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Anesth Analg 2005;101:1689-1694
© 2005 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000184185.69471.F6

ANESTHETIC PHARMACOLOGY

Identification of the Central Imidazoline Receptor Subtype Involved in Modulation of Halothane-Epinephrine Arrhythmias in Rats

Kiyokazu Kagawa, MD*, Yukio Hayashi, MD*, Isao Itoh, MD*, Mitsuo Iwasaki, MD*, Koji Takada, MD*, Takahiko Kamibayashi, MD*, Atsushi Yamatodani, MD{dagger}, and Takashi Mashimo, MD*

Department of *Anesthesiology and {dagger}Medical Physics School of Allied Health Sciences, Osaka University Faculty of Medicine, Japan

Address correspondence and reprint requests to Yukio Hayashi, MD, Department of Anesthesiology, Osaka University Faculty of Medicine (D-7), 2–2, Yamada-oka, Suita, Osaka 565–0871, Japan. Address e-mail to yhayashi{at}anes.med.osaka-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
We previously reported that imidazoline receptors in the central nervous system are involved in modulation of halothane-epinephrine arrhythmias. These receptors have been subclassified as I1 and I2 subtypes, but it is not known which receptor subtype is involved in halothane-epinephrine-induced arrhythmias. We designed the present study to clarify the involvement of central imidazoline receptor subtype in the modulation of halothane-epinephrine-induced arrhythmias. Rats were anesthetized with halothane and monitored continuously for systemic arterial blood pressure and premature ventricular contractions. The arrhythmogenic dose of epinephrine was defined as the smallest dose that produces three or more premature ventricular contractions within a 15-s period. Intracisternal moxonidine dose-dependently inhibited the epinephrine-induced arrhythmias during halothane anesthesia. Intracisternal efaroxan, a selective I1 antagonist with little affinity for I2 subtype, but not rauwolscine, an {alpha}2 antagonist without affinity for imidazoline receptors, blocked the antiarrhythmic effect of moxonidine. Intracisternal BU 224 and 2-BFI, selective I2 ligands, also inhibited the epinephrine-induced arrhythmias dose-dependently; however, these effects were abolished by efaroxan. We conclude that central I1, but not I2, receptors play an important role in inhibition of halothane-epinephrine arrhythmia.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Certain cellular effects of clonidine, an {alpha}2 adrenoceptor agonist, have been reported to be mediated via nonadrenergic imidazoline receptors (1). Furthermore, substantial pharmacological evidence has permitted the subclassification of imidazoline receptors as I1 and I2 (2). The I1 subtype, located predominantly in the rostral ventrolateral medulla oblongata, is considered to be responsible for the hypotensive action of imidazoline receptor ligands (3,4). However, the I2 subtype, mainly distributed in the cerebral cortex, is reported to be involved in some psychiatric and neurologic disorders (e.g., depression, eating disorders, and Parkinson disease) (5,6). In addition, pharmacological assays suggest that pertussis toxin-sensitive G proteins are involved in the postreceptor mechanism of the I1 subtype (7), whereas the I2 subtype is associated with the catalytic site of monoamine oxidase (8). We previously reported (7,9) that rilmenidine, a selective imidazoline receptor agonist, prevents halothane-epinephrine arrhythmias and that central imidazoline receptors are mainly involved in this mechanism. In those studies, we identified the receptor type involved in the antiarrhythmic effect of rilmenidine by pharmacological evidence using idazoxan, an imidazoline receptor antagonist with an affinity for {alpha}2 adrenoceptors, and rauwolscine, a classical {alpha}2 adrenoceptor antagonist with no affinity for imidazoline receptors (10). However, those studies could not establish the imidazoline receptor subtype involved in modulation of halothane-epinephrine arrhythmias because rilmenidine has affinity for the I2 as well as I1 subtypes (11).

