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 Ca(2+)-activated K+ channels (KCa) in smooth muscle. The effects of other potassium channel blockers, apamin (0.1 microM, a small-conductance KCa blocker) and BRL 31660 (10 microM, 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 microM 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 less than 0.005), and 3.4 nM without and 41 nM with 100 nM ChTX (n = 4, p less than 0.05), respectively. The theophylline relaxation responses were inhibited to a lesser extent by ChTX (10 nM) (ED50 of 32 microM without and 71 microM with ChTX, n = 7, p less than 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.