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Anesth Analg 2007; 105:1644-1649
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000286178.98799.cd
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ANESTHETIC PHARMACOLOGY

The Anesthetic Effects of Etomidate: Species-Specific Interaction with {alpha}2-Adrenoceptors

Andrea Paris, MD*, Lutz Hein, MD{dagger}, Marc Brede, MD{ddagger}, Philipp-Alexander Brand, MD*, Jens Scholz, MD*, and Peter H. Tonner, MD*

From the *Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel; {dagger}Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Freiburg im Breisgau; and {ddagger}Department of Anaesthesia and Critical Care, University of Wuerzburg Hospitals, Wuerzburg, Germany.

Address correspondence and reprint requests to Andrea Paris, MD, Department of Anaesthesiology and Intensive Care Medicine, University Hospital Schleswig-Holstein, Campus Kiel Schwanenweg 21, D-24105 Kiel, Germany. Address e-mail to paris{at}anaesthesie.uni-kiel.de.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: The IV anesthetic, etomidate, has structural and clinical similarities to specific {alpha}2-adrenoceptor agonists such as dexmedetomidine. We investigated whether the sedative effects of etomidate may be mediated by {alpha}2-adrenoceptors.

METHODS: The anesthetic potency of etomidate (1–20 µM) was determined in Xenopus laevis tadpoles in the absence and presence of the specific {alpha}2-adrenoceptor antagonist atipamezole (10 µM). Anesthesia was defined as loss of righting reflex. Nonlinear logistic regression curves were fitted to the data and half-maximal effective concentrations and the slopes of the curves were calculated. Additionally, sedative/ hypnotic effects of etomidate (8 mg/kg IP) were studied by rotarod test in wild-type (WT) mice and mice carrying targeted deletions of the {alpha}2A-adrenoceptor gene ({alpha}2A-KO). Data are presented as mean ± sem.

RESULTS: The fraction of anesthetized tadpoles increased with increasing concentrations of etomidate. Atipamezole significantly increased the half-maximal effective concentration of etomidate (4.5 ± 0.2 µM; slope: 2.6 ± 0.3) to 8.4 ± 0.4 µM (slope: 2.3 ± 0.3). Etomidate resulted in time-dependent sedative effects in all mice, as assessed by rotarod performance. In WT mice, the sedative effects of etomidate were not decreased by atipamezole (2 mg/kg). Consistently, etomidate-induced sedation was not reduced in {alpha}2A-KO animals compared with WT mice.

CONCLUSIONS: The sedative effects of etomidate exhibit a species-specific interaction with {alpha}2-adrenoceptors. Although the decrease in potency of etomidate by atipamezole may be caused by an interaction with {alpha}2-adrenoceptors in X. laevis tadpoles, results in mice indicate that the hypnotic effect of etomidate does not require {alpha}2-adrenoceptors.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Etomidate, a potent, short-acting hypnotic, was introduced into clinical anesthesia in 1973 (1). The chemical structure of the carboxylated imidazole etomidate exhibits distinct similarities to specific {alpha}2-adrenoceptor agonists belonging to the class of imidazole compounds (Fig. 1), such as clonidine and dexmedetomidine (2). In addition, both etomidate and {alpha}2-adrenoceptor agonists induce sedation/hypnosis with only minimal respiratory depression, providing a potentially beneficial clinical profile (1,3,4).


Figure 123
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  		Figure 1. Chemical structure of etomidate and the {alpha}2-adrenoceptor agonists dexmedetomidine and clonidine.

 

In humans, the anesthetic effect of etomidate is thought to be mediated primarily through an action on {gamma}-aminobutyric acid type A (GABAA) receptors (5,6). However, like other general anesthetics, the exact mechanisms of its action remain to be shown.

