Anesth Analg 2004;98:346-352
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000097169.98992.E7
ANESTHETIC PHARMACOLOGY
Isoflurane Facilitates Hiccup-Like Reflex Through Gamma Aminobutyric Acid (GABA)A- and Suppresses Through GABAB-Receptors in Pentobarbital-Anesthetized Cats
Tsutomu Oshima, MD, and
Shuji Dohi, MD
Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Gifu-City, Japan
Address correspondence and reprint requests to Tsutomu Oshima, MD, Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, 40 Tsukasamachi, Gifu-City, Gifu 500-8705, Japan. Address e-mail to oshimat{at}cc.gifu-u.ac.jp
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Abstract
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The mechanism by which volatile anesthetics exert inconsistent effects on hiccups is unknown. We elicited a hiccup-like reflex by mechanical stimulation of the dorsal epipharynx in mechanically ventilated cats. The magnitude of the hiccup-like reflex was measured as the peak negative esophageal pressure (nPes) generated against an occluded airway. First, we examined the effects of different end-expiratory concentrations of isoflurane on nPes. Second, we determined the effects of 1.0 minimum alveolar anesthetic concentration of isoflurane on nPes after a peripherally restricted gamma aminobutyric acid (GABA)A-receptor antagonist, bicuculline methiodide (BM), a GABAB-receptor antagonist, CGP 35348, a peripherally restricted GABAB-receptor antagonist, CGP 54626, or saline had been administered IV. Third, BM, CGP 35348, or artificial cerebrospinal fluid was administered intracisternally before 1.0 minimum alveolar anesthetic concentration of isoflurane exposure. During isoflurane anesthesia, nPes was inversely proportional to the end-expiratory isoflurane concentration. The rank order of nPes values obtained after IV drug pretreatment and isoflurane exposure was BM < saline < CGP54626 < CGP35348. After intracisternal drug pretreatment and isoflurane administration, the order of nPes was BM < artificial cerebrospinal fluid < CGP35348. Isoflurane modulates the hiccup-like reflex in opposite directions through both central and peripheral GABAA and GABAB receptors, with the net effect being a dose-dependent suppression.
IMPLICATIONS: Isoflurane facilitated the hiccup-like reflex through activation of central and peripheral gamma aminobutyric acid (GABA)A receptors but suppressed it via activation of central and peripheral GABAB receptors. The net result was that the hiccup-like reflex was inhibited in proportion to the alveolar isoflurane concentration.
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Introduction
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Although the use of volatile anesthetics has been implicated as a cause of hiccups during the induction of general anesthesia, a conventional strategy for stopping these hiccups is to increase the inspired concentration of the volatile anesthetic (1,2). The mechanism by which volatile anesthetics exert these apparently inconsistent influences over hiccups is unknown.
Activation of gamma aminobutyric acid (GABA)A receptors by propofol (3), benzodiazepines (4), and barbiturates (5) may facilitate hiccups in humans (6), and the GABAB-receptor agonist baclofen has been established as one of the most effective drugs for the treatment of intractable hiccups (2,7). GABAA (8,9) and GABAB (10,11) receptors have each been identified centrally and peripherally, and sevoflurane reportedly modulates both GABAA and GABAB receptors (12). Isoflurane, a representative volatile anesthetic, has also been demonstrated to share many common mechanisms with IV anesthesia produced by propofol, benzodiazepines, and barbiturates, specifically at the GABAA receptor (13), whereas there is still no information available regarding GABAB receptor-mediated effects of isoflurane. We, therefore, hypothesized that isoflurane may exert the aforementioned conflicting effects on hiccups through central and peripheral GABAA and GABAB receptors while producing an overall suppressant effect on hiccups that may depend on the dose.
We previously demonstrated that a single, patterned motor discharge identical to a hiccup can be reproducibly provoked by mechanical stimulation of the dorsal epipharynx in pentobarbital-anesthetized cats (14). Using this animal model, we performed experiments to test the above hypothesis.
