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Anesth Analg 2007; 105:1722-1728
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000286230.02948.77
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NEUROSURGICAL ANESTHESIA

Section Editor:
Adrian W. Gelb

The Effects of Centrally Administered Dexmedetomidine on Cardiovascular and Sympathetic Function in Conscious Rats

Tetsuro Shirasaka, MD, PhD*, De-Lai Qiu, MD, PhD{dagger}, Hiroshi Kannan, MD, PhD{dagger}, and Mayumi Takasaki, MD, PhD*

From the Departments of *Anesthesiology and Intensive Care and {dagger}Integrative Physiology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.

Address correspondence and reprint requests to Tetsuro Shirasaka, MD, PhD, Department of Anesthesiology, Faculty of Medicine, University of Miyazaki, 5200 Kihara Kiyotake, Miyazaki 889-1692, Japan. Address e-mail to shirasak{at}med.miyazaki-u.ac.jp.


   Abstract
Top
 Abstract
Introduction
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: The {alpha}2-receptor is expressed in the brain, including the hypothalamus, where it is implicated in autonomic nervous system control. The effects of systemic administration of dexmedetomidine (DEX) on cardiovascular responses are well known; however, little is known about the effects of central administration of DEX on cardiovascular responses in conscious animals. In this study, we explored the effects and the mechanism of intracerebroventricularly (icv) administered DEX on cardiovascular responses and sympathetic nerve activity in conscious, unrestrained rats.

METHODS: We administered DEX (0.5, 1, and 2 µg/kg) icv and measured the mean arterial blood pressure (MAP), heart rate (HR), and plasma catecholamine in conscious rats (n = 58). Rats were also administered atropine (n = 8), propranolol (n = 8), or hexamethonium (n = 8) to assess the influence of vagal or sympathetic efferent activity in the DEX-induced responses. Some of the rats underwent carotid sinus and aortic nerve denervation to exclude the effect of the baroreceptor reflex.

RESULTS: Intracerebroventricular administration of DEX dose-dependently decreased MAP, HR, and plasma norepinephrine. Large dose of DEX decreased plasma epinephrine. The amplitude of MAP reduction induced by DEX was reduced by hexamethonium or propranolol. The amplitude of HR reduction was reduced by atropine or propranolol. The amplitude of MAP and HR reduction induced by DEX were smaller in hexamethonium-pretreatment rats than in intact ones. The amplitude of MAP and HR reduction induced by DEX were larger in sinus and aortic nerve denervation rats than in intact ones.

CONCLUSIONS: These results indicate that icv administration of DEX decreases MAP by sympathetic inhibition and decreases HR by sympathetic inhibition and vagal stimulation.


   Introduction
Top
 Abstract
 Introduction
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Dexmedetomidine (DEX) is a highly selective {alpha}2-adrenoceptor agonist with sedative and analgesic effects (1). Compared with clonidine, it is more selective for the {alpha}2-adrenoceptor (2). There has been substantial interest in the use of {alpha}2-adrenergic agonists in clinical anesthesia (2,3). DEX is not only peripherally administered but can also be centrally administered (4,5). Intrathecally or intracerebroventricularly (icv) administered DEX produces dose-dependent antinociception or sedation, respectively (5). Epidural administration of DEX also produces antinociception (6). Intrathecally administered DEX prolongs the duration of motor and sensory block induced by local anesthetics in spinal anesthesia in humans (4). Thus, central administration of {alpha}2-adrenergic agonists is effective in clinical anesthesia. IV administration of DEX has been reported to affect cardiovascular and sympathetic functions (6–8). The development of bradycardia during sedation with DEX has been frequently reported (9–12). Intrathecal administration of DEX decreased mean arterial blood pressure (MAP) and heart rate (HR) in halothane-anesthetized rats (13), whereas icv administration of clonidine produced hypotension (14). Thus, there are reports of the use of {alpha}2-adrenergic agonists in animals after icv or intrathecal administration. However, there are little data with respect to icv administration of DEX on cardiovascular and sympathetic responses.

