In two ring preparations, single doses of LTC4 (10−8 mol/L) were applied. 10−8 mol/L was close to the 50% effective dose (ED50) of LTC4 and produced a contractile response in the range 100%–200% of contractile response to nerve stimulation. Ten minutes was allowed for stabilization of contractile response to LTC4. This stabilized response was used as a control contractile response and set at 100%.
A volatile anesthetic was added to one of the tissue baths, whereas the other served as control for the effect of time. Volatile anesthetics relaxed the bronchial rings with a slow onset such that a stabilized effect resulted after 20 min.
Desflurane, sevoflurane, and halothane were added, via vaporizers, to the gas aerating the PSS. Concentrations of anesthetics were measured by gas chromatography, with a Varian gas chromatograph 7400, as described previously (13). Effects were studied at 1.0 minimum alveolar anesthetic concentration (MAC). Halothane was also studied at 2.0 MAC. With our experimental setup, larger concentrations than 1.0 MAC in the PSS were not achievable for desflurane and sevoflurane using maximal concentration from vaporizers with maximal aerating intensity in tissue chambers.
Acetylcholine chloride, atropine sulfate, propranolol hydrochloride, and tetrodotoxin were purchased from Sigma (St Louis, MO). NKA was from Scientific Marketing Associates (Barnet, Herts, United Kingdom), and LTC4 was purchased from Cascade Biochem Ltd (Reading, Berkshire, United Kingdom). SR48968 was a kind gift from Sanofi Recherche (Montpellier, Cédex, France). Sevoflurane and desflurane were kind gifts from Abbott (Abbott Park, IL) and Pharmacia & Upjohn (Peapack, NJ), respectively. Halothane was purchased from Zeneca AB (Gothenburg, Sweden). The study was supported by Abbott and Pharmacia & UpJohn.
Contractile responses in bronchial rings exposed to volatile anesthetics were compared with responses in rings not exposed to volatile anesthetics. In rings exposed to volatile anesthetics, control contractile responses to NKA and LTC4 were adjusted for the effect of time as described before (13). Responses to EFS were adjusted to the effect of time accordingly. Experimental data were expressed as mean ± sd. Statistical analysis was performed with SPSS (Chicago, IL) for windows. Statistical significance was tested with repeated-measures analysis of variance or Student’s t-test for paired or unpaired variables. P < 0.05 was regarded as statistically significant.
Pretreatment with atropine (10−6 mol/L) and propranolol (10−6 mol/L) did not significantly affect the action by volatile anesthetics on the slow phase of contractile responses to nerve stimulation. Neither did pretreatment with SR48968 (10−6 mol/L) significantly affect the action by volatile anesthetics on the rapid phase of contractile responses to nerve stimulation. Therefore, experiments on responses to EFS were performed in the absence of atropine and propranolol or SR48968. Concentrations of anesthetics were normalized to guinea pig MAC values of approximately 6% for desflurane, 1% for halothane, and 2% for sevoflurane (13). Equianesthetic concentrations were used, and only one concentration of volatile anesthetic was given to each muscle preparation.
Desflurane, halothane, and sevoflurane inhibited contractile responses to EFS in a reversible manner (Figs. 1 and 3). All three anesthetics inhibited both phases of contractile responses to EFS. The rapid atropine-sensitive contraction was more efficiently inhibited by halothane than by sevoflurane or desflurane (Fig. 3A). The NANC phase of contractile responses to EFS was equally inhibited by all three anesthetics (Fig. 3B).
Cumulative dose-response curves for NKA (10−9–10−7 mol/L) showed an ED50 of 3.8 ± 1.6 × 10−8 mol/L. A second group of cumulative dose-response curves were performed during exposure for sevoflurane or desflurane at 1.0 MAC or halothane at 1.0–2.0 MAC (Fig. 4; data for sevoflurane and halothane not shown). None of the volatile anesthetics had any effect on ED50 or efficacy, i.e., force development.
Cumulative dose-response curves to LTC4 (10−9–10−7 mol/L) revealed an ED50 of 6.6 ± 9.9 × 10−9 mol/L. Subsequent cumulative dose-response curves were performed after incubation with sevoflurane or desflurane at 1.0 MAC or halothane at 1.0–2.0 MAC (Fig. 5; data for halothane and desflurane not shown). The volatile anesthetics did not significantly affect ED50 or efficacy, i.e., force development.