Three subtypes of human {alpha}2-adrenoceptors ({alpha}2A, {alpha}2B, and {alpha}2C) have been characterized pharmacologically and by cloning of their cDNAs (7). In a previous study in mice (8), we demonstrated that etomidate interacts with {alpha}2-adrenoceptors and displaces the specific {alpha}2-adrenoceptor antagonist [3H]-RX821002 in HEK293 cells from all subtypes in a concentration-dependent manner. In vitro, it has been shown that etomidate acts as an agonist at {alpha}2-adrenoceptors, leading to an {alpha}2B-adrenoceptor-mediated increase in arterial blood pressure in vivo (8). However, interactions of etomidate-induced sedation with the {alpha}2-adrenoceptor system have not been studied in detail. In mice, the sedative effect of {alpha}2-adrenoceptor activation has been well characterized by pharmacological studies and by investigations in transgenic mouse models (7,9,10) and is almost exclusively mediated by the {alpha}2A-adrenoceptor subtype (9). As determined by loss of righting reflex (LRR), the anesthetic action of etomidate did not differ between wild-type (WT) mice and mice carrying targeted deletions of the {alpha}2A-adrenoceptor gene (8). However, LRR is a relatively crude, but also robust, measure that requires large doses inducing profound hypnotic actions in mice. Thus, subtle effects resulting from an interaction of etomidate with {alpha}2-adrenoceptors besides other mechanisms, such as GABA-mediated sedation/hypnosis, may have not been detected because of limited sensitivity of the test. To further elucidate if the sedative action of etomidate might at least be partially mediated by {alpha}2-adrenoceptors in mice, we studied etomidate at doses not inducing a LRR by placing mice on a rotarod.

In addition, to test the hypothesis that {alpha}2-adrenoceptors have a role in etomidate-induced sedation, we studied the effect of the specific {alpha}2-adrenoceptor antagonist, atipamezole, on etomidate requirements in Xenopus laevis tadpoles. This model is well suited to determine anesthetic requirements because steady-state conditions are readily attained and the concentrations at which anesthetics exert their action in tadpoles are similar to that of mammals, including humans (11).


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
All experiments were performed after approval of the local animal care committee.

Anesthetic Requirements of Etomidate in X. laevis Tadpoles
In preceding dose-finding experiments, tadpoles (10 animals per concentration) were exposed to the specific {alpha}2-adrenoceptor antagonist atipamezole (1, 5, and 10 µM) in the presence of a half-maximal effective concentration (EC50) dose of dexmedetomidine (12). Testing was performed as described for etomidate. The specific {alpha}2-adrenoceptor antagonist, atipamezole, in a concentration of 10 µM, completely antagonized the anesthetic effect of an EC50 dose of the specific {alpha}2-adrenoceptor agonist, dexmedetomidine, in tadpoles (12). Thus, we chose a dose of 10 µM atipamezole for experiments of the present study.

The anesthetic potency of etomidate (1–20 µM) was determined in the absence and presence of the specific {alpha}2-adrenoceptor antagonist, atipamezole (10 µM). Experiments were performed with early prelimb-bud tadpoles about 1 cm in length, as previously described in detail (12,13). Anesthesia was defined as LRR. Briefly, at least 10 animals per concentration were exposed to the anesthetic solutions. Starting after 10 min, the tadpoles were tipped with a flame-polished glass pipette. The inability of an animal to right itself within 5 s was scored as anesthesia. Testing was repeated every 10 min for 120 min to ensure that steady-state conditions were attained. After achieving equilibrium conditions, concentration-response curves were determined with at least eight different concentrations of etomidate. Experiments were repeated three times and data were pooled. No tadpole was used for more than one experiment.

Further control experiments investigated the effect of atipamezole (10 µM) on the anesthetic potency of the barbiturate, thiopental. Experiments were performed as described for etomidate. The anesthetic potency of thiopental in tadpoles has been characterized previously (13).

Sedative Effects of Etomidate in Mice
Adult WT mice and transgenic mice lacking the {alpha}2A-adrenoceptor subtype were used for the experiments (weight 18–27 g). The generation of mouse lines lacking the {alpha}2A-adrenoceptor subtype has been described previously (14). The genotype was confirmed by subtype-specific polymerase chain reactions performed with genomic DNA isolated from small tail biopsies (15). Mice were housed in groups (five animals per cage) in a specified pathogen-free facility with a 12-h light–dark cycle and given free access to water and food.

WT mice (n = 10) and transgenic mice lacking the {alpha}2A-adrenoceptor subtype ({alpha}2A-KO, n = 10) were used in all experimental groups. According to previous experiments (8), intraperitoneal etomidate doses between 5 and 10 mg/kg were tested for dose finding. Whereas 5 mg/kg etomidate did not result in reliable sedative effects in all mice, 10 mg/kg of etomidate resulted in a long lasting profound hypnotic effect and LRR in almost 30% of mice (8). The aim of our study was to investigate etomidate at doses not inducing a LRR so the mice could be placed on a rotarod. Thus, we chose a dose of 8 mg/kg etomidate to investigate the sedative effects of etomidate in WT and {alpha}2A-KO mice.