{alpha}2-adrenoceptors are located in specific brain nuclei that regulate cardiovascular activity and are involved in modulating sympathetic nervous system activity. For example, the rostral ventrolateral medulla (RVLM) is a vasomotor center where cardiovascular sympathetic premotor neurons are located (15). IV administration of clonidine inhibits a subpopulation of RVLM sympathetic premotor neurons (16). Thus, it is possible that central {alpha}2-adrenoceptors play some role in the central control of cardiovascular functions. A number of studies have focused on the effects of DEX on cardiovascular responses in anesthetized animals (7,17). Anesthesia profoundly affects cardiovascular and autonomic nervous system functions (18). The baroreceptor reflex system is involved in stabilizing MAP and controlling the output of the autonomic nervous system (19). To elucidate the direct effect of DEX on MAP, HR, and plasma catecholamine (CA) concentration, we investigated DEX-induced cardiovascular responses using conscious unrestrained intact or carotid sinus and aortic nerve denervated (SAD) rats. The purpose of this study was to explore the effects and the mechanism of icv administration of DEX on cardiovascular responses and sympathetic responses in conscious, unrestrained rats.


   METHODS
Top
 Abstract
 Introduction
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The experimental procedures were approved by the Ethics Committee on Animal Care of the Faculty of Medicine at the University of Miyazaki and conducted in accordance with international guidelines on the ethical use of animals in a laboratory.

Male Wistar rats weighing 450–500 g each were implanted with a lateral cerebroventricular cannula while under anesthesia with intraperitoneal (ip) injection of pentobarbital sodium (50 mg/kg). A 24-gauge stainless-steel guide cannula (length: 19 mm) was positioned 2.5 mm from the cortex surface and 1 mm above the left lateral cerebroventricle through a burr hole located stereotaxically 0.8 mm posterior and 1.5 mm lateral to the bregma. The guide cannula was fixed to the skull with three screws and dental cement. An acute increase (over 20 mm Hg) in MAP and a persistent (at least 10 min) water-drinking response to icv administration of 10 pmol angiotensin II were both considered to be indicators of cannula patency and proper placement in the ventricular system. After each experiment, Pontamine sky blue (1 µL) was injected to verify the correct placement of the icv cannula tip.

Approximately 10 days later, the cannulated rats were given pentobarbital anesthesia (50 mg/kg ip). SP-31 tubing heat-coupled to a SP-50 and a PE-50 catheter was inserted into the abdominal aorta and the inferior vena cava for the measurement of MAP and IV administration of drugs, respectively. The arterial catheter, filled with heparinized (10 U/mL) saline solution, was connected to a Statham pressure transducer (Gould, Saddle Brook, NJ) to monitor MAP, and the venous catheter was sealed. HR was monitored with a cardiotachometer (Model 1321; San-Ei, Tokyo, Japan) triggered by an electrocardiogram signal that was recorded via subcutaneous electrodes implanted into the chest.

SAD was performed according to the method of Krieger (20), as previously described (21). Under pentobarbital anesthesia (50 mg/kg ip), a midline incision was made in the ventral neck region, and the sternocleidomastoid muscles were reflected laterally to expose the common carotid arteries, the external and internal carotid arteries, the vagi, and the cervical sympathetic trunks. The sympathetic trunk, superior laryngeal nerve, and aortic depressor nerve were bilaterally sectioned under a surgical microscope. The bifurcation and all carotid branches were stripped of fibers and connective tissues and painted with a small amount of 10% phenol. Approximately 7 days after SAD, arterial and venous catheters were inserted. The effectiveness of SAD was confirmed by the lack of bradycardia responses to an {alpha}-adrenergic agonist, phenylephrine (16 µg/kg, IV).

For the measurement of plasma CA, another group of weight- and age-matched rats were anesthetized with pentobarbital sodium (50 mg/kg ip), and arterial and venous catheters were inserted into the abdominal aorta and inferior vena cava, respectively. One milliliter of arterial blood was withdrawn through the cannula in the abdominal aorta. These blood samples were immediately heparinized and centrifuged at 3000 rpm and reconstituted in 0.3 mL of 0.5 mol/L acetic acid solution to obtain the final samples. The CA concentration was measured by high-performance liquid chromatography and electrochemical detection using an Eicompak CA-5ODS column (Eicom, Kyoto, Japan).

All experiments were performed on conscious, freely moving rats, 1–5 days after surgery. Chow and water were not available during the recording time. After the MAP and HR were stabilized, DEX (Abbott, Osaka, Japan; 0.5, 1, and 2 µg/kg; 0.2 µg/µL) was infused icv in intact conscious rats through an infusion cannula (30-gauge stainless-steel tubing) connected to a 50-µL microsyringe by an automatic injector (LMS, Tokyo, Japan) at a rate of 1 µL/min for 1.5–5 min. This injection was made by inserting the infusion cannula 1 mm beyond the tip of the guide cannula.

