JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chi, O. Z.
Right arrow Articles by Weiss, H. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chi, O. Z.
Right arrow Articles by Weiss, H. R.
Anesth Analg 2000;90:603-608
© 2000 International Anesthesia Research Society

NEUROSURGICAL ANESTHESIA

The Effects of Morphine on Blood-Brain Barrier Disruption Caused by Intracarotid Injection of Hyperosmolar Mannitol in Rats

Oak Za Chi, MD*, Doo Ik Lee, MD{ddagger}, Xia Liu, MD*, and Harvey R. Weiss, PhD{dagger}

Departments of *Anesthesia, and {dagger}Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey; and {ddagger}Department of Anesthesiology, Kyung Hee University Medical School, Seoul, Korea

Address correspondence and reprints to Oak Za Chi, MD, Department of Anesthesia, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 125 Paterson St., Ste. 3100, New Brunswick, NJ 08901-1977.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
This study was performed to evaluate whether morphine could alter the degree of disruption of the blood-brain barrier (BBB) caused by hyperosmolar mannitol. Under isoflurane anesthesia, rats in a control group were infused with 25% mannitol into the internal carotid artery before measuring the transfer coefficient (Ki) of 14C-{alpha}-aminoisobutyric acid. Infusion of morphine 3 mg/kg in the small-dose morphine group and 10 mg/kg in the large-dose morphine group was completed, 10 min before administering mannitol. There were no statistical differences in systemic blood pressures between these three groups of animals. In the control group, the Ki of the ipsilateral cortex where mannitol was injected, increased to 4.6 times that of the contralateral cortex (19.5 ± 8.5 vs 4.2 ± 1.2 µL · g-1 · min-1, P < 0.002). The Ki of the ipsilateral cortex of the small-dose morphine group was 13.5 ± 7.6 µL · g-1 · min-1. The Ki of the ipsilateral cortex of the large-dose morphine group was 9.2 ± 4.5 µL · g-1 · min-1 and was smaller than that of control animals (P < 0.05). There was no significant difference in the Ki of the contralateral cortex among the three groups. In conclusion, morphine attenuated BBB disruption induced by hyperosmolar solution without significant effects on systemic blood pressure.

Implications: Our study suggests that morphine may be effective in reducing the blood-brain barrier disruption by hyperosmolar mannitol without significant effects on systemic blood pressure.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Maintaining the integrity of the blood-brain barrier (BBB) is essential for homeostasis of the brain. Even with minimal disruption of the BBB, circulating neurotoxins, hormones, and ions could enter into the brain and interfere with the internal milieu resulting in potential damage to neurons (1–2). Anesthetics can reportedly decrease the permeability of the BBB (3–6). However, the mechanism of these alterations has not been determined. The various effects of anesthetics on blood pressure, cerebral metabolism, and the carriers and the pumping systems of the BBB, and their lipid solubility may all affect the permeability of the BBB. During neurosurgery, cerebral edema may occur with BBB disruption in the area near the operation (7). It is important to minimize the degree of BBB disruption during neurosurgical anesthesia.

Our previous study demonstrated that under isoflurane anesthesia, pentobarbital significantly attenuated the BBB disruption induced by hyperosmolar mannitol (6). In this study, morphine was tested to determine whether it could modify the degree of BBB disruption by hyperosmolar mannitol. Morphine has been reported to influence the development of the BBB transport systems of certain peptides (8). However, studies on the effects of morphine on BBB functions are lacking. A decrease of or no effects on cerebral metabolism have been reported with the administration of morphine, and it has a low lipid solubility (9–12). In contrast, barbiturates decrease cerebral metabolism and have a high lipid solubility. They affect systemic blood pressure more profoundly than morphine (12,13). We speculated that administering morphine during isoflurane anesthesia could also alter the degree of BBB disruption through a change of cerebral metabolism, blood pressure, or its other biological activity.

