SK Potassium Channel Antagonists As Novel Bronchodilators

Rationale: The repertoire of bronchodilators for asthma management is currently limited. Our studies revealed that multiple, redundant pathways exist that constrict airway and limit the ability of bronchodilators to effectively open airway passages. Thus, potent bronchodilators may need to target a common downstream signaling cascade essential for contraction. Our preliminary studies have uncovered intracellular, sarcoplasmic reticulum small-conductance (SK) K⁺channel as a potential novel downstream target for potent bronchodilators.

Methods: We screened a number of drugs using in-vitro isometric contraction studies of mouse trachea and bronchi. In addition, we conducted calcium imaging from dissociated mouse and human airway muscle cells. 

Results: : We found two structurally unrelated membrane permeant SK antagonists relax ASM by ~90%. One is NS8593 ((R)-N-(Benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine) that reduces channel opening by decreasing Ca²⁺-sensitivity. The other is UCL 1684 (6,10-diaza-3(1,3)8,(1,4)-dibenzena-1,5(1,4)-diquinolinacy clodecaphane), a SK channel-specific pore blocker. The airway muscle relaxant effect of these drugs occur at submicromolar concentrations and appear to be mediated through a novel mechanism: intracellular (sarcoplasmic reticulum) SK potassium channels.  Non-permeant SK blocker (Apamin) had no affect on contractility. Consistent with effects on sarcoplasmic reticulum, calcium imaging revealed a reduced cholinergic-evoked calcium release, and reduced sarcoplasmic reticulum calcium load with UCL1684. The affect of these drugs are specific to airway smooth muscle since vascular (aorta) muscle contractility was unaffected.

Conclusions: Given the unique reliance of airway smooth muscle on calcium-routed through sarcoplasmic reticulum, antagonists of sarcoplasmic reticulum SK channels may provide a novel and specific drug target as bronchodilators for asthma and COPD.