Under similar experimental conditions in intact rats, to assess the influence of sympathetic nerve activity on the DEX-induced responses in MAP, hexamethonium (10 mg/kg + 15 mg · kg–1 · h–1; Sigma Chemical, St. Louis, MO) was administered IV 5 min before DEX administration to block sympathetic efferent activity. Under similar experimental conditions in intact rats, to assess the influence of parasympathetic nerve or sympathetic nerve activity on the DEX-induced responses in the HR, atropine methyl nitrate (4 mg/kg; Sigma Chemical), propranolol (4 mg/kg; Sigma Chemical), or vehicle (saline) was administered IV 5 min before DEX administration to block vagal or sympathetic efferent activity. The doses of hexamethonium (22), atropine (21), or propranolol (21) were based on previous reports. Fifty-eight rats were randomly divided into the following five groups: animals with an intact neuraxis (intact: n = 10); animals with SAD (n = 8); animals administered a vehicle, atropine methyl nitrate (4 mg/kg), and propranolol (4 mg/kg) (n = 8); animals administered a vehicle and hexamethonium (n = 8); and animals in which the plasma CA was measured (n = 24). To evaluate the dose-dependent responses of MAP and HR in intact rats, each rat was tested with each concentration once a day. In these cases, the concentration of the administered drugs was selected at random, and subsequent drug administrations were made on a different day. In vehicle-, atropine-, and propranolol-pretreated rats, vehicle, atropine, or propranolol followed by DEX was administered once a day, and another drug administration was made on a different day. In four different groups of rats (n = 8 per group), we administered DEX (0.5, 1.0, and 2.0 µg/kg) icv and collected blood samples for the measurement of plasma CA. Blood samples were obtained 15 min before, and 10 and 60 min after, vehicle or DEX icv administration.

All data are expressed as the mean ± se. In each group, the effects of each treatment on the variables within each group were evaluated by repeated-measurement analysis of variance (ANOVA). The differences between individual means were determined using ANOVA followed by Scheffé F-test. In comparisons among the groups, statistically significant differences were evaluated by Scheffé F-test. P < 0.05 was considered statistically significant.


   RESULTS
Top
 Abstract
 Introduction
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The icv administration of 5 µL (1 µL/min) of vehicle (physiological saline solution) did not produce any effects on MAP and HR in conscious rats (Fig. 1A). Intracerebroventricularly administered DEX resulted in a dose-dependent decrease in MAP, of 6.8 ± 3.3, 11.6 ± 3.7, and 16.4 ± 2.5 mm Hg from the baseline value at 0.5, 1, and 2 µg/kg, respectively (Figs. 1A[a] and 1B[a]). On the other hand, HR decreased dose dependently and reached the lowest value 15–20 min after DEX administration (Figs. 1A and 1B). The HR gradually returned to the baseline level at 0.5 and 1 µg/kg doses within 50 min of DEX administration, whereas the HR significantly decreased even at 50 min after DEX administration at a 2.0 µg/kg dose. For each variable, the differences between lowest values from baseline values after icv administration of DEX were compared between each dose (Fig. 1B). Significant differences were observed between the 0.5 and 2 µg/kg doses with regard to the decrease in MAP and HR (Fig. 1B).


Figure 135
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  		Figure 1. (A) Time course of changes in the mean arterial blood pressure (MAP; a) and heart rate (HR; b) during the 60 min after intracerebroventricular (icv) administration of dexmedetomidine (DEX) (0.5, 1.0, and 2.0 µg/kg) in conscious rats. The vertical dotted line indicates time 0 min. beats per min; icv, intracerebroventricular. All data are the mean ± se; n is the number of animals. *P < 0.05 vs each baseline value. {dagger}P < 0.05 vs DEX (0.5 µg/kg). (B) Dose-response relationships of a decrease in MAP (a) and HR (b) against DEX doses (n = 10 in each dose). All data are the mean ± se *P < 0.05 vs each baseline value. {dagger}P < 0.05 vs dexmedetomidine (0.5 µg/kg).

