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Anesth Analg 1999;89:370
© 1999 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

Intravenous Dexmedetomidine Inhibits Cerebrovascular Dilation Induced by Isoflurane and Sevoflurane in Dogs

Hiroto Ohata, MD, Hiroki Iida, MD, Shuji Dohi, MD, and Yukinaga Watanabe, MD

Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Gifu, Japan

Address correspondence and reprint requests to Hiroki Iida, MD, Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Gifu City, Gifu 500-8705, Japan. Address e-mail to iida{at}cc.gifu-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Our aim in this study, performed using a closed cranial window preparation, was to investigate the effect of systemic pretreatment with dexmedetomidine on cerebrovascular response to isoflurane or sevoflurane. After instrumentation under pentobarbital anesthesia, 48 dogs were assigned to one of two groups: the isoflurane group or the sevoflurane group (n = 24 each). Twenty-four dogs received saline (n = 6) or one of three different doses of dexmedetomidine (0.5, 1.0, or 2.0 µg/kg) (n = 6 each) IV. Animals were then exposed to three different minimum alveolar anesthetic concentrations (MACs; 0.5, 1.0, and 1.5) of either isoflurane or sevo- flurane. Cerebrovascular diameters were measured at each stage. Pretreatment with dexmedetomidine decreased pial vessel diameters. Both isoflurane and sevoflurane significantly dilated both arterioles and venules in a concentration-dependent manner. Isoflurane- and sevoflurane-induced dilation of cerebral arterioles was significantly attenuated in the presence of dexmedetomidine. The dexmedetomidine-induced attenuation of the vascular responses was not dependent on the dose of dexmedetomidine and was not different between isoflurane and sevoflurane. The vasodilation of cerebral pial vessels induced by isoflurane and sevoflurane could be attenuated by the systemic administration of dexmedetomidine, and this interaction between dexmedetomidine and volatile anesthetics showed no evidence of dose-dependency.

Implications: The systemic administration of dexmedetomidine attenuates the dilation of cerebral vessels induced by isoflurane and sevoflurane in pentobarbital-anesthetized dogs. This interaction was not dependent on the clinical (0.5–2.0 µg/kg) dose of dexmedetomidine and was not different between isoflurane and sevoflurane anesthesia.


   Introduction
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 Abstract
 Introduction
Methods
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 Discussion
 References
 
|ga;-2q;40q;1q2-Adrenergic receptors are widely distributed within the cerebral vasculature, and specific cerebral vasoconstrictive responses produced by activation of these receptors have been proposed (1). Because of the high potency and selectivity of dexmedetomidine as an {alpha}2-adrenoceptor agonist, it would be expected to affect cerebral vasculature. Indeed, local application through a cranial window causes pial arteriolar constriction in pentobarbital-anesthetized dogs (2) and isoflurane-anesthetized rats (3). The systemic administration of 20 µg/kg dexmedetomidine decreases pial arteriolar diameter in halothane-anesthetized rats (4).

It has been reported that volatile anesthetics such as isoflurane and sevoflurane can exert significant vasodilator effects on a variety of vascular beds (5–7). These anesthetics are often used in neurosurgical anesthesia for uncoupling of the cerebral blood flow (CBF) and metabolism (8,9). The effect of systemic administration of dexmedetomidine on the cerebrovascular dilation induced by clinical doses of isoflurane and sevoflurane has not been well defined. We therefore performed a dose-response study of dexmedetomidine to compare cerebrovascular responses to isoflurane or sevoflurane. {alpha}2-Adrenoceptors are present on both small and large cerebral arterioles (10,11) and can participate in sympathetic vasoconstriction (12). However, larger arterioles respond more to sympathetic stimulation (13). Accordingly, we also examined the responses in different pial vessel sizes.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
The experimental protocols were approved by our institutional committee for animal care. Forty-eight dogs weighing 6–12 kg were anesthetized with IV pentobarbital sodium (20 mg/kg) and subsequently maintained on a continuous infusion of pentobarbital sodium (2 mg · kg-1 · h-1) for the entire experiment. After tracheal intubation, the lungs were mechanically ventilated with oxygen-enriched room air (50 vol% oxygen). The tidal volume and respiratory rate were adjusted to maintain a PaCO2 of 35–40 mm Hg. Polyvinyl chloride catheters were placed in the left femoral vein and artery for the administration of drugs and fluid (6 mL · kg-1 · h-1), as well as for arterial blood pressure measurements and blood sampling. The rectal temperature was maintained at 36.5–37.5°C by a water-circulated warming blanket.