This study was performed to evaluate the effects of an increasing dose of morphine on the degree of BBB disruption caused by hyperosmolar mannitol. Opening of the BBB by hyperosmolar drugs has been used to introduce therapeutic chemicals and antibiotics into the brain tissue (14). This method of opening the BBB was used in this experiment because it is reversible, and its major effects are mostly on the BBB itself (15,16). In this study, small- (3 mg/kg) and large-dose (10 mg/kg) morphine were used to test whether these doses were effective in changing the degree of BBB disruption produced by an intracarotid injection of 25% mannitol in isoflurane anesthetized rats. The transfer coefficient (Ki) of 14C-{alpha}-aminoisobutyric acid (14C-AIB) was used to measure BBB permeability.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
This study was approved by our institutional animal care and use committee. Twenty-one male Long-Evans rats weighing 310–350 g were anesthetized with 1.4% isoflurane in an air and oxygen mixture (FIO2 0.25–0.3). The lungs were mechanically ventilated through a tracheal tube. A femoral artery and a femoral vein were catheterized, and the femoral arterial catheter was connected to a Statham P23AA transducer (Gould Instruments, Cleveland, OH). Blood pressure was continuously monitored and recorded on a R-611 recorder (Beckman, Fullerton, CA). The right common, internal, and external carotid arteries were exposed. The external carotid artery was catheterized with a polyethylene tube after its branches were ligated. The tip of the catheter was placed in the external carotid artery approximately 1 mm distal to the carotid bifurcation. The femoral venous catheter was used to administer drugs and radioactive tracers. Body temperature was maintained at 37°C with a heat lamp and a servocontrolled rectal thermistor throughout the experimental period. Arterial blood pressure was recorded, and 0.2-mL arterial blood samples were drawn anaerobically and analyzed for PaO2, PaCO2, and pH, by using a blood gas analyzer (Model ABL330; Radiometer America, Westlake, OH). Rats were divided into three groups. In the control group (n = 7), no drugs were administered before opening the BBB with hyperosmolar mannitol. In the small-dose morphine group (n = 7), morphine 3 mg · kg was infused IV over a 3-min period. In the large-dose morphine group (n = 7), morphine 10 mg · kg was infused IV over a 10-min period. All of the rats received the same volume of normal saline (approximately 2 mL) during the experimental period. In all of the rats that received morphine, 10 min after the infusion was completed, 25% mannitol was administered to open the BBB. The experiment was performed randomly.

To open the BBB, a solution of 25% mannitol, filtered and warmed to 37°C, was infused through the catheter in the carotid artery for 30 s at a rate of 0.25 mL · kg-1 · s-1. To determine the blood-brain Ki, 2 min after mannitol infusion, 20 µCi of 14C-AIB (Amersham, Arlington Heights, IL) was rapidly injected IV and flushed with 0.5 mL of normal saline. Blood samples were collected from the femoral arterial catheter at 20 s intervals for the first 2 min and then, every minute for the next 8 min. Five minutes after injecting 14C-AIB, 20 µCi of 3H-dextran (70,000 daltons; Amersham, Arlington Heights, IL) was injected IV and flushed with 0.5 mL of normal saline. After collecting the 10-min arterial blood samples, the animals were decapitated, and their brains were quickly frozen in liquid nitrogen. The following brain regions were dissected: ipsilateral cortex (where mannitol was injected), contralateral cortex, cerebellum, basal ganglia, and pons. Brain samples were solubilized in SolueneTM (Packard, Downers Grove, IL) before counting the radioactivity. Arterial blood samples were centrifuged, and the plasma was separated. Plasma and brain samples were counted on a liquid scintillation counter that was equipped for dual label counting. Quench curves were prepared by using carbon tetrachloride, and all samples were automatically corrected for quenching. The blood-brain Ki for 14C-AIB was determined by assuming a unidirectional transfer of 14C-AIB over a 10-min period of the experiment by using the following equation as described by Gross et al. (17): Go


where Am is the amount of 14C-AIB radioactivity in the tissue per gram, and Vp is the volume of plasma retained in the tissue. It is determined from the 3H-dextran data and the following equation: Vp = A'm/C'p; where A'm is the amount of 3H-dextran radioactivity in the tissue per gram, and C'p is the concentration of 3H-dextran in the plasma at the time of decapitation. Cp(t) is the arterial concentration of 14C-AIB over time t, and CT is the arterial plasma concentration of 14C-AIB at the time of decapitation. In the equation used to determine Ki, Vp x CT is a correction term which accounts for the label 14C retained in the vascular compartment of the tissue, Am.