 

We next examined the possible involvement of sympathetic efferent activity in DEX (2.0 µg/kg)-induced changes in MAP and HR using hexamethonium pretreatment (10 mg/kg + 15 mg · kg –1 · h–1), intact, and SAD rats. SAD treatment virtually eliminated phenylephrine-induced decreases in [Delta]HR/MAP from –6.2 ± 0.8 to –0.7 ± 0.2 bpm/mm Hg (P < 0.01; n = 8). These results indicate that the denervation of the arterial baroreceptors was complete. Intracerebroventricular administration of DEX (2 µg/kg) resulted in a rapid and progressive decrease in MAP and reached its lowest value 45 min after icv administration in SAD rats. On the other hand, HR also decreased gradually and progressively in SAD rats. Because the baseline period for MAP and HR were different in the hexamethonium pretreatment (93.5 ± 3.7 mm Hg, 291 ± 10.3 bpm), intact (108.7 ± 5.2 mm Hg, 318 ± 9.5 bpm), and SAD (117.1 ± 7.9 mm Hg, 325.4 ± 12.4 bpm) rats, respectively, the differences between lowest values from baseline values for MAP and HR observed during the 60 min after icv administration of DEX were used for comparison. The decrease in MAP (16.4 ± 2.5 mm Hg; intact, 5.4 ± 3.1 mm Hg; hexamethonium pretreatment) and HR (35.7 ± 9.3 bpm; intact, 10.5 ± 7.1 bpm; hexamethonium pretreatment) as smaller in hexamethonium pretreatment rats than in intact ones (Fig. 2A). The decreases in MAP (16.4 ± 2.5 mm Hg; intact, 38.2 ± 4.4 mm Hg; SAD) and HR (35.7 ± 9.3; intact, 75.2 ± 13.3 bpm; SAD) were larger in SAD rats than in intact ones (Fig. 2A). There were also significant differences for MAP and HR between hexamethonium pretreatment and SAD rats (Fig. 2A).


Figure 235
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  		Figure 2. (A) Bar graph showing the differences between lowest values from baseline values for mean arterial blood pressure (MAP) (a) and heart rate (HR) (b) during the 60 min after intracerebroventricular (icv) administration of dexmedetomidine (DEX) (2 µg/kg) in pretreatment with hexamethonium (HEX) (n = 8), intact (n = 8) and sinus and aortic nerve denervated (SAD) (n = 8) rats. HEX (10 mg/kg + 15 mg · kg–1 · h–1; n = 8) was IV administered 5 min before DEX administration. *P < 0.05 vs intact rats. {dagger}P < 0.05 vs pretreatment with HEX. All data are the mean ± se. (B) Bar graph showing the differences between lowest values from baseline values for MAP (a) and HR (b) during the 60 min after icv administration of DEX (2.0 µg/kg) in intact rats. Vehicle (saline; n = 8), atropine (4 mg/kg; n = 8), or propranolol (4 mg/kg; n = 8) was IV administered 5 min before DEX (2.0 µg/kg) administration. All data are the mean ± se *P < 0.05 vs vehicle.

 

We next examined the possible involvement of vagal or sympathetic efferent activity in the DEX (2 µg/kg)-induced changes in the HR using intact rats. Vehicle (saline IV, n = 8), atropine (4 mg/kg IV, n = 8), or propranolol (4 mg/kg IV, n = 8) was administered as a pretreatment. Because the baseline period for HR were different among the vehicle (317 ± 8.9 bpm), atropine (355 ± 7.4 bpm), and propranolol (284 ± 6.7 bpm) pretreatments; the differences between lowest values from baseline values for HR observed during the 60 min after icv administration of DEX were used for comparison. The differences between lowest values from baseline values for HR (vehicle 36.2 ± 7.3 bpm) induced by DEX (2 µg/kg) was attenuated by both atropine (15.4 ± 8.2 bpm; P < 0.05) and propranolol (8.5 ± 6.6 bpm; P < 0.01) pretreatment (Fig. 2B). The differences between lowest values from baseline values for MAP (vehicle 17.1 ± 2.2 mm Hg) induced by DEX (2 µg/kg) was not attenuated by atropine (12.4 ± 4.8 mm Hg; P > 0.05) but by propranolol (8.5 ± 3.6 mm Hg; P < 0.05) pretreatment (Fig. 2B[a]).

Intracerebroventricular administration of DEX decreased plasma norepinephrine (NE) dose dependently in conscious rats. A small dose of DEX (0.5 µg/kg) significantly decreased plasma NE from 131.3 ± 10.6 pg/mL to 83.4 ± 14.4 pg/mL and 94.5 ± 9.8 pg/mL at 10 and 60 min after administration, respectively (Fig. 3A). The magnitude of the decrease in plasma NE induced by central DEX was significantly larger in the 2.0 µg/kg group than in the 0.5 µg/kg group at 60 min after administration (Fig. 3A). A large dose of DEX (2.0 µg/kg) significantly decreased plasma epinephrine (Epi) from 68.3 ± 10.8 pg/mL to 37.8 ± 7.1 pg/mL and 34.2 ± 5.5 pg/mL at 10 and 60 min after administration, respectively (Fig. 3B).


