(Stroke. 1996;27:729-736.)
© 1996 American Heart Association, Inc.
Articles |
From the Departments of Anesthesiology/Critical Care Medicine (T.H., R.C.K., T.K., R.J.T.) and Pediatrics (S.W.B.), The Johns Hopkins Medical Institutions, Baltimore, Md.
| Abstract |
|---|
|
|
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Methods Pentobarbital-anesthetized rats were
pretreated intravenously with either saline vehicle,
methionine sulfoximine (0.83 mmol/kg), which inhibits glutamine
synthetase and potentially
-glutamylcysteine synthetase, or
buthionine sulfoximine (4 mmol/kg), which inhibits
-glutamylcysteine synthetase. Three hours after pretreatment,
cohorts received an intravenous infusion of either sodium
or ammonium acetate for 6 hours. Pial arteriolar diameter was measured
through a closed cranial window, and blood flow was measured with
radiolabeled microspheres during normocapnia and 10 minutes of
hypercapnia.
Results With sodium acetate infusion, pial arteriolar diameter increased during hypercapnia in groups pretreated with vehicle (23±3% [mean±SE]; n=6), methionine sulfoximine (37±11%; n=5), and buthionine sulfoximine (32±3%; n=5). With ammonium acetate infusion, pial arteriolar diameter increased only in the group pretreated with methionine sulfoximine (31±4%; n=8) but not in those pretreated with vehicle (-2±4%; n=8) or buthionine sulfoximine (4±4%; n=6). Methionine sulfoximine, but not buthionine sulfoximine, also prevented loss of the cerebral blood flow response to hypercapnia, an increase in cortical tissue water content, and an increase in pressure under the cranial window during normocapnia in hyperammonemic rats. In contrast to hypercapnia, hypoxemia increased arteriolar diameter 30±7% (n=5) during ammonium acetate infusion.
Conclusions Loss of the blood flow response to hypercapnia during acute hyperammonemia is not due simply to swollen astrocyte processes passively impeding blood flow because extraparenchymal resistance arterioles also lose their reactivity selectively to hypercapnia. Lost reactivity depends on glutamine synthesis rather than on ammonium ions per se and may reflect indirect effects of astrocyte dysfunction associated with glutamine accumulation or possibly effects of glutamine on nitric oxide production.
Key Words: ammonia carbon dioxide cerebral arteries cerebral blood flow glutamine synthetase
| Introduction |
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Acute hyperammonemia also leads to vascular abnormalities. Depressed CBF responsivity to CO2 has been reported in primates,13 dogs,14 cats,15 and rats.11 We found that the depressed CBF response to hypercapnia could be prevented by glutamine synthetase inhibition with MSO.11 One explanation for the loss of CO2 responsivity is that glutamine-dependent astrocyte swelling causes compression of intraparenchymal vessels. Nonspecific cerebral edema formation caused by plasma osmolarity decreased to 255 mOsm/L also reduced the CBF response to hypercapnia.11 Thus, loss of blood flow responsivity to hypercapnia during hyperammonemia could be secondary to the mechanical effects of compression on intraparenchymal blood vessels. Cerebral capillary distortion can be observed in perfusion-fixed tissue of hyperammonemic rats.12 If the loss of blood flow responsivity to CO2 is related to a local effect of swollen astrocytes, then extraparenchymal pial arterioles not subjected to the direct compressive forces of astrocyte processes would be expected to retain vascular reactivity to CO2.
In the present study, we measured both pial arteriolar diameter and
CBF responses to hypercapnia during 6 hours of hyperammonemia. Three
hypotheses were tested. First, we tested whether hyperammonemia blunts
pial arteriolar responsivity to hypercapnia to the same degree that the
CBF response is blunted. Second, we tested whether inhibition of
glutamine synthesis with MSO prevented any attenuation of the pial
arteriolar diameter response to hypercapnia. In addition to inhibiting
glutamine synthetase, MSO can also inhibit
-glutamylcysteine
synthetase,16 an enzyme involved in glutathione synthesis.