In a first set of experiments, WT and {alpha}2A-KO animals received etomidate (8 mg/kg). In a second set of experiments, the specific {alpha}2-adrenoceptor antagonist, atipamezole, (2 mg/kg) was injected 30 min before the injection of etomidate (8 mg/kg). Previous experiments showed that the dose of atipamezole used in this study reverses {alpha}2-adrenoceptor-mediated effects in mice, as assessed by LRR (16).

All drugs were administered IP (0.1 mL/10 g body weight) and animals were weighed on the day of experimentation for calculation. Each mouse was studied with the two drug regimen (Group 1: etomidate, Group 2: etomidate plus atipamezole). Animals had at least 2 days to recover from injections before a new experiment was begun.

Sedation was assessed by a rotarod test. All animals were trained to remain on the rotarod for at least 60 s before the experiments. The rotarod (Ugo Basile, Varese, Italy), consisting of a gritted plastic roller flanked by two large round plates to prevent the animal from moving sideways, was run at a constant speed of 16 rpm. The time each mouse stayed on the rotarod was recorded as the endurance time by an investigator blinded with respect to the genotype of the mice. The mean of three trials was calculated as rotarod time at a defined time point. A maximum of 60 s was allowed for each animal. In experiments using atipamezole, baseline rotarod performance was recorded 25 min after administration of atipamezole. Rotarod performance was assessed 2, 5, 10, and 15 min after injection of etomidate.

Statistics
Statistical analysis was performed with commercially available software (GraphPad Software, San Diego, CA). Concentration-response curves were generated according to the method of Waud for quantal biological responses (17). EC50 as well as slopes of the curves were calculated and reported as mean ± sem. For comparison of experiments, variances in EC50 were calculated from the sem, the sum yielding the estimated variance of the difference in EC50. The ratio of the difference to the sem was then referred to as a standard normal distribution. The Bonferroni correction was used to correct for multiple comparisons.

Multiple analysis of variance (MANOVA) factoring for time, genotype and presence or absence of atipamezole was used with appropriate posttesting to analyze the effects of the different sedative regimens within a treatment group and to compare the sedative effects of etomidate or etomidate plus atipamezole, respectively, between mice of different genotypes (WT and {alpha}2A-KO mice, respectively). Results are presented as mean ± sem. A value of P < 0.05 was considered statistically significant.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Anesthetic Requirements of Etomidate in X. laevis Tadpoles
With increasing concentrations of etomidate the fraction of anesthetized animals increased in the presence and absence of the specific {alpha}2-adrenoceptor antagonist, atipamezole (10 µM). The logistic concentration-response plots exhibited sigmoidal curves (Fig. 2). Calculation of the EC50 of etomidate yielded a value of 4.5 ± 0.2 µM (slope: 2.6 ± 0.3) which increased significantly to 8.4 ± 0.4 µM (slope: 2.3 ± 0.3) in the presence of atipamezole. Atipamezole alone did not alter the behavior of the tadpoles as assessed by LRR.


Figure 223
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  		Figure 2. Concentration-response curves for loss of righting reflex (LRR) in Xenopus laevis tadpoles in presence of etomidate (•) and etomidate plus the specific {alpha}2-adrenoceptor antagonist atipamezole ({blacktriangleup}). Each data point represents the mean response for an average of at least 10 tadpoles. The half-maximal effective concentration (EC50) of etomidate (1–20 µM) is 4.5 ± 0.2 µM (slope: 2.6 ± 0.3). The EC50 of etomidate plus atipamezole (10 µM) is 8.4 ± 0.4 µM (slope: 2.3 ± 0.3).

 

In control experiments, calculation of the EC50 for the barbiturate thiopental yielded a value of 25.5 ± 2.0 µM (13) which was not significantly different in the presence of atipamezole (23.1 ± 3.2 µM, data not shown).

Sedation/Hypnosis Induced by Etomidate in Mice
Etomidate (8 mg/kg) resulted in time-dependent sedative effects in all mice (Fig. 3). Sedation peaked 2 min after injection in all mice and rotarod time was 11.9 ± 7.0 s (P < 0.05 versus baseline) in WT mice and 1.5 ± 0.4 s (P < 0.05 versus baseline) in {alpha}2A-KO mice, respectively. The sedative effects declined afterwards. Rotarod performance was longer impaired in {alpha}2A-KO mice compared with WT mice and was similar to baseline 10 min (WT mice) and 15 min ({alpha}2A-KO mice) after injection of etomidate, respectively.