Figure 335
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  		Figure 3. Effect of intracerebroventricular administration of dexmedetomidine (0.5, 1.0, and 2.0 µg/kg) on plasma concentration of norepinephrine (NE; A) and epinephrine (Epi; B) in conscious rats. All data are the mean ± se; n is the number of animals. *P < 0.05 vs each baseline. {dagger}P < 0.05 vs dexmedetomidine (0.5 µg/kg).

 


   DISCUSSION
Top
 Abstract
 Introduction
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This is the first time that the effects of icv administration of DEX on cardiovascular and sympathetic nerve responses in conscious, unrestrained rats have been studied. Cardiovascular and autonomic functions are significantly affected by anesthetics, and responses to certain interventions are quite different between unanesthetized and anesthetized animals. For example, the pressor response caused by a microinjection of noradrenaline to the nucleus tractus solitarius (NTS), where baroreceptor and chemoreceptor afferents terminate in unanesthetized rats, is attenuated by pentobarbital anesthesia and abolished by urethane anesthesia (23). IV administered anesthetics also affect the baroreflex sensitivity and peripheral sympathetic outflows in qualitatively and quantitatively different manners (18). This is why we used conscious rats.

We have demonstrated in the present study that, in conscious rats, icv-administered DEX (0.5–2.0 µg/kg) induced a dose-dependent decrease in MAP, HR, and plasma NE. This is consistent with the result that icv administration of DEX (1 µg) induced a decrease in MAP in halothane-anesthetized rat (24). IV administration of DEX produces a transient increase in MAP and a lasting decrease in MAP and HR (25). Initial hypertensive effects after IV administration of DEX have been reported to be due to vasoconstriction, which is peripherally mediated by vascular smooth muscle through {alpha}2b-adrenoceptors (26,27), whereas these suppressive effects of cardiovascular function induced by DEX were thought to be mediated by central action. The RVLM serves an important site in mediating the hypotensive effects of {alpha}2-agonists (24,28). The dose-dependent reduction in catechol metabolism induced by IV administration of clonidine was observed in the RVLM (29). Intracerebroventricular administration of a hypotensive dose of clonidine produced an inhibition of discharge in the medullospinal sympathoexcitatory neurons (14). Clonidine injected into the RVLM decreased MAP, HR, and renal sympathetic nerve activity in conscious, unrestrained rats (28). These results suggest that icv-administered DEX induced cardiovascular and sympathetic responses through action on the RVLM. On the other hand, the intrathecal administration of {alpha}2-agonists also resulted in a rapid decrease in MAP and HR in halothane-anesthetized rats (13). A limitation of our study is related to the fact that we could not exclude the possibility that icv administration of DEX induced cardiovascular and sympathetic responses mediated by a spinal action.

The autonomic nervous system regulates circulatory reflexes via the arterial and cardiopulmonary baroreceptors located in the major blood vessels (30). The signal is integrated in RVLM/nucleus ambiguus complex or vasomotor center and leads to compensatory adjustments in sympathetic and parasympathetic activity. The baroreflex serves as a buffer to prevent excessive MAP swings (30). The hypotension and bradycardia induced by clonidine is due to an activation of the central pathway of the depressor baroreceptor reflex (31). Thus, the baroreceptor reflex system seems to be involved in the hemodynamic changes induced by DEX. The decrease in MAP was significantly larger in SAD rats than in intact ones. As in the case of the decrease in MAP, the decrease in HR was also significantly larger in SAD rats than in intact ones. These data indicate that the baroreceptor reflex suppresses the MAP and HR change induced by DEX. {alpha}2-Adrenoceptors are particularly important in central nervous baroreflex regulation. IV administration of clonidine induces bradycardia mediated by facilitation of baroreceptor impulses localized in the NTS at the first synapse of baroreceptor fibers (32). The nucleus ambiguus is also suggested to be involved in the baroreflex-mediated bradycardia induced by {alpha}2-adrenoceptor agonists (33). It is possible that icv-administered DEX enhanced the baroreflex-induced bradycardia mediated by activation of the baroreceptor-reflex center of the brainstem, such as NTS and nucleus ambiguus.