Administration of MSO does not decrease glutathione in
brain.17 However, to control for this potential effect of
MSO, we also used BSO, an analogue of MSO that is a more potent
inhibitor of
-glutamylcysteine synthetase but that
does not inhibit glutamine synthetase.18 We tested a third
hypothesis that treatment with BSO does not prevent attenuation of pial
arteriolar diameter or CBF responsivity to hypercapnia.
| Materials and Methods |
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We constructed a cranial window over the parietal cortex by performing a 3x4-mm craniotomy inside a 7-mm-diameter plastic ring cemented to the skull with acrylic as previously described.20 The dura was incised and retracted under a well of artificial cerebrospinal fluid. A glass coverslip was cemented over the fluid-filled ring to seal the cranial window. A catheter connected to a side port of the ring was used to monitor pressure inside the window. Pial vessels were observed through the window with an Olympus binocular microscope (model BHMJ) connected to a video camera. Images were stored on videotape and played back on a video monitor for later analysis. In each rat, the diameters of two to four arterioles (baseline diameter, 11 to 60 µm) were measured. The percent changes for individual arteriolar segments were averaged for each rat, and this average value was used in the statistical analysis.
CBF was measured with radiolabeled microspheres.11 19 Approximately 0.2 million spheres (15 µm in diameter) labeled with 153Gd, 113Sn, or 46Sc (Dupont-NEN Products) were injected into the left ventricle. The microsphere reference sample was withdrawn at a rate of 0.68 mL/min and was replaced with blood from a donor rat. After the anesthetized rat was killed with potassium chloride, cortical gray matter samples were quickly dissected, weighed, placed in a dry oven at 100°C for 48 hours, and reweighed. Percent water content of the tissue was calculated. The remaining brain was sectioned into remaining cerebrum, diencephalon, midbrain, medulla plus pons, and cerebellum. Tissue and reference blood samples were counted for radioactivity. The dried gray matter sample was also counted and included in the values for total cerebrum. Counts per minute were corrected for spectral overlap, and blood flow was calculated as 0.68 tissue counts/blood counts. Values were normalized by wet weight.
Plasma ammonia was measured by a cation exchangevisible spectrophotometric technique,21 and osmolarity was measured by freezing-point depression (Advanced Instruments, model 3DII). Arterial blood gases and pH were measured with an ABL3 electrode system, and hemoglobin concentration was measured with an OSM3 Hemoximeter (Radiometer).
Rats received an intravenous infusion of either sodium acetate or ammonium acetate at a rate of approximately 50 µmol/kg per min (0.1 mL/min). Because sodium acetate causes metabolic alkalosis, hydrochloric acid was added to the infusate 30 minutes after the start of the infusion to control arterial pH. For each of the two salt infusions, rats were pretreated with either the saline vehicle (3 mL/kg), MSO (150 mg/kg; 0.83 mmol/kg), or BSO (880 mg/kg; 4 mmol/kg). Pretreatments were given as a 1-hour continuous intravenous infusion starting approximately 3 hours before baseline measurements were made. This dose of MSO is the same as that previously used to inhibit glutamine accumulation in rats.3 22 This dose of BSO has been shown by others to decrease brain glutathione concentration within 24 hours.23 The sample size of groups was n=6, n=5, and n=5 for the sodium acetate rats pretreated with vehicle, MSO, and BSO, respectively, and n=8, n=8, and n=6 in the ammonium acetate rats pretreated with vehicle, MSO, and BSO, respectively.
Pial arteriolar diameter was measured during a 10-minute period of hypercapnia before the start of salt infusion, at hourly intervals during salt infusion under normocapnic conditions, and during a second 10-minute period of hypercapnia at 6 hours of salt infusion. The salt infusion continued through the second hypercapnic period. Microsphere measurements of CBF were made at 6 hours of salt infusion during normocapnia and the second hypercapnic period. Plasma ammonium and osmolarity and arterial blood pH, PO2, PCO2, and hemoglobin concentration were measured at baseline and at 2 and 6 hours of salt infusion. Blood gases were also measured during each hypercapnic period.
To test whether pial arterioles were capable of dilation to another physiological stimulus during hyperammonemia, diameter was measured during 10 minutes of hypoxic hypoxia at 6 hours of ammonium acetate infusion in a separate cohort of 5 rats.