Moxonidine is the most selective agonist for the I1 subtype (11,12). However, BU-224 and 2-BFI are selective imidazoline I2 ligands (5,13). Efaroxan has been shown to be a highly selective antagonist for the I1 subtype with little affinity for the I2 subtype (5). Using these I1 and I2 ligands, the present study was designed to determine the central imidazoline receptor subtype involved in the modulation of halothane-epinephrine-induced arrhythmias.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The study protocol was approved by the Animal Care Committee of Osaka University Faculty of Medicine. Male Sprague-Dawley rats, weighing 360–430 g, were used and housed in groups of 4 in a temperature-controlled environment under 12-h light:12-h dark cycles, with free access to food and water. The rats were anesthetized with 2.0% halothane in oxygen. After tracheotomy, the lungs were mechanically ventilated with a tidal volume of 12 mL/kg at 40–50 breaths/min (Rodent Ventilator; Ugo Basile, Vasere, Italy). The ventilation rates were adjusted to maintain Paco2 at 40 ± 5 mm Hg. The inspired concentration of halothane 1.5% was monitored continuously with an anesthetic gas analyzer (CAPNOMAC ULTIMA multiple gas monitor; Datex, Helsinki, Finland). Lead II of the electrocardiogram (ECG) and heart rate were monitored continuously by an ECG amplifier and pulse counter unit (AC-611G; Nihon Kohden, Tokyo, Japan). Polyethylene catheters (PE-50 and PE-10) were inserted into a femoral artery for blood sampling and pressure monitoring with a pressure transducer unit (AP-641G; Nihon Kohden) and into a femoral vein for administration of drugs. The ECG and arterial blood pressure were recorded continuously with a thermal array recorder (WS-641G; Nihon Kohden). A heating pad was used to maintain rectal temperature at 38.0°C ± 0.5°C. Arterial pH values and oxygen tension were maintained at 7.40 ± 0.05 and more than 100 mm Hg, respectively. After completion of the preparation, anesthesia was maintained for a further 30 min to achieve a steady-state.

The arrhythmogenic dose of epinephrine was defined as the dose that produced 3 or more premature ventricular contractions within 15 s of injection. Epinephrine was injected at logarithmically spaced doses (0.5, 0.71, 1.0, 1.41, 2.20, 2.83, 4.0, 5.67, 8.0, and 11.4. µg/kg) after an initial dose of 4.0 µg/kg (14), and the concentration of epinephrine was adjusted to inject the epinephrine volume of 0.2 mL. The 4.0-µg/kg dose of epinephrine served as an indicator for the direction of subsequent doses of epinephrine to establish the arrhythmogenic dose, i.e., smaller or larger dose of epinephrine. This method reduces the number of epinephrine injections required to determine the arrhythmogenic dose. A period of 10–30 min was allowed between injections until the arterial blood pressure and heart rate became stable.

When the criterion for arrhythmogenic dose was satisfied, a 2.0-mL arterial blood sample was collected for the measurement of the plasma concentration of epinephrine. The blood samples were put into precooled plastic tubes containing 20 µL of 0.2 M EDTA-2Na and 0.2 M Na2S2O5, which were centrifuged at 4000 rpm for 10 min at 2°C to separate the plasma. For analysis of epinephrine, 0.5 mL of plasma was acidified by the addition of 0.25 mL of 2.5% perchloric acid to precipitate protein. The samples were stored at –40°C for no longer than 7 days until analysis. The plasma concentration of epinephrine was determined in a fully automated high-performance liquid chromatography-fluorometric system (HLC-8030 Catecholamine Analyzer; Tosoh, Tokyo, Japan) by a diphenyl ethylenediamine condensation method. This assay method has a limit of sensitivity of 10 pg/mL for epinephrine, and the inter- and intraassay variation were <3%.

We determined the arrhythmogenic doses and plasma concentration of epinephrine in the presence of moxonidine 0, 5, 10, and 20 µg/kg. Moxonidine or vehicle was administered intracisternally (IC). In each rat, a 30-gauge stainless steel needle was inserted into the cisterna magna through the atlanto-occipital membrane. The correct position of the cannula was checked by the efflux of clear cerebrospinal fluid. The first administration of epinephrine was started 30 min after the IC drug administration. To determine the receptor mediating the effect of moxonidine, the arrhythmogenic doses and plasma concentration of epinephrine were determined in the presence of moxonidine (20 µg/kg IC) with IC vehicle (10 µL), rauwolscine (10 µg/kg), or efaroxan (5 µg/kg). The doses of rauwolscine and efaroxan were determined to be approximately equal with regard to {alpha}2 adrenoceptors inhibiting efficacy (15). In these groups, moxonidine and the antagonists were injected IC 30 min before the epinephrine injection. Second, the arrhythmogenic doses and plasma concentration of epinephrine were determined in the presence of BU 224 or 2-BFI 3, 10, and 30 µg/kg doses. BU 224 or 2-BFI was administered IC, and then 30 min later, the first administration of epinephrine was started. In addition, we examined the arrhythmogenic doses and plasma concentration of epinephrine in the presence of BU 224 or 2- BFI (30 µg/kg IC) together with efaroxan (5 µg/kg IC) to examine the involvement of I1 receptors. In this study, moxonidine, BU 224, 2-BFI, efaroxan, and rauwolscine were dissolved in saline to such a concentration that each rat received a dose in a volume of 10 µL.

