ROLE OF POTASSIUM CHANNELS IN BRONCHODILATOR RESPONSES IN HUMAN AIRWAYS

The plasma membrane of airway smooth muscle contains a high density of K+ channels of various types that mainly regulate membrane potential. To examine whether these K+ channels are involved in bronchodilating mechanisms in human airways, relaxation concentration-response studies to isoproterenol, theophylline, and a K+-channel opener, lemakalim (BRL 38227), were obtained in the presence or absence of charybdotoxin (ChTX) (10 or 100 nM), an inhibitor of large conductance Ca2+-activated K+ channels (Kca) in smooth muscle. The effects of other potassium channel blockers, apamin (0.1-mu-M, a small-conductance K(Ca) blocker) and BRL 31660 (10-mu-M, an ATP-sensitive K+-channel blocker) on isoproterenol-induced bronchodilation were also examined. All relaxation studies were performed on spontaneous tone and in the presence of 1-mu-M indomethacin. ChTX produced a dose-dependent significant rightward shift in the isoproterenol relaxation response curves without changing maximum relaxation; geometric mean values of EC50 were 4.6 nM without and 19 nM with 10 nM ChTX (n = 7, p < 0.005), and 3.4 nM without and 41 nM with 100 nM ChTX (n = 4, p < 0.05), respectively. The theophylline relaxation responses were inhibited to a lesser extent by ChTX (10 nM) (ED50 of 32-mu-M without and 71-mu-M with ChTX, n = 7, p < 0.05), whereas lemakalim-induced relaxation response was not affected. Other K+-channel blockers, apamin and BRL31660, failed to affect isoproterenol-induced bronchodilation. These results suggest that ChTX-sensitive K+ channels are involved in bronchodilation induced by beta-agonists and theophylline in human airways.