A factorial analysis of variance was used to assess the differences in Ki between the experimental groups and between the various examined regions, and the differences in vital signs, blood gases, and hemoglobin concentration between all of the experimental groups. The factors considered were treatment and regions. The statistical significance of difference was determined by using Duncan’s procedure. All data were expressed as means ± SD, and significance was defined as P < 0.05.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Arterial blood pressure and heart rate were similar between the control, small-dose morphine, and large-dose morphine groups before administering morphine (Table 1). After administering 3 mg/kg (small-dose morphine group) or 10 mg/kg of morphine (large-dose morphine group), the blood pressure and heart rate were not significantly altered from the pretreatment values. The posttreatment vital signs were not significantly different from those of the control animals. Ventilation was adjusted to keep the blood gases within the normal range during the experimental period and to keep it similar among the groups. Blood gases and the hemoglobin concentration of the control group were pH, 7.39 ± 0.07; PaCO2 33 ± 3 mm Hg; PaO2 108 ± 12 mm Hg; and hemoglobin 12.8 ± 0.7 g/100 mL. For the small-dose morphine group, these values were 7.36 ± 0.05, 35 ± 4 mm Hg, 113 ± 20 mm Hg, and 11.8 ± 0.7 g/100 mL, respectively. For the large-dose morphine group, these values were 7.39 ± 0.04, 37 ± 5 mm Hg, 116 ± 17 mm Hg, and 12.5 ± 1.3 g/100 mL, respectively.


View this table:
[in this window]
[in a new window]
  		Table 1. Vital Signs Before and After Treatment with Morphine
 
The Ki of the contralateral cortex of the control group was 4.2 ± 1.2 µL · g-1 · min-1 (Figure 1). In the ipsilateral cortex where the hyperosmolar mannitol was injected, the Ki was 4.6 times that of the contralateral cortex (P < 0.002). In the small-dose morphine group, the Ki of the contralateral cortex was 3.8 ± 2.4 µL · g-1 · min-1, and the Ki of the ipsilateral cortex was approximately 3.6 times that of the contralateral cortex (P < 0.05). In the large-dose morphine group, the Ki of the contralateral cortex was 4.0 ± 1.2 µL · g-1 · min-1, and the Ki of the ipsilateral cortex was approximately 2.3 times that of the contralateral cortex (P < 0.05). There was no statistically significant difference in the Ki of the contralateral cortex among these three groups of animals. The Ki of the ipsilateral cortex of the large-dose morphine group was 53% smaller (by 10.3 µL · g-1 · min-1) than that of the control group (P < 0.05). The difference in the Ki of the ipsilateral cortex between the control and the small-dose morphine groups, or between the small-dose morphine and the large-dose morphine groups was not statistically significant (Figure 1).



View larger version (26K):
[in this window]
[in a new window]
  		Figure 1. Ki, transfer coefficient of 14C-{alpha}-aminoisobutyric acid of the ipsilateral and the contralateral cortices of all of the experimental groups. Values are mean ± SD. *Significantly different from the corresponding data of the contralateral cortex in the same group. {dagger}Significantly different from the corresponding data of the control group.

 
In all of the experimental groups, the Ki of all of the noncortical regions was similar to that of the corresponding contralateral cortex in the same group and was similar among groups in each brain region. The Ki of cerebellum, pons, and basal ganglia of the control animals were 6.3 ± 1.9, 4.9 ± 1.6, and 6.3 ± 4.3 µL · g-1 · min-1, respectively. For the small-dose morphine group, they were 6.1 ± 2.8, 3.3 ± 1.5, and 3.8 ± 1.5 µL · g-1 · min-1, respectively. For the large-dose morphine group, they were 5.1 ± 1.3, 4.5 ± 1.2, and 5.6 ± 1.7 µL · g-1 · min-1, respectively.

In the control group, the calculated plasma volume of the ipsilateral cortex of the control group was significantly higher than that of the contralateral cortex (+34%, P < 0.05, Table 2). In the small- and in the large-dose morphine groups, there were no statistical differences in the Ki between the contralateral cortex and the ipsilateral cortex. There were no statistical differences in the plasma volume between the noncortical brain regions and the contralateral cortex in the same group or between the groups in the same region.