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Methods
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All surgical procedures and experimental protocols were approved by the Animal Care and Use Committee of Gifu University School of Medicine (Gifu, Japan). Experiments were performed on 50 cats weighing 3.0–5.5 kg. The cats were initially anesthetized with intraperitoneal pentobarbital (30 mg/kg). Additional doses (10 mg/kg) were given intraperitoneally as required (to a maximum of 3 doses). The surgical procedure has been described elsewhere (14). A cuffed endotracheal tube (5 mm ID) was inserted below the larynx. To allow access to the epipharynx, a submental opening was made just rostral to the epiglottis. Bipolar twisted stainless-steel wire electrodes, insulated except for 1 mm at the tips, were implanted using a 23-gauge hypodermic needle into the posterior cricoarytenoid muscle (PCA) of the larynx and the costal diaphragm (DIA). The position of the electrode wires was confirmed at the end of the experiment. The electromyogram activity from these muscles was amplified with an AC amplifier (AB621G; Nihon Kohden, Japan). A thin-walled latex balloon was positioned in the middle third of the esophagus and connected to a differential pressure transducer (TP-603T; Nihon Kohden) for measurement of esophageal pressure (Pes) as an index of intrapleural pressure. The right femoral vein was cannulated for continuous infusion of Ringer’s lactate solution and the right femoral artery for measurement of arterial blood pressure and for withdrawal of blood gas samples for analysis using a blood gas analyzer (Stat Profile, Nova Biomedical, Waltham, MA). Rectal temperature was maintained at 36°C–37°C with the aid of a heating bed.
The required mechanical stimulation was applied by means of a cotton-tipped swab advanced through the submental opening. The target region was the dorsal epipharynx behind the uvula, overlying the occipital bone. Mechanical stimulation of this region evoked the fixed motor pattern of a hiccup, which was characterized by a brief powerful inspiratory event accompanied by synchronous activity related to glottic movement towards closure. Figure 1 shows representative changes in the electromyogram activities from PCA and DIA accompanied by changes in Pes obtained during the hiccup-like reflex. Mechanical stimulation at mid-inspiration rapidly inhibited the ongoing PCA activity. Direct observation through the submental opening revealed glottic adduction during this response. The DIA activity exhibited spasmodic bursts consisting of discharges of very large amplitude. During the response, Pes showed a spiky negative pressure swing, a reflection of the DIA activity.
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Figure 1. Example of hiccup-like reflex elicited by mechanical stimulation of dorsal epipharynx in the spontaneously breathing cat. Stimulation (indicated by arrow) was delivered in the midinspiratory phase. PCA = electromyogram activity in posterior cricoarytenoid muscle of the larynx; DIA = electromyogram activity in diaphragm; Pes = esophageal pressure, with inspiration downward.
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After we had identified the trigger site for the hiccup-like reflex, the cats were mechanically ventilated with a mixture of oxygen and air (fraction of inspired oxygen = 0.6) to maintain PaO2 >200 mm Hg, PaCO2 of 22–27 mm Hg, and arterial pH value of 7.40–7.50. The magnitude of the hiccup-like reflex was evaluated by measuring the peak negative Pes generated during the hiccup-like reflex (nPes). During the measurement of this reflex response, the cat was apneic, and the airway was occluded at functional residual capacity. At each measurement period, 10 stimulating trials were applied. Care was taken to ensure that the force and duration of stimulation remained as constant as possible throughout the experiments.
The same protocol was followed in all the mechanically hyperventilated cats. After measurements of nPes, isoflurane was added to the inspiratory gas. After 30 min of isoflurane exposure, nPes was again assessed. Thereafter, the isoflurane was discontinued, and the final nPes measurements were made after a 30-min recovery. Isoflurane was administered using a constant-flow Cyprane Keighley vaporizer (Isotec; Datex-Ohmeda, Hatfield, United Kingdom). Airway gas was sampled at a total flow rate of 90 mL/min from a side port for continuous measurement of carbon dioxide, oxygen, and isoflurane concentrations using a gas analyzer (M1025B; Hewlett Packard, Palo Alto, CA) connected in series. An end-expiratory concentration of 1.63% was taken as 1 minimum alveolar anesthetic concentration (MAC) for isoflurane in cats (15).
Experiment 1
Fifteen mechanically hyperventilated cats were divided into 3 equal groups, according to the end-expired concentration of isoflurane that was maintained at 0.5 MAC, 1 MAC, or 1.5 MAC.