Activation of sympathetic activity induced by SAD leads to hypertension in rats (34). The effects of cardiovascular depression induced by clonidine have been reported to be more pronounced in spontaneously hypertensive rats than in normotensive ones (35). Similarly in our study, a comparison between decreased (pretreatment with hexamethonium) and normal (intact) and increased (SAD) sympathetic nerve activity rats, DEX induced the largest inhibition in MAP and HR in SAD rats. These results suggest that the inhibitory effects of DEX in the cardiovascular system are proportional to the level of sympathetic nerve activity.

Our present findings, which show that a decrease in HR was prevented by either atropine or propranolol pretreatment, are consistent with previous research that has demonstrated that bradycardia induced by IV administration of DEX was prevented by autonomic nervous system blockage (36). These results suggest that DEX decreased HR by a reduction in sympathetic tone and an enhanced parasympathetic outflow. Severe bradycardia, including cardiac arrest after administration of {alpha}2 agonists, has been well documented (10,11). In conscious sedation during outpatient colonoscopy, DEX induced a larger decrease in HR and MAP than other anesthetics (12). These studies have indicated that a dose sufficient to produce sedation caused statistically significant hypotension and bradycardia during colonoscopy. Vasovagal reactions have been reported in 0.8% of unsedated patients as a consequence of stretching the colon and mesenteric attachments from looping of the instrument shaft (37). It is possible that DEX exacerbated these vagal effects. These data are supported by our results, in which DEX stimulated parasympathetic nerve tone at the level of the heart. Stimulation of presynaptic {alpha}2-adrenoceptors may modulate acetylcholine release from cholinergic neurons innervating the heart (38). Various mechanisms may contribute to parasympathetic activation of the heart with DEX. The response may result from a sympathovagal interaction at the level of the brainstem. The {alpha}2-agonist stimulates the NTS, which receives sensory information from the cranial, facial, glossopharyngeal, and vagus nerves (39). Chemical stimulation of the NTS induces central parasympathetic augmentation (40). Therefore, central parasympathetic augmentation may be one of the mechanisms responsible for the decreased HR.

The decrease in MAP induced by central DEX was prevented by hexamethonium or propranolol pretreatments. These results indicate that the decrease in MAP was mediated by sympathetic inhibition, which is supported by the fact that decreases in plasma NE and Epi were observed. These sympatholytic actions induced by DEX are also demonstrated in the renal sympathetic nerve activity (7,17). These data suggest that icv administration of DEX decreased central sympathetic outflow through action on the regulatory centers in the brain.

Our results confirm the previous speculation that {alpha}2-agonists induce sympatholytic effects through {alpha}2-adrenoceptors in the central nervous system (41). The major source of circulating Epi is the adrenal glands, although circulating NE spills over into the circulation from its site of release at the neuroeffector junction. The decreased circulating level of Epi after the administration of a large dose of DEX (2.0 µg/kg) suggests the inhibition of the sympathoadrenomedullary system. Clonidine, when administered pre- and intraoperatively, has been shown to reduce postoperative NE and Epi in patients undergoing coronary bypass (42) or major abdominal surgery (43). In our unstressed subjects, baseline plasma Epi levels may have been too low.

Intrathecal administration of DEX produces antinociceptive effects (5) and a similar prolongation in duration of motor and sensory block (4). The largest dose of intrathecal DEX, 100 µg, was used in a sheep model, where a 7-day follow-up showed no neurological deficits in the studied animals (6). In a human study using spinal block, the 2-wk follow-up questionnaire showed that intrathecal DEX preservative-free, at a dose of 3 µg, was not associated with any new onset of back, buttock or leg pain, or weakness (4). In that study, the addition of DEX to bupivacaine did not cause a significant decrease in MAP intraoperatively or postoperatively. Epidural administration of DEX also produced dose-dependent antinociceptive effects (44). These results suggest that DEX may be effective in epidural and spinal anesthesia during intra- and postoperative analgesia in clinical anesthesia. Further studies will be required to define the neurotoxicity of DEX on spinal nerves.

In conclusion, the present study provides the first evidence that icv administration of DEX induced cardiovascular responses mediated by sympathetic inhibition and parasympathetic activation by a central action in conscious, unrestrained rats.


   ACKNOWLEDGMENTS
 
The authors thank Abbott Japan (Osaka, Japan) for providing the dexmedetomidine used in this study.


   Footnotes
 
Accepted for publication August 2, 2007.

Supported by a Grant-in-Aid for Scientific Research (17591642) from the Ministry of Education, Science, Sports, and Culture, Japan, and a grant from the Department of Anesthesiology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.


   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