Figure 323
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  		Figure 3. Effects of etomidate (8 mg/kg) alone and etomidate plus atipamezole (2 mg/kg, injected 30 min before etomidate), on rotarod performance in wild-type (WT) mice and mice lacking {alpha}2A-adrenoceptor subtypes ({alpha}2A-KO). Atipamezole (Atip) and etomidate were injected IP into mice (n = 10 per genotype) and sedation was assessed by rotarod time. Deletion of the {alpha}2A-adrenoceptor subtype did not reduce the sedative/hypnotic effect of etomidate compared with WT mice. Administration of the specific {alpha}2-adrenoceptor antagonist atipamezole did not reduce the sedative effect of etomidate in {alpha}2A-KO mice and even increased sedative effects of etomidate in WT mice (5 min after injection of etomidate). Data presented as mean ± sem *P < 0.05 versus baseline, #P < 0.05 etomidate versus etomidate plus atipamezole in WT mice.

 

To investigate the interaction of etomidate with {alpha}2-adrenoceptors, we next tested whether the sedative action of etomidate is influenced by the specific {alpha}2-adrenoceptor antagonist, atipamezole, that was administered 30 min before etomidate and has been shown to interact with all receptor-subtypes (Fig. 3). Administration of atipamezole alone did not alter rotarod performance compared to animals without treatment. Atipamezole plus etomidate resulted in time-dependent sedative effects that peaked 5 min after injection of etomidate (WT mice: rotarod time 1.6 ± 0.5 s, P < 0.05 versus baseline; {alpha}2A-KO mice: 1.5 ± 0.4 s, P < 0.05 versus baseline). Rotarod performance was more impaired in WT mice after etomidate plus atipamezole compared with etomidate alone 5 min after injection (P < 0.05). Additionally, rotarod performance was impaired longer after administration of atipamezole compared with etomidate alone in WT mice, and was similar to baseline 15 min after injection.


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The results of the present study show that the specific {alpha}2-adrenoceptor antagonist, atipamezole, increases the EC50 of etomidate in X. laevis tadpoles by 87%, indicating that this reduction in potency by atipamezole may be caused by an interaction of etomidate with {alpha}2-adrenoceptors. In contrast, etomidate-induced sedation was not reduced in mice lacking the {alpha}2A-adrenoceptor subtype compared with WT mice. Consistently, sedative effects of etomidate were not decreased by atipamezole in WT-mice, but even seemed to be more pronounced, suggesting that neither acute nor long-term lack of {alpha}2-adrenoceptor activity is likely to play an important role in mediating the anesthetic action of etomidate in mice.

As with most other anesthetics, the exact molecular targets by which etomidate mediates its anesthetic effects remain unclear. It has been shown that etomidate exhibits GABA-modulatory effects, and at higher concentrations GABA-mimetic effects at GABAA receptors (6). Other ligand-gated ion channels, such as glycine or neuronal nicotinic acetylcholine receptors, are only weakly affected by etomidate at high concentrations (5,18). Because etomidate has structural similarities to specific {alpha}2-adrenoceptor agonists such as dexmedetomidine we investigated the binding of etomidate at {alpha}2-adrenoceptors in a previous study (8). Interestingly, we were able to demonstrate that etomidate interacts with {alpha}2-adrenoceptors and displaces the specific {alpha}2-adrenoceptor antagonist [3H]-RX821002 in HEK293 cells from all subtypes in a concentration-dependent manner. Additionally, etomidate activates {alpha}2B-adrenoceptors, resulting in a transient increase in arterial blood pressure after IV injection of etomidate (8). We therefore used two well-validated animal models to investigate more closely whether the sedative effect of etomidate is at least partially mediated via {alpha}2-adrenoceptors, both in aquatic animals and mammals.

In a first set of experiments, the anesthetic concentration of etomidate was determined in X. laevis tadpoles in the absence and presence of atipamezole, in a concentration that completely antagonized the effect of the specific {alpha}2-adrenoceptor agonist dexmedetomidine. Determination of anesthetic potency in tadpoles is a well characterized animal model, and the effects of anesthetics on tadpoles have been studied extensively (12,13,19). Because steady-state conditions of aquatic animals with surrounding solutions are readily achieved, pharmacokinetic influences on drug interactions can be excluded. The results of the present study show that the addition of atipamezole shifted the concentration-response curve of etomidate to the right. In contrast, control experiments showed that the specific {alpha}2-adrenoceptor antagonist, atipamezole, did not influence the anesthetic potency of the barbiturate thiopental supporting the {alpha}2-adrenoceptor-specific action of atipamezole on etomidate in tadpoles. Although there are limitations to this model, previous studies showed that the response of tadpoles to anesthetics is similar to that of mammals, including humans (11).