View this table:
[in this window]
[in a new window]
  		Table 2. Plasma Volume of Brain Regions in the Experimental Groups
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Our data demonstrate that, under isoflurane anesthesia, administering a large dose of morphine significantly reduced the Ki of 14C-AIB when the BBB was disrupted by hyperosmolar mannitol. There was no significant change in systemic blood pressure.

All of the animals in this study were anesthetized with the same concentration of isoflurane. Therefore, the effects of isoflurane on Ki should have been equal in the three groups of animals (3). The blood gases including PaCO2 were similar between the experimental groups. Because transfer of 14C-AIB across the BBB is usually independent of cerebral blood flow, measuring cerebral blood flow was considered unnecessary (18,19). The rate and duration of infusion and the concentration of hyperosmolar mannitol that was used, have been reported to produce a reversible and optimal opening of the BBB without serious immediate or delayed neurotoxicity (15). Osmolarity of a substance and duration of its intraarterial infusion, regions of the brain, anesthetics, blood pressure, PaCO2, and steroids can all affect the degree of osmotic disruption of the BBB (15,20).

Anesthetics reportedly alter BBB permeability in normal, as well as in BBB-disrupted areas of the brain. Saija et al. (5) demonstrated, in their in vivo study, that pentobarbital and ketamine decreased the Ki of 14C-AIB when compared with the awake state. Our previous studies also showed decreased Ki of 14C-AIB under isoflurane or fentanyl anesthesia when compared with the awake state (3,4). The results of our previous works showed that, under isoflurane anesthesia, adding pentobarbital did not affect Ki significantly in normal tissue. However, when the BBB was disrupted, pentobarbital did attenuate the degree of its disruption (6). The mechanism of this protective effect of anesthetics on BBB function is not clear. Perhaps, most anesthetics have some protective effect on the BBB. Therefore, we hypothesized that the degree of osmotic BBB disruption could be altered by treatment with morphine, although its effect on blood pressure or cerebral metabolism is not profound, and it has a low lipid solubility (9–12). This experiment showed that morphine was effective in reducing disruption of the BBB during isoflurane anesthesia.

In this study, the plasma volume measured with 3H-dextran reflects the actual intravascular plasma volume as well as the amount of 3H-dextran that leaked into the brain tissue. The plasma volume of the ipsilateral cortex was greater than that of the contralateral cortex in the control animals. This suggests that mannitol increased actual plasma volume and/or disrupted the BBB, causing extravasation of dextran. The difference in the plasma volume between the ipsilateral and contralateral cortex became insignificant with the administration of morphine. Our data suggest that morphine attenuated the leakage and/or decreased the actual plasma volume.

It has been suggested that blood pressure is one of the most important factors in determining the degree of the BBB disruption (6,21). The difference of mean arterial blood pressure between the large-dose morphine group and the control group was not statistically significant (87 ± 29 vs 105 ± 19 mm Hg) despite a 53% difference in the Ki of the ipsilateral cortex. In the small-dose morphine group, the degree of alteration of Ki was much greater (-31%) than that of the blood pressure change (-6%), although there was no statistical significance for either variable. Our data suggest that alteration of blood pressure by morphine was not likely the primary reason for the attenuation of hyperosmolar disruption of the BBB by large-dose morphine. Nevertheless, our data cannot completely eliminate the influence of morphine on blood pressure as the cause of attenuation of the hyperosmolar disruption of the BBB, because there may have been a significant difference between these groups if more animals had been tested. In the contralateral cortex and noncortical regions of the brain, there was no significant difference in the Ki among three groups of animals. These data suggest that in a normal brain, baseline BBB permeability was not affected by adding morphine during isoflurane anesthesia.