In bronchial rings precontracted submaximally with LTC4 (10−8 mol/L), sevoflurane and desflurane at 1.0 MAC induced a slow relaxation. Halothane (1.0–2.0 MAC) did not significantly affect the contractile response to LTC4 (Fig. 6).
The principal findings in this study were that halothane, sevoflurane, and desflurane inhibited contractile responses to cholinergic and NANC neurotransmission. Sevoflurane and desflurane relaxed airway smooth muscle during steady-state contraction by LTC4, whereas halothane did not.
Some volatile anesthetics, for example, isoflurane and desflurane, irritate airways in awake patients. During anesthesia, sevoflurane decreases airway resistance more efficiently than halothane and isoflurane (14). Desflurane increases airway resistance after tracheal intubation in smokers (15). The lack of influence by sympathetic and parasympathetic nerves in isolated smooth muscle may explain why desflurane relaxes bronchial smooth muscle in vitro and increases airway resistance in vivo.
Excitatory NANC nerves may induce bronchoconstriction (NK2 receptors), mucus secretion, vasodilation, and vascular hyperpermeability (NK1 receptors) (7). In this study, contractile responses to EFS were attenuated by volatile anesthetics. Possible explanations include inhibition of transmitter release, reduced receptor activation, or interaction with intracellular contractile processes. We found sensitivity to NKA to be unaltered by anesthetics. In previous studies, volatile anesthetics inhibited contractile responses to EFS (13) and excitatory junction potentials (16) without alteration of acetylcholine sensitivity. Halothane inhibited acetylcholine release from preganglionic nerve terminals (17). These investigations support our suggestion of reduced transmitter release. Possible cellular sites of action are blocks of interaction between transmitter containing vesicles and synaptic membranes, stabilization of the axonal membrane, or depressed intracellular Ca2+ mobilization (13).
Neurogenic inflammation can be modulated via altered release of sensory neuropeptides (7). In the current study, the lack of effect by volatile anesthetics on sensitivity to NKA is compatible with the suggestion that they do not affect NK2 receptor activation or intracellular processes responsible for the initiation of NK2 receptor-mediated contraction.
Leukotrienes are produced in increased amounts in airways of asthmatics. They produce bronchoconstriction, recruit inflammatory cells, and enhance excitability of airway sensory nerves (18). Anesthetics did not alter sensitivity to LTC4. Our results are consistent with the suggestion that volatile anesthetics did not influence activation of leukotriene receptors or intracellular processes responsible for the initiation of contractile responses to LTC4. Tudoric et al. (6) reported inhibitory effects by halothane and isoflurane on contractile responses to allergen and leukotriene D4 in vitro. Passive sensitization enhanced LTC4 release and sensitivity in human isolated bronchi (19). We used tissue from nonsensitized animals, whereas Tudoric et al. (6) used sensitized animals, which may explain the different results. This would be of interest in a discussion of drug choice in allergy-mediated bronchoconstriction and in nonallergic bronchial hyperreactivity.
The lack of effect by anesthetics on initiation of contractile response to LTC4 and relaxation of steady-state contraction induced by LTC4 may seem contradictory. Initiation and maintenance of contractile response to muscarinic stimulation may be linked to different intracellular mechanisms. Rapidly cycling phosphorylated cross bridges are responsible for muscle shortening and slowly cycling dephosphorylated cross bridges for maintenance of steady-state tone (20). Separate intracellular processes for initiation and maintenance of leukotriene-mediated contractions are likely. We suggest that sevoflurane and desflurane act on intracellular mechanisms responsible for the maintenance of contractions induced by LTC4, most likely on slowly cycling intracellular cross bridges. Halothane is structurally different from both sevoflurane and desflurane, suggesting different affinity for single or multiple sites of membrane bound proteins (21,22) such as ion channels, which might explain the different effects on contractile response to LTC4. Co-administration of sevoflurane or desflurane and halothane might reduce the relaxing effect on LTC4-induced bronchoconstriction.
In summary, halothane, sevoflurane, and desflurane attenuated airway smooth muscle tone via inhibition of cholinergic and NANC neurotransmission, most likely via both pre- and postjunctional mechanisms. Sevoflurane and desflurane both reduced LTC4-induced bronchoconstriction, whereas halothane did not. The relaxing effects by sevoflurane and desflurane on contraction induced by the asthmatic mediator LTC4 suggest a beneficial role in the treatment of asthmatic patients.
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