Experiment 2
Twenty mechanically hyperventilated cats were divided into 4 equal groups according to IV administered drug: bicuculline methiodide (BM) (20 µmol/kg), CGP35348 (45 µmol/kg), CGP54626 (20 µmol/kg), or saline. The test drug was administered after preliminary measurements of nPes. Control measurements of nPes at 10-min postinjection were followed by administration of 1.0 MAC of isoflurane using the aforementioned experimental protocol.
Experiment 3
Fifteen mechanically hyperventilated cats were divided into 3 equal groups according to the intracisternally-administered drug: BM (50 nmol), CGP35348 (200 nmol), or artificial cerebrospinal fluid (CSF). The cat was fixed prone in a stereotaxic frame for intracisternal catheterization and thereafter was returned to the supine. The test drug was administered after preliminary measurements of nPes. Control measurements of nPes at 10-min postinjection were followed by the administration of 1.0 MAC of isoflurane using the aforementioned experimental protocol. The drug was dissolved in mock artificial CSF (NaCl 146.5 mM, KCl 3.5 mM, CaCl2 1.3 mM, MgCl26H2O 1.14 mM, NaH2PO42H2O 0.15 mM, urea 1.1 mM, glucose 3.4 mM, and NaHCO3 3.5 mM). The pH value of the solution was adjusted to 7.2–7.4, and the osmolarity was approximately 300 mosmol/kg H2O. A volume of CSF equal to the amount of drug solution plus the volume for flushing the cannula was withdrawn and discarded before the drug administration. In all experiments, cannula placement and drug distribution were confirmed by infusion of acridine orange and postmortem examination of the brain.
BM was obtained from Sigma Chemical (St. Louis, MO). CGP35348 and CGP54626 were purchased from Tocris Cookson (Bristol, United Kingdom).
In Experiments 2 and 3, nPes was expressed as a percentage of the mean nPes obtained in the control period in each cat (%nPes) as well as raw data. Data were analyzed by means of Bonferroni’s multiple comparison tests after a one-way analysis of variance. In all tests, a value of P < 0.05 was considered statistically different. Group data are presented as the mean ± SD, unless otherwise indicated.
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Results
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Experiment 1
As shown in Figure 2, during isoflurane anesthesia, nPes was significantly smaller at 1.5 MAC than at 1.0 MAC (P < 0.001) and significantly smaller at 1.0 MAC (P < 0.001) and 1.5 MAC (P < 0.001) than at 0.5 MAC. Thus, nPes was inversely proportional to the isoflurane concentration. After a 30-min recovery from isoflurane exposure, nPes was significantly smaller in the group exposed to 1.5 MAC than in that exposed to 0.5 MAC (P < 0.001). During the period of exposure, mean arterial blood pressure (MAP) tended to be inversely proportional to the isoflurane concentration with a statistically significant difference between the 0.5 MAC and 1.5 MAC groups (P = 0.002) (Table 1).
Experiment 2
After an IV injection of the test drug but before isoflurane administration, nPes was significantly smaller in the BM group than in the saline group (P < 0.001) (Table 2). During isoflurane anesthesia, nPes was significantly larger: (a) in the groups treated with saline (P = 0.023), CGP35348 (P < 0.001), or CGP54626 (P < 0.001) than in the BM group, (b) in the groups treated with IV CGP35348 (P < 0.001) or CGP54626 (P < 0.001) than in the saline group, and (c) in the group treated with CGP35348 than in the CGP54626 group (P < 0.001). When the data were expressed in terms of %nPes, the findings were similar (Fig. 3).
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Figure 3. Effects of IV administered gamma aminobutyric acid (GABA)A- or GABAB-antagonists on isoflurane-induced suppression of the peak negative esophageal pressure (%nPes) (mean ± SD). The rank order of %nPes values obtained during isoflurane anesthesia was bicuculline methiodide (BM) < saline < CGP54626 < CGP35348. *P < 0.001 versus saline; **P = 0.028 versus saline and P < 0.001 versus CGP35348 and CGP54626; ***P < 0.001 versus saline and CGP35348. %nPes is expressed as a percentage of the mean absolute value obtained for the peak negative esophageal pressure swing during the hiccup-like reflex in 10 control stimulating trials, i.e., after administration of the test drug but before isoflurane exposure in the same animal. Total number of stimulating trials at each measurement period was 10 x 5 (cats) = 50.
