1Department of Anesthesiology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan
It is important for anaesthetists to know how anaesthetic agents that are used clinically can affect airway smooth muscle tone, as patients with airway hyper-reactivity such as asthma or emphysema regularly present for anaesthesia. Hirshman and Bergman1 first reviewed the factors influencing intrapulmonary airway calibre during anaesthesia. Subsequently, many investigators have reported direct and indirect effects of several anaesthetic agents on airway smooth muscle tone, using appropriate and sophisticated techniques. It is essential first to understand the basic physiology of the regulation of airway smooth muscle tone.
Regulation of airway smooth muscle tone
Airway smooth muscle tone is determined by the balance of constrictor and dilator mechanisms, which, in turn, are mediated by receptors and channels on the surface of smooth muscle cells. Activation of these receptors and channels alters the intracellular concentration of free Ca2+ ([Ca2+]i), which itself controls the contractile state of muscle through the Ca2+-dependent stimulation of myosin light chain kinase (MLCK) (Fig. 1E). The active kinase then switches on myosin by phosphorylation of its 20-kDa subunits. However, the sensitivity of Ca2+ is not fixed. It is possible under certain circumstances to increase muscle tone without increasing [Ca2+]i by altering the relationship between [Ca2+]i, and tension.2 At least two cellular mechanisms contribute to increases in [Ca2+]i: Ca2+ release from intracellular stores and Ca2+ influx through cell membrane-associated Ca2+ channels, especially voltage-dependent Ca2+ channels (VDCCs).3 The mechanisms of Ca2+ mobilization depend on the agent inducing the contraction and on the duration of the contractile stimulus. Pharmacological agonists such as acetylcholine initiate contraction by binding to G protein (Gq)-coupled receptors to activate phospholipase C (PLC), which generates inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). The latter activates protein kinase C (Fig. 1D), whereas IP3 mobilizes Ca2+ from the sarcoplasmic reticulum (Fig. 1E). In contrast, agents such as K+ at a high concentration induce contraction by depolarizing the cell membrane in a graded manner with resultant activation of VDCCs. However, entry of extracellular Ca2+ is necessary for maintenance of contraction under both sets of conditions.2
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Each research group in this area has their own research technique. Browns group3 (Johns Hopkins University, USA) and Hirotas group4 (Hirosaki University, Japan) are measuring rather distal airway diameter using high-resolution computed tomography (CT) and superfine fibreoptic bronchoscope techniques, respectively (Fig. 1A). Yamakages group2 5 (Sapporo Medical University, Japan) has succeeded in simultaneously measuring airway smooth muscle tension and [Ca2+]i during exposure to various anaesthetic agents, using a fluorescence technique (Fig. 1B). Warners group6 (Mayo Clinic, USA) is using a skinned fibre technique (Fig. 1B), which can fix [Ca2+]i and measure the Ca2+ sensitivity. Since 1995, Yamakages group7 8 has also been using an electrophysiological technique to clarify the effects of anaesthetic agents on Ca2+ and K+ channels, which regulate Ca2+ influx and membrane potential, respectively (Fig. 1C). The importance of the ß-receptor in asthmatics is currently being investigated by Emalas group9 (Columbia University, USA) using biochemical techniques (Fig. 1D). Other intracellular second messengers, cAMP and IP3, have been investigated, particularly by Shibatas group10 (Nagasaki University, Japan), using radioimmuno/enzyme immunoassay techniques (Fig. 1E). As in other tissues, the mechanisms of action of anaesthetic agents have been clarified over the past decade using these advanced techniques.
Inhibitory actions of volatile anaesthetics on airway smooth muscle
As volatile anaesthetics are potent bronchodilators,1 many investigators have been trying to clarify the mechanisms underlying their actions. Both Yamakage,2 and Warner and colleagues,11 using the Ca2+ indicator fura-2, demonstrated that relaxation of contracted tracheal smooth muscle by volatile anaesthetics at clinically relevant concentrations is associated with a decrease in [Ca2+]i. Although the decrease in [Ca2+]i caused by the volatile anaesthetic seems to be the main mechanism, a decrease in Ca2+ sensitivity because of inhibition of the activity of protein kinase C has also been reported.2 As sustained contraction of airway smooth muscle requires the continued entry of extracellular Ca2+, and as block of VDCCs by dihydropyridines-sensitive Ca2+ channel blockers suppresses the sustained increase in [Ca2+]i in agonist-stimulated tracheal smooth muscle,2 it is natural to suppose that volatile anaesthetics can also inhibit VDCC activity. Yamakage and colleagues12 demonstrated that volatile anaesthetics have an inhibitory effect on whole-cell inward Ca2+ currents through VDCCs of porcine tracheal smooth muscle cells at clinically relevant concentrations, and that the inhibitory potencies of the anaesthetics on the currents are closely related to their lipid-phase solubilities.
Volatile anaesthetics also inhibit initial phasic contraction as well as tonic contraction. It has been suggested that transient Ca2+ release from the sarcoplasmic reticulum because of an agonist-induced increase in the intracellular amount of IP3 is important for phasic contraction. Inhibition of IP3-induced Ca2+ release and a decrease in Ca2+ content in the sarcoplasmic reticulum by volatile anaesthetics have been demonstrated.5 It has also been demonstrated that volatile anaesthetics cause a decrease in the amount of agonist-induced IP3.5
It is known that volatile anaesthetics, such as halothane, enflurane, isoflurane, sevoflurane, and desflurane, have a strong bronchodilatory effect in vitro on airway smooth muscle.1 Isoflurane and desflurane, however, are very pungent, and these anaesthetics might therefore induce an asthmatic attack by facilitating neurally mediated acetylcholine release during anaesthetic induction.13 Halothane has a proarrhythmogenic property, and care should be taken in the use of this anaesthetic agent when using aminophylline simultaneously.
