Halothane and potassium channels in airway smooth muscle

Abstract

Earlier studies have suggested that halothane may relax smooth muscle in part by opening adenosine triphosphate-sensitive potassium (KATP) channels. We tested this hypothesis in vitro by examining the interaction of halothane with glibenclamide, a KATP channel blocker, and YM934, a KATP channel opener, in strips of canine tracheal smooth muscles mounted in an organ bath system. To examine the specificity of any effects of halothane on the KATP channel, we assessed the interaction of halothane with tetraethylammonium (TEA), an antagonist of the large-conductance, calcium-activated potassium channel. Experiments were conducted with drugs added before exposure to increasing concentrations of acetylcholine (ACh), and with drugs added after stable increases in force produced by ACh were achieved (ACh precontraction). Exposure to halothane 0.62 mmol litre-1 (equivalent to approximately 2 MAC) increased significantly the ED50 for ACh-induced contractions (by 0.24 (SEM 0.07) mumol litre-1). TEA 1 mmol litre-1 but not glibenclamide 10 mumol litre-1 significantly augmented this increase in ED50 (by an additional 0.17 (0.06) mumol litre-1). In strips precontracted with ACh, TEA, but not glibenclamide, potentiated concentration-dependent relaxation induced by halothane. Incubation with YM934 0.32 mumol litre-1 increased significantly the ED50 for ACh-induced contractions (from 0.12 (0.02) to 0.55 (0.11) mumol litre-1), an increase not affected by exposure to halothane 0.72 mmol litre-1. When added to strips precontracted with approximately ACh 0.3 mumol litre-1, YM934 produced concentration-dependent relaxation; halothane had little effect on this relaxation. These results do not support the hypothesis that halothane relaxes canine tracheal smooth muscle in part by opening KATP channels.

Relaxation of proximal and distal isolated human bronchi by halothane, isoflurane and desflurane

“…This is consistent with several studies that suggest that activation of K ATP channels could play a prominent role in volatile anaesthesia-induced relaxation of peripheral airways [24], coronary vessels [25], and cerebral vessels [28]. In contrast, FUKUSHIMA et al [14] found that glibenclamide pretreatment did not modify the concentrationdependent relaxation produced by halothane on canine tracheal strips incubated with indomethacin and precontracted with acetylcholine. Differences between contracting stimuli, tracheal versus distal airway smooth muscle, and/or between species may account for these conflicting results.…”

“…The concentration-dependent relaxant effect of volatile anaesthetics on human airway smooth muscle within clinical useful concentrations (0.66-2.0 MAC) is in accordance with most of the studies performed on animal airway smooth muscle [11,13,14,[16][17][18][19]. However, KORENAGA et al [8] found that dog tracheal airway smooth muscle contraction was significantly reduced by 1.2 MAC of halothane only when contraction was indirectly evoked by nerve stimulation.…”

“…SAYINER et al [10] also suggested that volatile anaesthetics could be less effective at preventing contractile responses than at relaxing precontracted preparations (since intracellular mechanisms causing force initiation and force maintenance are different). The results of WIKLUND et al [18], but not those of FUKUSHIMA et al [14], support this hypothesis. It would be also in accordance with the ability of volatile anaesthetics to attenuate calcium sensitisation [15].…”

“…There are many studies available on the relaxant effects produced by volatile anaesthetics directly administered in vitro on isolated airway smooth muscle [8][9][10][11][12][13][14][15][16][17][18][19]. However, few of them have been performed on distal airway smooth muscle [13,16,17,19] or have involved desflurane [13,17,18].…”

“…For example, in dogs in vivo, the direct relaxant effect of halothane on airway smooth muscle contributed as much as the indirect effect on the vagal pathway [4]. These direct relaxant effects in vivo have been reproduced in vitro in many animal studies [8][9][10][11][12][13][14][15][16][17][18][19]. However, the intensity of the relaxation in vitro varies widely among studies.…”