A closed cranial window was used to observe the pial microcirculation. Each anesthetized animal was placed in the sphinx position, with the head immobilized in a stereotaxic frame. Another catheter was placed in the sagittal sinus for blood sampling. The scalp was retracted, the temporal muscle was removed, and a hole 2 cm in diameter was made in the parietal bone. After coagulation of dural vessels using a bipolar electrocoagulator, the dura and arachnoid membrane were cut and retracted over the bone. A ring fitted with a cover glass was secured over the hole with the aid of bone wax and dental acrylic. The space under the window was filled with artificial cerebrospinal fluid (aCSF). The composition of aCSF was Na+ 151 mEq/L, K+ 4 mEq/L, Ca2+ 3 mEq/L, Cl- 110 mEq/L, and glucose 100 mg/dL; pH was adjusted to 7.48, and the solution was bubbled with 5% CO2 in air at 37.0°C. The volume of fluid below the window was 0.5–1.0 mL. Four polyvinyl chloride catheters were inserted through the ring. One catheter was attached to a reservoir bottle containing aCSF, which allowed adjustment of intrawindow pressure. Two catheters were used for drainage of aCSF, and the last one was used for continuous monitoring of intrawindow pressure.

All experiments were performed in vivo using the following protocols. The animals were allowed to recover from the surgical procedures for at least 30 min. We examined the cerebrovascular response to isoflurane or sevoflurane after the systemic administration of dexmedetomidine. Forty-eight dogs were randomly divided into two groups (n = 24 each): the isoflurane group (ISO) or the sevoflurane group (SEV). After pretreatment values, including pial vascular diameters, mean arterial pressure (MAP), heart rate, arterial and sagittal blood gas tensions, and pH, had been measured, each of 24 dogs received saline (control group; CONT; n = 6) or one of three different doses (0.5, 1.0, or 2.0 µg/kg) of dexmedetomidine (DEX-0.5, DEX-1.0, and DEX-2.0, respectively; n = 6 each) IV. In the CONT group, dogs were given 5 mL of saline IV via an infusion pump over a 15-min period. Posttreatment values were then measured. Fifteen minutes after the saline infusion, baseline values were measured. The dogs were then assigned to consecutively receive three different minimum alveolar anesthetic concentrations (MAC) measured by end-tidal concentration: 0.5, 1.0, and 1.5 MAC [1.39% for 1.0 MAC of isoflurane and 2.36% for 1 MAC of sevoflurane in dogs, respectively (14)] of either isoflurane (n = 6) or sevoflurane (n = 6). The administration of the volatile anesthetic was begun soon after the baseline measurements had been taken. During exposure to each volatile anesthetic, the switch was made from one concentration to the next with an interval of at least 15 min between concentrations. Experimental variables were measured again after a 15-min equilibration period under each dose of volatile anesthetic. In the DEX groups, dogs were pretreated with dexmedetomidine (0.5, 1.0, or 2.0 µg/kg given as a 5-mL IV infusion over 15 min) instead of saline; in all other respects, the protocols were the same as those used for the CONT group.

In each dog, the inner diameters of four pial arterioles and four pial venules (two each were >=100 µm, two each were <100 µm) were measured using a videomicrometer (Model VM-20; Flovel, Tokyo, Japan) attached to a microscope (Model OMK-1; Olympus, Tokyo, Japan) by another investigator. The data from each pial view were stored on videotape for later playback and analysis. The percent changes recorded for individual arteriolar and venular segments were averaged for each type of vessel in each dog, and this average value was used in the statistical analysis. Arterial and sagittal sinus blood gas tensions and pH were measured at 37°C immediately after withdrawal using STAT Profile-5® (NOVA Biomedicals, Waltham, MA). Oxygen saturation and hemoglobin were measured spectrophotometrically using a Radiometer Hemoximeter OSM-3® (Radiometer, Copenhagen, Denmark). Arterial and cerebral venous oxygen contents were calculated from the measured oxygen saturation and hemoglobin concentration and corrected for dissolved oxygen. The cerebral oxygen extraction (COE) ratio was calculated by dividing the arterial to sagittal sinus oxygen content difference by the arterial oxygen content.

In all experiments, we maintained arterial blood pressure constant at baseline values by using a continuous IV infusion of phenylephrine; this counteracted the decreases in arterial blood pressure associated with the administration of anesthetics.

