ROLE OF CALCIUM‐ACTIVATED POTASSIUM CHANNELS IN THE RELAXATION OF TRACHEAL SMOOTH MUSCLES BY FORSKOLIN

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Abstract
SUMMARY: 1. The role of calcium‐activated potassium (KCa) channels in bronchodilation produced by a direct adenylyl cyclase activator, forskolin, was investigated. The involvement of intracellular cyclic AMP (cAMP) in the process was also examined.2. The isometric tension records from guinea‐pig tracheal smooth muscles indicated that application of charybdotoxin (ChTX), a selective inhibitor of large conductance KCa channels, led to a suppression of the relaxant effect of forskolin in the precontracted tissue by carbachol (CCh). However, the inhibitory action by ChTX had a much greater effect on the relaxation caused by isoproterenol than by forskolin.3. In contrast to the effect of ChTX, glybenclamide, a cromakalim‐sensitive K+ channel inhibitor and apamin, a small conductance KCa channel blocker, had no effects on the bronchodilation produced by forskolin.4. The effects of forskolin and nifedipine on tone produced by high K+ was compared. Concentration‐inhibition curves in guinea‐pig trachealis precontracted by 20 mmol/L K+ solution were similar for forskolin and nifedipine. Conversely, relaxation by forskolin was significantly diminished when tissues were contracted with 40 mmol/ L K+ solution, whereas nifedipine relaxations were unaffected.5. A single channel record from a cell‐attached patch in a porcine tracheal myocyte demonstrated that forskolin stimulates reversibly KCa channels without affecting the unitary amplitude.6. The results are consistent with forskolin‐induced relaxation occurring at least in part through the opening of ChTX‐sensitive KCa channels, by means of a cAMP‐dependent channel modulation. The lesser effect of ChTX on forskolin compared with isoproterenol‐induced relaxations suggests a tighter coupling between relaxation and channel opening by β‐adrenergic receptor stimulation, and is consistent with cAMP‐independent mechanisms of receptor‐channel coupling.