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Posterior Hypothalamic Noradrenaline Release During Emergence from Sevoflurane Anesthesia in Rats

Ohkawa, Hirobumi MD; Kushikata, Tetsuya MD; Satoh, Tetsumi MD; Hirota, Kazuyoshi MD; Ishihara, Hironori MD; Matsuki, Akitomo MD

Brief Communication

Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki, Japan.

Accepted for publication August 4, 1995.

Address correspondence to Akitomo Matsuki, MD, Department of Anesthesiology, University of Hirosaki School of Medicine, Hirosaki, 036, Japan.

Many studies about the mechanism of general anesthesia have been focused mainly on the cerebral cortex and the reticular formation as the sites of its action [1,2]. However, the hypothalamus, particularly the posterior hypothalamus (PH), plays a critical role in the maintenance of consciousness or wakefulness [3,4]. Noradrenaline (NA), one of the major neurotransmitters in the central nervous system (CNS), is also believed to regulate wakefulness and attention [5,6]. Although general anesthetics influence some of neurotransmitters in the CNS [7,8], it is expected that NA release from the PH will be influenced by general anesthetics. We investigated the effect of induction and emergence from sevoflurane anesthesia on the NA release from the PH in rats.

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This study was approved by the animal experiment committee of our institution. Thirteen male Wistar rats weighing 280-300 g were used. All experiments were conducted from 10:00 AM to 3:00 PM because of the circadian rhythm of NA release [9]. For eight rats, a microdialysis probe (CMA/11, BAS) was inserted under pentobarbital anesthesia (50 mg/kg intraperitoneally). The position of the PH (posterior 3.6 mm, lateral 1.2 mm, ventral 9.5 mm in relation to the bregma) was determined according to the atlas of Paxinos and Watson [10]. After all measurements, the location of the probe tip was verified by histologic examination.

Forty-eight hours after the insertion, the probe was perfused in freely moving rats at a flow rate of 2 micro Liter/min with artificial cerebrospinal fluid of the following composition (in mM): NaCl 128, KCl 2.6, CaCl2 1.3, MgCl2 0.9, NaHCO3 20, Na2 HPO4 1.3, and pargyline (monoamine oxidase inhibitor) 1 mM, which was included to prevent degradation of noradrenaline.

During 30-min periods, samples of 60 micro Liter dialysate were collected and injected into a high-performance liquid chromatography equipped with electrochemical detector (Coulochem; ESA, Bedford, MA). After four consecutive samples showing stable NA release were obtained, the rat was exposed to 3% sevoflurane for 30 min. During anesthesia, the rectal temperature of the rats was maintained at 37 +/- 0.5 degrees C by using a heating pad. After the cessation of sevoflurane inhalation, we obtained four subsequent samples for 2 h. After that, tetrodotoxin (10-6 M) was added to the perfusate for two subsequent samples to substantiate that NA was not released from traumatized neural cells.

Using the remaining five rats, the left femoral artery was cannulated under pentobarbital anesthesia (50 mg/kg intraperitoneally). Forty-eight hours after the cannulation, arterial blood gases, mean arterial blood pressure (MAP), and heart rate (HR) were measured before, 30 min after the beginning, and 30 min after the end of 3% sevoflurane inhalation.

All values were expressed as mean +/- SD. Repeated-measures analysis of variance and Scheffe's F test were used for NA values. For analysis of arterial blood gases, MAP, and HR, Student's t-test was used. P < 0.05 was considered significant.

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Changes in the NA release from the PH in rats are shown in Figure 1. There were no significant changes in NA release during the preanesthetic and anesthetic periods. It increased significantly during the first 30-min period after sevoflurane inhalation. Then NA release returned to the preanesthetic levels. NA release decreased to undetectable levels by tetrodotoxin.

Figure 1

Figure 1

The results of arterial blood gas analyses, MAP, and HR are shown in Table 1. During sevoflurane anesthesia, PaCO2 increased, while pHa, MAP and HR decreased. However, all these values were within normal limits.

Table 1

Table 1

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Experimental lesion of the PH causes loss of consciousness in rats and cats [3,4]. Oniani et al. [11] reported that a high frequency discharge of neurons in the PH was observed during the awake period in cats. Lin et al. [12] injected a gamma-aminobutyric acid agonist, muscimol, into the PH to induce sleep in experimental animals. These reports show the importance of the PH on regulation of consciousness.

Cordeau et al. [5] proved that sleep was antagonized by injecting NA into the third ventricle in cat. On the contrary, alpha2-adrenoceptor agonists, such as clonidine and dexmedetomidine, inhibit the activity of brain noradrenergic neurons leading to sedation [13] and reduced dose requirements for general anesthetics [14,15]. In addition, there is a positive correlation between NA contents in the brain and minimum alveolar anesthetic concentration (MAC) for inhaled anesthetics. Johnston et al. [16] administered dextroamphetamine to release the NA in the CNS and observed an increased MAC for halothane in dogs. Roizen et al. [17] reported that ablation of NA in the CNS decreased MAC for halothane in rats. They also reported the increased content of NA in the CNS after inhalation of halothane or cyclopropane in rats [18]. These results suggest that NA has an important role in maintenance of consciousness or depth of anesthesia. Saunier et al. [19] showed that NA neurons are strongly activated in the rat during recovery froom halothane anesthesia. Our results are consistent with their findings.

Yokoo et al. [6] reported increased NA release from the hypothalamus by emotional stress in rats. In our study, excitement was never observed in any rats during the induction or recovery from sevoflurane anesthesia.

Elam et al. [20] described a reciprocal relationship between MAP and activities of NA neurons. In our study, MAP decreased only during anesthesia. It is therefore unlikely that our result was caused by MAP changes. Elam et al. [21] also reported a positive relationship between PaCO2 and the activities of NA neurons. In our study, PaCO2 increased approximately 9 mm Hg during anesthesia, and an increase of approximately 10% in the activities of NA neurons is expected according to the data of Elam et al. [21]. In our study, increase in NA release was more than 30%; thus, it was not due to increased PaCO2 per se.

It was interesting to have observed no significant change in NA release during sevoflurane-anesthesia. At first we speculated that too rapid changes in NA release were detected due to sampling time limitation; however, there may be another cause for the absence of change in NA release during the anesthesia. In other words, it is speculated that the mechanism of induction and maintenance of sevoflurane anesthesia is not simply a reversal of the mechanism of emergence from the anesthesia.

In conclusion, this study demonstrated a transient increase in NA release from the PH during recovery from sevoflurane anesthesia in rats. It is not clear whether the result of this study is a cause or a result of emergence from sevoflurane anesthesia. However, it seems that there is a strong relationship between NA release from the PH and emergence from sevoflurane anesthesia.

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© 1995 International Anesthesia Research Society