Values are given as mean ± SD. A two-way analysis of variance within anesthetic groups and within pretreatment drug groups was used to compare pial vessel diameter, percent change in diameter with respect to baseline diameter, blood gas and hemodynamic variables, and dose of phenylephrine during the various measurement periods. P < 0.05 was considered significant. If a significant anesthetic or pretreatment drug effect was demonstrated, a subsequent one-way repeated-measures analysis of variance, followed by a paired t-test with Bonferroni correction, was performed to assess the effect within a group, and a one-way analysis of variance, followed by an unpaired t-test with Bonferroni correction, was performed to assess the difference between groups.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
No significant differences for hemodynamic and physiologic variables, such as MAP, arterial blood gas tension, and pH, were found when pretreatment values were compared between groups (Table 1 ). Posttreatment values of heart rate was decreased, and that of MAP was increased significantly after the administration of DEX-1.0 and DEX-2.0 in both the ISO and SEV groups (Table 1). After initiating the dexmedetomidine infusion, a transient dose-dependent increase in MAP was observed in all animals. This was followed by a progressive decrease in MAP for all doses of dexmedetomidine, although values returned to pretreatment values by 30 min. MAP and PaCO2 were maintained at baseline values during the administration of each MAC of isoflurane and sevoflurane (Table 2 ). Isoflurane and sevoflurane increased cerebral venous oxygen content (CvO2) and decreased COE in a dose-dependent manner in both the CONT and DEX groups, but these responses were not different between isoflurane or sevoflurane, with or without dexmedetomidine (Table 3 ). The IV administration of dexmedetomidine itself produced a significant decrease in the diameter of the pial vessels examined in both volatile anesthetic groups, and this vasoconstrictive action for dexmedetomidine was not dose-dependent (Table 4 ).


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  		Table 1. Hemodynamic and Physiological Measurements
 

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  		Table 2. Hemodynamic Measurements
 

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  		Table 3. Physiological Variables
 

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  		Table 4. Diameters of Cranial Vessels (µm)
 
Isoflurane and sevoflurane significantly dilated pial vessels in a similar concentration-dependent manner (Figures 1 and 2 ). The administration of dexmedetomidine significantly decreased: 1) the isoflurane- and sevoflurane-induced increase in the diameter of small arterioles (<100 µm) at 0.5, 1.0, and 1.5 MAC in the DEX-0.5 group; 2) the sevoflurane-induced increase in large arterioles (>=100 µm) at 0.5, 1.0, and 1.5 MAC in the DEX-0.5 group; 3) the isoflurane-induced increase in the diameter of small arterioles at 1.0 and 1.5 MAC in the DEX-1.0 group; and 4) the sevoflurane-induced increase in the diameter of large and small arterioles at 1.5 MAC in the DEX-1.0 group and small arterioles at 1.5 MAC in the DEX-2.0 group. Among the venous vessels examined, only small venules at 1.0 and 1.5 MAC in the ISO group showed a significant reduction with DEX-0.5 in the volatile anesthetic-induced diameter increase (Figures 1 and 2). Dose-dependent effects of dexmedetomidine on the cerebrovascular dilator effects of isoflurane and sevoflurane were not observed with the dose range used in this study.



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  		Figure 1. Percent change (increase) in large (>=100 µm) arteriolar (A), small (<100 µm) arteriolar (B), large venular (C), and small venular (D) diameters with three different minimum alveolar anesthetic concentrations (MACs) of isoflurane (ISO) and the effect of different doses of dexmedetomidine (DEX) when given as pretreatment. CONT = saline control group, DEX-0.5 = 0.5 µg/kg dexmedetomidine group, DEX-1.0 = 1.0 µg/kg dexmedetomidine group, DEX-2.0 = 2.0 µg/kg dexmedetomidine group. *P < 0.05.

 


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  		Figure 2. Percent change (increase) in large (>=100 µm) arteriolar (A), small (<100 µm) arteriolar (B), large venular (C), and small venular (D) diameters with three different minimum alveolar anesthetic concentrations (MACs) of sevoflurane (SEV) and the effect of different doses of dexmedetomidine (DEX) when given as pretreatment. CONT = saline control group, DEX-0.5 = 0.5 µg/kg dexmedetomidine group, DEX-1.0 = 1.0 µg/kg dexmedetomidine group, DEX-2.0 = 2.0 µg/kg dexmedetomidine group. *P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our major findings are that the systemic administration of dexmedetomidine reduces the cerebral vascular dilation induced by isoflurane and sevoflurane and that these reductions are more striking in arterioles than in venules. Moreover, the effect on the reduced dilator response to isoflurane and sevoflurane is not dependent on the dose of dexmedetomidine. The concentration-dependent decrease in COE seen with both isoflurane and sevoflurane was similar in the CONT and DEX groups, and increasing the dose of dexmedetomidine (0.5–2.0 µg/kg) did not affect COE for either isoflurane or sevoflurane.

