Regional and species differences in glyburide‐sensitive K⁺ channels in airway smooth muscles as estimated from actions of KC 128 and levcromakalim

Abstract

1 The purpose of the present experiments was to elucidate the differences in actions of two K+ channel openers, KC 128 and levcromakalim, on the carbachol-induced contraction, membrane potential and 86Rb+ efflux of the dog tracheal and bronchial smooth muscles. Furthermore, we compared the effects of these agents on guinea-pig and human airway smooth muscles. 2 In the dog tracheal and bronchial smooth muscle tissues, levcromakalim induced a concentrationdependent relaxation of the carbachol-induced contraction. The IC50 values were 0.35 AM (pIC5: 6.46 ± 0.10, n = 9) and 0.55 JM (pIC5o: 6.26 ± 0.07, n = 5), respectively. KC 128 relaxed bronchial smooth muscles precontracted by carbachol with an IC50 value of 0.19 AIM (pICG0: 6.73 ± 0.10, n = 7).However, KC 128 had almost no effect on the contraction evoked by carbachol in the trachea (ICGo> 10 0tM). The relaxations induced by levcromakalim and KC 128 were antagonized by glyburide (0.03-1 gM) but not by charybdotoxin (100 nM). 3 Levcromakalim (1 gM) hyperpolarized the membrane of both dog tracheal and bronchial smooth muscle cells, whereas KC 128 (1 tM) hyperpolarized the membrane of bronchial but not of tracheal smooth muscle cells.4 Levcromakalim (10 g.M) increased 'Rb+ efflux rate from both tracheal and bronchial smooth muscle tissues but KC 128 (10 gM) increased 86Rb+ efflux rate only from bronchial and not tracheal smooth muscle tissues. Glyburide (1 tM) prevented the hyperpolarization and the 'Rb+ efflux induced by these agents at the same concentration as observed for mechanical responses. 5Both KC 128 and levcromakalim relaxed the guinea-pig isolated tracheal smooth muscles precontracted by carbachol (100 nM), histamine (3 gM) or U46619 (10 nM). KC 128 was approximately 10 times more potent than levcromakalim for each agonist. 6 In human bronchial smooth muscles, levcromakalim but not KC 128 induced a concentrationdependent relaxation of the carbachol-induced contraction. 7 It is concluded that KC 128 has relaxant and hyperpolarizing effects in the dog bronchial and guinea-pig tracheal smooth muscles, but not in the dog tracheal and human bronchial smooth muscles. On the other hand, levcromakalim acts consistently on all the above airway smooth muscle tissues. These results indicate that there are regional and species differences in distribution of K+ channels, and at least two different K+ channel opener-and glyburide-sensitive K+ channels are present in the dog airway smooth muscles.

Allergic responses reduce the relaxant effect of beta-agonists but not potassium channel openers in guinea-pig isolated trachea

“…In the present study, the IC50 of levcromakalim was in agreement with other reports using vascular and airway smooth muscle [9,[26][27][28][29]; it was more potent than THEO. However, levcromakalim cannot be a first-line regimen for bronchodilatation, since the β-adrenergic agonist, ISO, was much more potent than levcromakalim in this study.…”

“…4c and 5c). It is likely that tissue and species-related differences of KATP channels may exist [29]. Thus, levcromakalim may be suitable for additional treatment of severe asthma attack, such as "status asthmatics", when β-adrenergic agonist and THEO, even used in combination, do not reverse airway narrowing.…”

Activity of glibenclamide-sensitive K+ channels under unstimulated conditions in smooth muscle cells of pig proximal urethra

“…In single-channel recordings, Kamouchi and Kitamura (1994) showed that K ATP did not open under unstimulated conditions in rabbit portal vein, and again the channels are thus unlikely to play an important role in determining the resting membrane potential. On the other hand, it has been widely reported that glibenclamide (1-10 µM) markedly depolarized the resting membrane, not only in vascular smooth muscle (rabbit mesenteric artery, Nelson et al 1990;Itoh et al 1992; canine saphenous vein, Nakashima and Vanhoutte 1995) but also in non-vascular smooth muscle (guinea-pig trachealis, Murray et al 1989; dog bronchial smooth muscle, Kamei et al 1994). and frozen at -70°C.…”

Effects of ATP-sensitive potassium channel openers on the contractile and phosphatidylinositol responses of the rat trachea

“…These authors found that K ATP channel openers inhibited inositol phosphate or IP 3 accumulations. However, the inhibitory effects of K ATP channel openers on carbachol (CCh)-induced contraction differ between species and with the concentration of spasmogens [5,6]. No data are available on the effects of K ATP channel openers on inositol monophosphate (IP 1 ), a degradation product of the PI response of the rat.…”