One of the primary mechanisms of morphine in attenuating the BBB disruption could be related to its metabolic effect. Previous studies showed that in the presence of anesthetics, such as nitrous oxide or halothane, morphine decreased the cerebral metabolic rate (10,11), whereas in the absence of anesthetics, no change in cerebral metabolic rate was reported (9). In this study, it is possible that morphine attenuated hyperosmolar disruption of the BBB by decreasing cerebral metabolism. In one study, a 43% increase in oxygen consumption was demonstrated in the ipsilateral cortex where mannitol was injected when compared with that of the contralateral cortex (22). Pappius et al. (23) reported an increase in local cerebral glucose uptake after BBB disruption by hyperosmolar mannitol. This increase in metabolism after BBB disruption could be caused by the transport of catecholamines or neurotransmitters from blood or the release of them from brain parenchyma in response to disturbances in the internal milieu of the brain (1,24). Those substances may, in turn, affect BBB function. There is evidence that capillary transport can affect the metabolic rate, and that neuronal activity and the metabolic rate can affect capillary transport (25,26). In this study, morphine could have suppressed this increased metabolism caused by disrupting the BBB, resulting in a decreased Ki.

Another possible mechanism of BBB protection caused by morphine could be its direct action on the BBB. A substance that has a high affinity for lipids dissolves into biological membranes and may affect the size and shape of intercellular tight junctions (27,28). Because morphine has a low lipid solubility (0.8;1, fat/plasma protein partition coefficient), this possibility is remote (12). Morphine may also directly affect carriers or the pumping systems of the BBB. Perhaps, protecting BBB is one of the general properties of anesthetics.

In conclusion, our study demonstrated that large-dose morphine attenuated BBB disruption caused by hyperosmolar mannitol without a significant alteration in systemic blood pressure. The mechanism of this effect of morphine is not clear; however, the blood pressure effect of morphine is not likely to be the primary cause of the attenuation of BBB disruption.