All data were expressed as mean ± sd. Data were analyzed by one-way analysis of variance, and comparisons between groups were assessed by Scheffé test. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
The hemodynamic data before epinephrine administration are presented in Table 1. Moxonidine significantly decreased arterial blood pressure and heart rate dose-dependently, and coadministration of efaroxan inhibited these hemodynamic actions. BU 224 and 2-BFI also showed similar hemodynamic actions, which was attenuated by efaroxan. Moxonidine (0, 5, 10, and 20 µg/kg IC) increased the arrhythmogenic dose and the plasma concentration of epinephrine in a dose-dependent manner. Coadministration of efaroxan (5 µg/kg IC) abolished the antiarrhythmic effect of moxonidine (20 µg/kg IC), but rauwolscine (10 µg/kg IC) did not significantly attenuate the effect of moxonidine (20 µg/kg IC) (Fig. 1). The hemodynamic data obtained at the onset of arrhythmias were not significantly different in each moxonidine group (Table 2). Both IC BU 224 and 2-BFI significantly increased the arrhythmogenic dose and the plasma concentration of epinephrine, and the effects of BU 224 and 2-BFI were abolished by coadministration of efaroxan (Figs. 2 and 3). There were no significant hemodynamic changes at the arrhythmias in the BU 224 and 2-BFI studies (Table 2).


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  		Table 1. Hemodynamic Data Before Epinephrine Administration in the Presence of Intracisternal (IC) Moxonidine, Efaroxan, and Rauwolscine (A), IC BU-224 and Efaroxan (B), and IC 2-BFI and Efaroxan (C) During Halothane Anesthesia

 


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  		Figure 1. Arrhythmogenic dose (open columns) and plasma concentration (solid columns) of epinephrine in the presence of intracisternal (IC) moxonidine (0, 5, 10, and 20 µg/kg), combined with the administration of efaroxan, rauwolscine, and moxonidine during halothane anesthesia. The values are expressed as mean ± sd, and the number of observations is shown in parentheses. Mox 20 + Efaroxan = IC moxonidine 20 µg/kg and efaroxan 5 µg/kg; Mox 20 + Rauwolscine = IC moxonidine 20 µg/kg and rauwolscine 10 µg/kg. *P < 0.05 compared with the moxonidine 0 µg/kg value.

 

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  		Table 2. Hemodynamic Data At the Onset of Arrhythmias in the Presence of Intracisternal (IC) Moxonidine, Efaroxan, and Rauwolscine (A), IC BU-224 and Efaroxan (B), and IC 2-BFI and Efaroxan (C) During Halothane Anesthesia

 


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  		Figure 2. Arrhythmogenic dose (open columns) and plasma concentration (solid columns) of epinephrine in the presence of intracisternal (IC) BU 224 (0, 3, 10, and 30 µg/kg), combined with the administration of efaroxan and BU 224 during halothane anesthesia. The values are expressed as mean ± sd, and the number of observations is shown in parentheses. BU 30 + Efaroxan = IC BU 224 30 µg/kg and efaroxan 5 µg/kg. *P < 0.05 compared with the BU 224 0 µg/kg value.

 