Effects of other anaesthetic agents on airway smooth muscle
All i.v. anaesthetics have, to some degree, in vitro inhibitory effects on airway smooth muscle tone. As with volatile anaesthetics, Yamakage and colleagues7 reported that the i.v. anaesthetics thiopental, ketamine, and propofol inhibited the inward Ca2+ currents through VDCCs of porcine tracheal smooth muscle cells, but with subtle electrophysiological differences. It has also been reported that midazolam inhibited airway smooth muscle contraction by decreasing [Ca2+]i,14 and that diazepam and midazolam had inhibitory effects on VDCCs.8 High concentrations of these agents were, however, necessary to inhibit K+ channels,8 producing membrane depolarization. It has been reported that the lack of antagonistic effects of their antagonists is related to the non--aminobutyric acid-mediated electrophysiological effects of benzodiazepines on airway smooth muscle contractility.8 Unlike volatile anaesthetics, all i.v. anaesthetics were required in rather high concentrations to elicit an inhibitory effect.
As demonstrated in a study by Pizov and colleagues,15 propofol seems to be better than barbiturates for use in asthmatic patients. This might be because of the propofol-induced inhibition of neurally mediated acetylcholine release.3 It has been reported, however, that propofol can induce bronchospasm during anaesthetic induction,16 and the reason for this was suggested to be an allergic reaction or anaphylaxis. However, it would be inappropriate to conclude that propofol should not be used in asthmatic patients. Brown and colleagues17 reported recently that a new formulation of propofol with a metabisulfite preservative also had a bronchodilatory effect but that the preservative had a dramatic effect in reducing propofols ability to attenuate bronchoconstriction.
I.v. lidocaine has a direct relaxant effect on airway smooth muscle contraction by decreasing [Ca2+]i.18 This agent also inhibits neurally mediated acetylcholine release,17 and its use during anaesthesia as a treatment of asthma is, therefore, acceptable.
Protamine is used to reverse heparin anticoagulation, but during this reversal, it may have a number of adverse effects, including bronchoconstriction, which is caused by the generation of anaphylatoxic complements induced by the heparinprotamine complex. In contrast, it has been shown that both protamine and the heparinprotamine complex can inhibit canine tracheal smooth muscle contraction by decreasing [Ca2+]i in vitro.19 These agents decrease the agonist-induced increase in [Ca2+]i by inhibition of VDCCs.19
Different reactivities to volatile anaesthetics in proximal and distal airways
Most studies have focused on the direct effects of anaesthetics on the larger, more proximal airway because of easier access. However, the distal airway, especially between the third and seventh generation bronchi, is important in the regulation of airflow resistance, and a series of studies have shown that there are significant physiological and pharmacological differences between tracheal and bronchial smooth muscles. Mazzeo and colleagues20 demonstrated, by measuring muscle tension, that volatile anaesthetics had a more inhibitory effect on distal airway muscle tone than on proximal airway muscle tone. On the other hand, Croxton and colleagues21 showed that peripheral airway smooth muscle was more resistant to dihydropyridines-sensitive (L-type) VDCC antagonists than was tracheal smooth muscle, indicating that L-type VDCCs are the predominant mechanism for Ca2+ entry in tracheal smooth muscle. Yamakage and colleagues22 demonstrated, using the whole-cell patch clamp technique, that approximately 30% of porcine bronchial smooth muscle cells included T-type VDCCs as well as L-type VDCCs, although tracheal smooth muscle cells had only L-type VDCCs. The same group23 also demonstrated that the volatile anaesthetics, isoflurane and sevoflurane, significantly inhibited the activities of both types of VDCCs in a dose-dependent manner; however, the anaesthetics had greater inhibitory effects on T-type VDCC activity in bronchial smooth muscle. The existence of T-type VDCCs in bronchial smooth muscle and the high sensitivity of this channel to volatile anaesthetics seem to be, at least in part, responsible for the different reactivities to the anaesthetics in tracheal and bronchial smooth muscles.
Isoflurane and sevoflurane inhibited whole-cell K+ currents to a greater degree in tracheal than in bronchial smooth muscle cells.23 More than 60% of the total K+ currents in tracheal smooth muscle, but less than 40% in bronchial smooth muscle, appear to be mediated through delayed rectifier K+ channels. The inhibitory effects of the anaesthetics on the delayed rectifier K+ channels were greater than those on the remaining K+ channels. Different distributions and different anaesthetic sensitivities of K+ channel subtypes could play a role in the different inhibitory effects of the anaesthetics on tracheal and bronchial smooth muscle contractions.
From now on ...
The direct interactions between anaesthetic agents and airway smooth muscle tone have been clarified in considerable detail over the past decade. However, the clinical significance of the results of these basic science studies is another matter. Hirshmans group24 developed a Basenji-Greyhound dog model of asthma in 1980; however, only the effects of local anaesthetics have been investigated using it. Further investigations are needed to clarify the interactions between anaesthetic agents and airway smooth muscle, using easily available and reliable asthmatic models, especially as asthma mortality rates are increasing worldwide.25
References
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