Role of Potassium Channels in Bronchodilator Responses in Human Airways

Abstract

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.

Beyond the dogma: novel 2-adrenoceptor signalling in the airways

“…These channels, which are composed of four subunits, are abundant in ASM and are a substrate for PKA [89,[91][92][93]. Furthermore, their role in regulating ASM contractility is suggested from the finding that pharmacological blockade of these channels with charybdotoxin, and the more selective iberiotoxin, prevents hyperpolarisation and b 2 -adrenoceptor-mediated relaxation [93][94][95][96]. …”

Bronchodilating effects of the novel potassium channel opener HOE 234 in human airways in vitro.

“…We have not addressed the airway selectivity of this drug in the present study, but HOE 234 was found to have more potent dilatory effects, in human bronchi, than was previously reported for ATP-sensitive K+ channel opener BRL 38227 (Miura et al, 1992). If HOE 234 is to be potentially useful in the treatment of bronchial asthma further experiments must be carried out to ascertain the airway selectivity of this drug compared to its effects on vascular smooth muscle.…”

“…Bronchodilating effects of a K+ channel opener, BRL 38227, have been reported by Black and co-workers (1990) on human airway smooth muscle. We have previously shown that BRL 38227 relaxes human bronchi effectively and that this relaxation is inhibited by ATP-sensitive K+ blocker, BRL 31660, but not by charybdotoxin or apamin which block large or small conductance Ca2+-activated K+ channels, respectively (Miura et al, 1992). HOE 234 was significantly more potent at producing relaxation than BRL 38227 in comparable tissues on both spontaneous and increased tone, although the maximum relaxation produced by the two drugs was similar.…”

Second messengers, ion channels and pharmacology of airway smooth muscle

“…These are summarized in table 2. Because membrane hyperpolarization causes myocyte relaxation, stimulation of the calcium-activated potassium channel (K Ca , also called BK or Maxi K) results in relaxation [33]. The mechanisms underlying regulation of K Ca have been dissected over the last few years and it is now clear that this channel is subject to complex regulation, being stimulated by both Gsa directly [34] and the catalytic subunit of protein kinase A [35].…”