Etomidate-induced sedation was assessed in mice by rotarod performance resembling more closely the clinical setting of etomidate injection. The rotarod test is well-validated in rodents, and parallels the clinically important motor incoordination induced by sedative drugs (20). In vivo, the sedative effect of {alpha}2-adrenoceptor activation is almost exclusively mediated by the {alpha}2A-receptor subtype (9). However, etomidate-induced sedation, as assessed by the rotarod test, was not reduced in {alpha}2A-KO compared with WT animals. A limitation and a common criticism of studies in transgenic mice is the possible induction of compensatory mechanisms that are not operational in WT mice and may mask the functional results of a targeted mutation. To confirm our results using a pharmacological approach by acute and specific inhibition of {alpha}2-adrenoceptor activation, the effects of atipamezole on etomidate-induced sedation were determined.

Atipamezole is a specific, non-subtype selective {alpha}2-adrenoceptor antagonist. Because of its pharmacologic receptor specificity, together with behavioral observations, atipamezole can be viewed as a specific pharmacological tool suitable for evaluating the effects on {alpha}2-adrenoceptors in vivo (21). However, the present results show that injection of atipamezole did not reduce sedative effects of etomidate in WT mice. Compared with etomidate alone, rotarod performance was compromised even longer. Thus, both approaches complement each other, suggesting that {alpha}2-adrenoceptors are unlikely to play an important role in mediating the anesthetic action in mice. This is in accordance with previous findings demonstrating that etomidate shows the lowest affinity to the {alpha}2A-adrenoceptor subtype (8).

It is unclear why {alpha}2A-KO mice and mice following injection of atipamezole demonstrated even more pronounced etomidate-induced effects as assessed by the rotarod test. Pharmacokinetic effects are possible, because the deletion of the {alpha}2A-adrenoceptor subtype, as well as pharmacologic antagonism by atipamezole, increase endogenous norepinephrine release, thus potentially leading to hemodynamic changes that may have influenced the effects of etomidate (7,22). Moreover, {alpha}2-adrenergic pathways have been shown to play an important role in the control of motor behavior, mood and cognition (23). Therefore, the effects of pharmacological antagonism by atipamezole or targeted deletion of the {alpha}2A-adrenoceptor subtype in KO mice on locomotor behavior may have influenced the effects of etomidate on rotarod performance. However, because baseline performance in {alpha}2A-KO mice and WT mice with, and without atipamezole, did not differ significantly, a major bias seems unlikely.

The reason for the conflicting results in X. laevis tadpoles compared with mice is unclear. We cannot exclude that the different animal models used, measuring LRR in tadpoles and rotarod performance in mice, account for the differing results. However, consistent with the present study, previous investigations displayed no significant difference in etomidate-induced LRR between {alpha}2-KO mice and WT mice (8). Alternatively, species-specific differences in tissue distribution or function of distinct subtypes of {alpha}2-adrenoceptors may account for the conflicting results. Species variations are well known for the {alpha}2A-adrenoceptor subtype, and pharmacological binding characteristics differ significantly among different species (24). In contrast, knowledge about {alpha}2-adrenoceptors in X. laevis tadpoles is limited. Because the sedative action induced by {alpha}2-adrenoceptor agonists is mediated by a single type of receptors, species-specific tissue distributions of {alpha}2-adrenoceptors are more likely to influence the results.

In conclusion, the sedative effects of etomidate exhibit a species-specific interaction with {alpha}2-adrenoceptors. The decrease in potency of etomidate by the specific {alpha}2-adrenoceptor antagonist atipamezole suggests an interaction with {alpha}2-adrenoceptors in X. laevis tadpoles. In contrast, the sedative effects were not reduced in {alpha}2A-KO mice or in atipamezole-treated WT mice, suggesting that {alpha}2-adrenoceptors are unlikely to play an important role in mediating the anesthetic action of etomidate in mice. Thus, data from animal models should be extrapolated with caution to other species, including humans. Studies on specifically acting anesthetics targeting a single receptor may particularly display a strong dependence on the animal model chosen.


   Footnotes
 
Accepted for publication July 27, 2007.


   REFERENCES
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press