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Experiment 3
After intracisternal injection of the test drug but before isoflurane administration, nPes was significantly smaller in the BM group than in the artificial CSF (P < 0.001) or CGP35348 (P = 0.003) group (Table 2). During isoflurane anesthesia, nPes was significantly larger: (a) in the groups treated with artifical CSF (P = 0.009) or CGP35348 (P < 0.001) than in the BM group and (b) in the group with CGP35348 than in the artifical CSF group (P < 0.001). When the data were expressed in terms of %nPes, the findings were similar (Fig. 4). After injection of the test drug but before isoflurane administration, MAP was significantly greater in the BM group than in the artificial CSF group (P = 0.012) (Table 1).
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Figure 4. Effects of intracisternally administered gamma aminobutyric acid (GABA)A- or GABAB-receptor antagonists on isoflurane-induced suppression of the peak negative esophageal pressure (%nPes) (mean ± SD). The rank order of %nPes values obtained during isoflurane anesthesia was bicuculline methiodide (BM) < artificial cerebrospinal fluid (CSF) < CGP35348. *P < 0.001 versus artificial CSF; **P = 0.011 versus artificial CSF and P < 0.001 versus CGP35348. %nPes is expressed as a percentage of the mean absolute value obtained for the peak negative esophageal pressure swing in 10 stimulating control trials, i.e., after the administration of the test drug but before isoflurane exposure in the same animal. Total number of stimulating trials at each measurement period was 10 x 5 (cats) = 50.
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Discussion
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This study provides the first evidence that isoflurane modulates hiccups in opposite directions through GABAA- and GABAB-receptors. The inhibitory effect of isoflurane on nPes was augmented by the GABAA-receptor antagonist BM but antagonized by the GABAB-receptor antagonists CGP35348 and CGP54626. Furthermore, this provides a study rationale for the conventional treatment of hiccups by increasing the inspired concentration of volatile anesthetics because the value of nPes recorded during a hiccup-like reflex was inversely proportional to the end-expiratory concentration of isoflurane.
Receptors for GABAA (8,9) and GABAB (10,11) are among the most abundant receptors known, and they have been identified both centrally and peripherally. Moreover, both GABAA- and GABAB-receptors seem to be sensitive to volatile anesthetics because sevoflurane modulates both receptors in rat hippocampus (12). Central administration of antagonists is a standard approach used to evaluate the site of action of systemically administered drugs, although the antagonists must be administered at doses that are inactive when given systemically (16). The dose of BM used here for intracisternal injection was selected on the basis of neurophysiological studies demonstrating that in cats, the application of 5–25 µg of BM to the medullary ventral surface reversed the effects of GABA (17). In the present study, intracisternal BM increased MAP more markedly than IV BM, whereas neither triggered convulsions. However, the dose of CGP35348 used for intracisternal injection was selected on the basis of pharmacologic evidence that intracerebroventricular administration of 10 µg ofCGP35348 completely blocked the antitussive activity of baclofen in guinea pigs (16).
In this study, BM, which probably does not penetrate the blood-brain barrier (BBB) (18,19), augmented the isoflurane-induced decrease in nPes whether delivered by IV or intracisternal administration. The dose of intracisternal BM was 1200-times smaller than the effective systemic dose. IV BM should antagonize peripheral GABAA receptors. Moreover, intracisternal BM should reverse central GABAA receptors. Therefore, these findings indicate that isoflurane facilitates the hiccup-like reflex through activation of both central and peripheral GABAA receptors. Nevertheless, there are several limitations of our study regarding the administration of BM. First, the validity of BM as a peripherally restricted GABAA receptor antagonist has to be considered. Several animal experiments indicate that BM does not cross the BBB in adult animals but possibly penetrates only in the immature (18,19). In our study, only adult cats were used, and no convulsions were observed after IV BM. Therefore, IV administered BM was unlikely to penetrate the BBB in this study. Second, BM has been demonstrated as a blocker of posthyperpolarizations mediated by Ca2+-activated K+ channels as well as a GABAA receptor antagonist (20). Although there is less than a 10-fold difference between the half-maximal inhibitory concentrations (IC50s) for the two effects, BM is more potent on GABAA receptors. Although the possible involvement of Ca2+-activated K+ channels cannot be excluded, the present study strongly suggests the involvement of GABAA receptors in the generation of hiccup-like reflex during isoflurane anesthesia.
