenge when targeting BKCa channels for smooth muscle indications such as overactive bladder.


BKCa openers Smooth muscle Bladder Vascular Contractility 



Potassium channel opener


Large conductance calcium-activated K+ channel


Molar concentration of test compound for 50% inhibition of response


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Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • John Malysz
    • 1
  • Steven A. Buckner
    • 1
  • Anthony V. Daza
    • 1
  • Ivan Milicic
    • 1
  • Arturo Perez-Medrano
    • 1
  • Murali Gopalakrishnan
    • 1
  1. 1.Neuroscience ResearchGlobal Pharmaceutical Research and Development, Abbott LaboratoriesAbbott ParkUSA

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