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  		Figure 3. Arrhythmogenic dose (open columns) and plasma concentration (solid columns) of epinephrine in the presence of intracisternal (IC) 2-BFI (0, 3, 10, and 30 µg/kg), combined with the administration of efaroxan and 2-BFI during halothane anesthesia. The values are expressed as mean ± sd, and the number of observations is shown in parentheses. 2-BFI 30 + Efaroxan = IC 2-BFI 30 µg/kg and efaroxan 5 µg/kg. *P < 0.05 compared with the 2-BFI 0 µg/kg value.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The role of the imidazoline compounds in the cardiovascular regulation of the central nervous system were originally elucidated by Bousquest et al. (16) and are now well recognized. Tibrica et al. (1) showed that imidazoline receptors are involved in the hypotensive effect of clonidine, which was originally believed to be exerted by activation of central {alpha}2 adrenoceptors. Imidazoline receptors are not homogenous entities but can be subdivided into subtypes I1 and I2 (2,17), although this classification has not yet been confirmed by molecular cloning. The availability of imidazoline compounds has contributed to understanding the role of central imidazoline receptors in the pathogenesis of several types of arrhythmias. Lepran and Papp (18) showed that IV moxonidine prevented the arrhythmias induced by coronary reperfusion, and Mest et al. (19) reported an antiarrhythmic effect of moxonidine on ouabain-induced arrhythmias in guinea pigs. We have reported that the imidazoline receptor agonist rilmenidine increased the arrhythmogenic dose of epinephrine during halothane anesthesia, and the centrally administered imidazoline receptor antagonist idazoxan blocked the beneficial action of rilmenidine (7,9). However, idazoxan binds to both I1 and I2 subtypes but has a greater affinity for the I2 receptors than the I1 receptors (11). In this study, we used more selective ligands for the I1 subtype. Whereas the I1:I2 ratio of rilmenidine and idazoxan are 102 and 10–1, respectively, the affinities of moxonidine and efaroxan for I1 are 100,000 times greater than for I2 (11). Furthermore, binding data using [3H]-2BFI, a highly selective I2 ligand, showed that the affinity of moxonidine for the I2 subtype is very weak (Ki value of moxonidine was 17 µM and 54 µM for rabbit whole-brain membrane and rat whole-brain membrane, respectively) (5,20). Two binding studies from independent groups have shown that the affinity of efaroxan for the I2 subtype is low (Ki value of efaroxan for [3H]-idazoxan binding in rat cortex is 58 µM, and its Ki for [3H]-2BFI in rat whole brain is >100 µM) (5,21). Therefore, our present data strongly suggest that the I1 subtype is responsible for the antiarrhythmic action of moxonidine.

Furthermore, we examined the effect of centrally administered BU 224 and 2-BFI (selective I2 ligands) on the genesis of halothane-epinephrine arrhythmias. There have been no investigations to examine the involvement of I2 subtype in the modulation of halothane-epinephrine arrhythmias. BU-224 and 2-BFI are selective I2 ligands, and binding distribution of these compounds is very similar (22). However, previous studies showed that the pharmacological activities of these compounds were different. Diaz et al. (23) reported that BU-224 produced spinal antinociception as an agonist at I2 receptors in rats. In comparison, Sanchez-Blazquez et al. (24) showed that 2-BFI enhanced supraspinal morphine analgesia through agonistic activity at I2 receptors, and this effect was antagonized by BU-224 in mice. Hudson et al. (13) documented that BU 224, but not 2-BFI, increased 5-hyrdoxytryptamine and dopamine in frontal cortex and striatum. These data may indicate that BU-224 and 2-BFI have different intrinsic activities at I2 receptors. However, our data showed that BU-224 and 2-BFI exerted similar antiarrhythmic effects, and these effects were inhibited by efaroxan (Figs. 2 and 3). Considering that both BU-224 and 2-BFI have additional affinity for the I1 subtype (25), our data suggest that the antiarrhythmic actions of BU-224 and 2-BFI are not mediated by I2 receptors but I1 receptors.

Moxonidine and efaroxan have an affinity for {alpha}2 adrenoceptors (12,26), so the contribution of {alpha}2 adrenoceptors on the antiarrhythmic action of moxonidine should be clarified. In our experiment, rauwolscine, an {alpha}2 adrenoceptor antagonist with low affinity for imidazoline receptors, had little effect on the antiarrhythmic action of the largest dose (20 µg/kg) of moxonidine, whereas efaroxan, an {alpha}2 adrenoceptor antagonist with high affinity for I1 receptors, completely inhibited the effect of moxonidine (Fig. 1). Therefore, we may conclude that moxonidine exerts its antiarrhythmic effect through I1 receptors, not {alpha}2 adrenoceptors.

Hemodynamic variables such as arterial blood pressure and heart rate are important factors in modulating the onset of halothane-epinephrine arrhythmias (27). At the onset of arrhythmias, hemodynamic variables in the moxonidine-treated rats were not significantly different from those of the control rats, despite a larger plasma epinephrine concentration (Fig. 1). Similarly, BU 224 or 2-BFI did not significantly change the hemodynamic data at the start of arrhythmias, although the arrhythmogenic threshold was increased (Figs. 2 and 3). This might suggest that moxonidine, BU 224, and 2-BFI inhibited the positive inotropic and chronotropic action of epinephrine by inhibiting the sympathetic neural activity through I1 receptors (28).

In conclusion, central I1 receptors play an important role in modulation of halothane-epinephrine arrhythmias as compared with no significant role of central I2 receptors.


   Footnotes
 
Accepted for publication June 9, 2005.


   References
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 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 and Stanford University Libraries' HighWire Press®. Copyright 2005 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press