We also found that the isoflurane-induced decrease in nPes was completely antagonized by IV CGP35348, which easily passes the BBB (21), but only partially blocked by intracisternal CGP35348 or by IV CGP54626, which does not cross the BBB (22). The dose of intracisternal CGP35348 was 600-times smaller than the effective systemic dose. IV CGP35348 should antagonize both central and peripheral GABAB receptors, whereas intracisternal CGP35348 should antagonize central GABAB receptors. However, IV CGP54626 should antagonize peripheral GABAB receptors. On this basis, our findings indicate that isoflurane suppresses the hiccup-like reflex via activation of both central and peripheral GABAB receptors.
Because of the design of this study, we were examining ipso facto the combined effects of isoflurane and pentobarbital. Pentobarbital, which also acts on GABAA receptors (5), most likely facilitates hiccups. Indeed, both IV and intracisternal BM decreased nPes when our cats were only under pentobarbital anesthesia, i.e., before the administration of isoflurane. These findings indicate that pentobarbital itself facilitates the hiccup-like reflex through both central and peripheral GABAA receptors. In Experiment 1, the facilitating effect of pentobarbital was unlikely to have confounded the intergroup comparisons because the 3 groups would have been equally affected by pentobarbital. However, in the BM groups in Experiments 2 and 3, the low level of nPes seen under isoflurane most likely included a BM-induced decrease in the facilitating effect of pentobarbital as a GABAA-receptor agonist. To try to exclude this confounding factor, we also used %nPes, i.e., nPes values expressed as a percentage of the control nPes in Experiments 2 and 3. In fact, our findings were essentially the same whether %nPes or nPes was used as the index. However, the two GABAB receptor antagonists CGP35348 and CGP54626 exerted no significant influences over the hiccup-like reflex in pentobarbital-anesthetized cats, i.e., before the isoflurane administration. These findings indicate that pentobarbital itself exerts no significant effects on the hiccup-like reflex through central or peripheral GABAB receptors.
Our previous study, using the same model, showed that both the phase of the respiratory cycle and the presence of hypercapnia affect the amplitude of the hiccup-like reflex (14). To exclude these confounding influences, the cats in the present study were mechanically ventilated to maintain hypocapnia and suppress spontaneous respiration. We have also previously demonstrated that the hiccup-like reflex evoked by electrical stimulation of a locus in the medullary reticular formation (23) is suppressed after microinjection of the GABAB-receptor agonist baclofen into the hiccup-evoking area of the medulla (24). This finding suggests that the centrally evoked hiccup-like reflex can be inhibited through GABAB receptors located within the central portions of the putative hiccup reflex arc. In the present study, peripheral effects were likely more evident because we examined the effects of systemically administered isoflurane on the peripherally elicited hiccup-like reflex.
In Experiment 1, the values of nPes recorded during isoflurane anesthesia were inversely proportional tothe end-expiratory isoflurane concentration. Possibly, this finding may be attributable not only to the aforementioned GABAergic effects, but also to other undetermined factors such as a dose-dependent impairment of neuromuscular transmission (25) and reduced tissue perfusion, as might occur because of a proportional decrease in MAP. Further studies are required to examine the possible contributions of these non-GABAergic mechanisms to hiccup modulation during isoflurane anesthesia.
In conclusion, in the cat, isoflurane facilitates the hiccup-like reflex through activation of central and peripheral GABAA receptors but suppresses it via activation of central and peripheral GABAB receptors. However, the net result is that the hiccup-like reflex is inhibited in proportion to the alveolar isoflurane concentration.
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Acknowledgments
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Supported, in part, by Grant-in-Aid 12671460 from Japan Society for the Promotion of Science.
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Accepted for publication September 9, 2003.
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Abstract
Introduction
P < 0.001 versus control and recovery in the same MAC group; 
P < 0.001 versus control in the 1.5 MAC group; #P < 0.001 versus recovery in the 0.5 MAC group; nPes = the peak negative esophageal pressure generated during the hiccup-like reflex. At each measurement period, 10 stimulating trials were applied. Total number of stimulating trials at each measurement period was 10 x 5 (cats) = 50.