The mechanism underlying the dexmedetomidine-induced attenuation of vasodilator responses we observed is not clear. Zornow et al. (15) suggested that decrease in CBF induced by the systemic administration of dexmedetomidine might have been due to an {alpha}2-adrenoceptor–mediated vasoconstriction of cerebral resistance vessels. We have previously shown that dexmedetomidine constricts pial arterioles and venules in dogs and that such responses are mediated by {alpha}2-adrenergic stimulation (2). Ganjoo et al. (4) investigated the in vivo effects of the systemic administration of dexmedetomidine (20 µg/kg) on pial arteriolar diameter in rats and suggested that the vasoconstrictive effects of dexmedetomidine may be differentially and regionally mediated. Moreover, Asano et al. (3) demonstrated that dexmedetomidine might cause vasoconstriction not only by a local {alpha}2-adrenergic mechanism, but also at different sites in the central nervous system (3). Thus, vasoconstriction mediated via the effects of a peripheral {alpha}2-adrenergic mechanism, and the stimulation of central nervous system by {alpha}2-agonists could be responsible for dexmedetomidine attenuation of the vasodilator effects of volatile anesthetics.

Volatile anesthetics increase cyclic adenosine monophosphate (cAMP), leading to activation of protein kinases and, thereby, enhanced calcium extrusion and relaxation in the rat aorta (16). However, the effector mechanism associated with {alpha}2-adrenoceptors seems to involve inhibitory membrane-bound guanine nucleotide-binding proteins (17). These proteins regulate an inhibition of adenylate cyclase and result in decreasing accumulation of cAMP (18). These opposing effects of volatile anesthetics and {alpha}2-agonists on cAMP may, at least in part, explain how dexmedetomidine can attenuate the vasodilator effect of volatile anesthetics. However, these ideas are only speculative.

We did not observe any dose-dependency in the attenuating effects of dexmedetomidine on the cerebrovascular dilation induced by isoflurane and sevoflurane. Asano et al. (3) demonstrated that the systemic administration of dexmedetomidine (1 and 10 µg/kg) caused a dose-related vasoconstrictive response in rat pial arterioles during 1.5 MAC isoflurane anesthesia. This difference in the effect of dose response may be due to the species differences (dog versus rat), the presence or absence of pentobarbital and phenylephrine at time of measurement, and/or dose differences of dexmedetomidine.

We have previously shown that the vasodilation of cerebral pial vessels induced by isoflurane and sevoflurane seems to be mediated, at least in part, via activation of ATP-sensitive potassium channels (19). Although it has been reported that ATP-sensitive potassium channels of neuronal cells can be activated by {alpha}2-agonist stimulation (20), we have few data as to whether ATP-sensitive potassium channels in the cerebral vascular structure are activated by dexmedetomidine (2). In an in vivo study in a canine model with a cranial window, Ishiyama et al. (2) demonstrated that a higher concentration of dexmedetomidine (10-3 M) had a weaker vasoconstrictor action than lower concentrations and suggested that this might be related to activation of an ATP-sensitive potassium channel by dexmedetomidine. Therefore, the lack of a dose-dependent effect of dexmedetomidine may be due, at least in part, to conformation effects of two volatile anesthetics and dexmedetomidine at ATP-sensitive potassium channels.

The dose of dexmedetomidine used in clinical studies is 0.3–1.0 µg/kg (21–23). We found several animal studies examining the cerebrovascular effects of dexmedetomidine (3,4,15,24–26), but only 10 µg/kg dexmedetomidine has been studied in a canine model (15,24). Clinical inferences should be made with caution because of the different dose of dexmedetomidine (>10-fold greater than clinically relevant doses). Thus, we used a clinically relevant dose of dexmedetomidine.

Although authors of a previous study demonstrated that pentobarbital has a limited effect on cerebrovascular tone in canine isolated vessel experiments (27), we cannot exclude the possibility that the observed effects on pial vessel reactivity induced by dexmedetomidine during isoflurane and sevoflurane anesthesia were affected by the presence of pentobarbital. In addition, the interaction of phenylephrine used for maintaining blood pressure during inhalation of isoflurane or sevoflurane in our study may have influenced the effect of volatile anesthetics on cerebral vasodilation and the effect of dexmedetomidine on cerebral vasoconstriction.

In conclusion, the systemic administration of dexmedetomidine attenuates the cerebral vascular dilator effect induced by isoflurane and sevoflurane. The mechanism underlying this effect may be related to its direct vasoconstrictor action as an {alpha}2-adrenoceptor agonist and/or to opposing actions on the same pathway by both dexmedetomidine and volatile anesthetics. The effect of dexmedetomidine on the isoflurane- and sevoflurane-induced dilator responses showed no evidence of dose-dependency.


   Acknowledgments
 
This work was supported by Grant-in-Aid for Scientific Research 09671555 from the Ministry of Education, Science and Culture, Japan.


   Footnotes
 
Presented in part at the annual meeting of the International Symposium on Cerebral Blood Flow and Metabolism, Baltimore, MD, June 15–19, 1997.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication April 28, 1999.




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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 1999 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press