   Acknowledgments
 
The authors wish to thank Patricia A. Sheffield, MA, for her expert editorial assistance.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Johansson BB, Nordborg C, Westergren I. Neuronal injury after transient opening of the blood-brain barrier: modifying factors. In: Johansson BB, Owman C, Widner H, eds. Pathophysiology of the blood-brain barrier. Fernstrom Foundation Series. Vol 14. Amsterdam:Elsevier, 1990:145–57.
  2. Murakami K, Kondo T, Chan PH. Blood-brain barrier disruption: edema formation and apoprotic neuronal death following cold injury. Suppl (Wien) 1997;70:234–6.
  3. Chi OZ, Anwar M, Sinha AK, Weiss HR. Effects of isoflurane on transport across the blood-brain barrier. Anesthesiology 1992;76:426–31.[ISI][Medline]
  4. Chi OZ, Wei HM, Anwar M, et al. Effects of fentanyl on {alpha}-aminoisobutyric acid transfer across the blood-brain barrier. Anesth Analg 1992;75:31–6.[Abstract/Free Full Text]
  5. Saija A, Princi P, De Pasquale R, Costa G. Modifications of the permeability of the blood-brain barrier and local cerebral metabolism in pentobarbital- and ketamine-anesthetized rats. Neuropharmacology 1989;28:997–1002.[ISI][Medline]
  6. Chi OZ, Chun TW, Liu X, Weiss HR. The effects of pentobarbital on blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats. Anesth Analg 1998;86:1230–5.[Abstract]
  7. Allen MB Jr, Johnston KW. Preoperative evaluation: complications, their prevention and treatment. In: Wonsiewicz M, ed. Youmans neurological surgery. Vol 2. Philadelphia:WB Saunders, 1990:833–900.
  8. Banks WA, Kastin AJ, Harrison LM, Zadina JE. Perinatal treatment of rats with opiates affects the development of the blood-brain barrier transport system PTS-1. Neurotoxicol Teratol 1996;18:711–5.[ISI][Medline]
  9. Levy RM, Fields HL, Stryker MP, Heinricher MM. The effect of analgesic doses of morphine on regional cerebral glucose metabolism in pain-related structures. Brain Res 1986;368:170–3.[ISI][Medline]
  10. Matsumiya N, Dohi S. Effects of intravenous subarachnoid morphine on cerebral and spinal cord hemodynamics and antagonism with naloxone in dogs. Anesthesiology 1983;59:175–81.[ISI][Medline]
  11. Takeshita H, Michenfelder JD, Theye RA. The effects of morphine and N-allylnormorphine on canine cerebral metabolism and circulation. Anesthesiology 1972;37:605–12.[ISI][Medline]
  12. Bailey PL, Stanley TH. Narcotic intravenous anesthetics. In: Miller RD, ed. Anesthesia. New York:Churchill Livingstone, 1990:281–366.
  13. Fragen RJ, Avram MJ. Barbiturates. In: Miller RD, ed. Anesthesia. New York:Churchill Livingstone, 1994:229–46.
  14. Gumerlock MK, Belshe BD, Madsen R, Watts C. Osmotic blood-brain barrier disruption and chemotherapy in the treatment of high grade malignant glioma patient series and literature review. Neurooncol 1992;12:33–46.
  15. Cosolo WC, Martinello P, Louis WJ, Chrisophidis N. Blood-brain barrier disruption using mannitol: time course and electron microscopy studies. Am J Physiol 1989;256:R443–7.[Abstract/Free Full Text]
  16. Brightman MW, Hori M, Rapoport SI, et al. Osmotic opening of tight junctions in cerebral endothelium. J Comp Neurol 1973;152:317–25.[ISI][Medline]
  17. Gross PM, Blasberg RG, Fenstermacher JD, Patlak CS. The microcirculation of rat circumventricular organs and pituitary gland. Brain Res Bull 1987;18:73–85.[ISI][Medline]
  18. Smith QR. Quantitation of blood-brain barrier permeability. In: Neuwelt EA, ed. Implications of the blood-brain barrier and its manipulation. Vol 1. Basic science aspects. New York: Plenum, 1989:85–118.
  19. Bradbury MW. Transport across the blood-brain barrier. In: Neuwelt EA, ed. Implications of the blood-brain barrier and its manipulation. Vol 1. Basic science aspects. New York: Plenum, 1989:119–36.
  20. Neuwelt EA, Barnett PA. Blood-brain barrier disruption in the treatment of brain tumors: animal studies. In: Neuwelt EA, ed. Implications of the blood-brain barrier and its manipulation. Vol 2. Clinical aspects. New York: Plenum, 1989:107–93.
  21. Chi OZ, Chang Q, Wang G, Weiss HR. Effects of nitric oxide on blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats. Anesth Analg 1997;84:370–5.[Abstract]
  22. Chi OZ, Wei HM, Lu X, Weiss HR. Increased blood-brain permeability with hyperosmolar mannitol increases cerebral O2 consumption and O2 supply/consumption heterogeneity. Flow Metab 1996;16:327–33.
  23. Pappius HM, Savaki HE, Fieschi C, et al. Osmotic opening of the blood brain barrier and local cerebral glucose utilization. Neurol 1979;5:211–9.
  24. MacKenzie ET, McCulloch J, O’Kean M, et al. Cerebral circulation and norepinephrine: relevance of the blood-brain barrier. Am J Physiol 1976;231:481–8.
  25. De Vivo DC, Trifiletti RR, Jacobson RI, et al. Defective glucose transport across the blood-brain barrier as a cause of persistent hypoglycorrhachia, seizures, and developmental delay. N Engl J Med 1991;325:703–9.[ISI][Medline]
  26. Lear JL, Kasliwal RK. Autoradiographic measurement of cerebral lactate transport rate constants in normal and activated conditions. J Cereb Blood Flow Metab 1991;11:576–80.[ISI][Medline]
  27. Seeman P. The membrane action of anesthetics and tranquilizers. Pharmacol Rev 1972;24:583–655.[Abstract]
  28. Franks NP, Leib WR. What is the molecular nature of general anesthetic target sites. Trends Pharmacol Sci 1987;8:169–74.
Accepted for publication November 2, 1999.




This article has been cited by other articles:


Home page
 J. Am. Soc. Nephrol.Home page
Y. A. IOANNOU
Gene Therapy for Lysosomal Storage Disorders with Neuropathology
J. Am. Soc. Nephrol., August 1, 2000; 11(8): 1542 - 1547.
[Full Text]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (3)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chi, O. Z.
Right arrow Articles by Weiss, H. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chi, O. Z.
Right arrow Articles by Weiss, H. R.

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