Statistical comparisons among groups were made with ANOVA and the Newman-Keuls multiple-range test. For measurements repeated over time, comparisons were made with baseline values by repeated-measures ANOVA and Dunnett's test. Comparisons of the percent diameter response with hypercapnia between the first and second hypercapnic challenge were made by paired t test. Comparison of the normocapnic and hypercapnic CBF values at 6 hours were made by paired t test. The level of statistical significance was set at P<.05 in all tests. Data are expressed as mean±SE.
| Results |
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There was little change in arterial pH or
PCO2 during the 6-hour salt infusion. The level
of induced hypercapnia was similar among groups during the first
hypercapnic challenge before salt infusion and during the second
hypercapnic challenge at 6 hours of salt infusion (Table 2
). The rats were well oxygenated throughout
the experiment. Modest hemodilution occurred during the salt infusion,
but there was no difference among groups.
|
Hypercapnia caused a moderate reduction in mean arterial
pressure, but there was no significant difference among groups (Table 3
). As expected, pressure within the closed cranial
window increased during hypercapnia. Ammonium acetate infusion caused
an increase in normocapnic intracranial pressure in groups pretreated
with vehicle or BSO but not with MSO (Table 3
). Likewise, cortical
tissue water content measured at the end of the experiment was elevated
in ammonium acetateinfused groups pretreated with either vehicle
or BSO but not with MSO (Table 4
).
|
|
During the 6-hour period of normocapnic hyperammonemia, significant
increases in pial arteriolar diameter occurred by 5, 3, and 1 hours in
groups pretreated with vehicle, MSO, and BSO, respectively (paired
t test). With sodium acetate infusion, increases occurred by
3 hours in the group pretreated with BSO (Fig 1
). At 6
hours, the increase in diameter in the vehicle and BSOammonium
acetate groups was greater than that in the MSOsodium acetate group,
but other group comparisons were not significant (Newman-Keuls
test).
|
During the first hypercapnic exposure before salt infusion but
approximately 3 hours after pretreatment, pial arterioles dilated in
all groups, and there was no difference in the response among groups
(Fig 2
). During the second hypercapnic exposure at 6
hours of sodium acetate infusion, the dilatory response was unchanged
from baseline dilatory response in groups pretreated with vehicle, MSO,
or BSO. However, with 6 hours of ammonium acetate infusion, the
dilatory response was lost in groups pretreated with vehicle or BSO. In
contrast, the response was not significantly different from the first
hypercapnic response in the hyperammonemic group pretreated with MSO.
Comparisons among groups of the 6-hour hypercapnic response indicated
significant differences between the corresponding ammonium acetate
versus sodium acetate groups pretreated with vehicle or BSO but not
with MSO. The response in the MSOammonium acetate group was greater
than that in the vehicle and BSOammonium acetate groups.
|
CBF and cerebrovascular resistance at 6 hours of salt infusion during
normocapnia were similar among the six groups (Fig 3
).
During hypercapnia, CBF increased in the three sodium acetate groups
and in the ammonium acetate group pretreated with MSO. However, CBF did
not increase in the hyperammonemic groups pretreated with vehicle and
BSO, and the response was significantly less than those in the
corresponding sodium acetate groups and in the ammonium acetate groups
pretreated with MSO. Cerebrovascular resistance decreased during
hypercapnia in all groups, but the decrease was less in the
hyperammonemic groups pretreated with vehicle and BSO.
|
In cerebellum, hypercapnia produced an increase in CBF in
hyperammonemic rats pretreated with MSO but not with vehicle or BSO
(Fig 4
). In diencephalon and medulla plus pons, there
was a small increase in flow during hypercapnia with vehicle
pretreatment, but the increase was less than that in the sodium acetate
controls. In midbrain, diencephalon, and medulla plus pons, hypercapnic
blood flow in hyperammonemic rats with MSO pretreatment exceeded that
in rats with vehicle pretreatment.
|
In a separate group of 5 rats, arterial PO2 was decreased from 161±5 to 45±2 mm Hg at 6 hours of ammonium acetate infusion. Pial arteriolar diameter increased 30±7%.
| Discussion |
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-glutamylcysteine synthetase but not glutamine synthetase,
failed to prevent any of the physiological changes
observed during hyperammonemia. Loss of the CBF response to hypercapnia during acute hyperammonemia has been described in several species, including the rat.11 13 14 15 We previously found that acute hyperammonemia caused increased cortical tissue water content3 and that swelling was localized in astrocytes, particularly in perivascular processes.12 In perfusion-fixed tissues, capillaries appeared more elliptical, suggesting some compression. Thus, it was possible that the compressive forces of swollen astrocyte processes mechanically limited an increase in blood flow. If this were the sole explanation, then one would expect that extraparenchymal arterioles not surrounded by astrocytes would retain vascular reactivity to hypercapnia. However, we found that pial arterioles lost their dilatory response in concert with the loss of the blood flow response to hypercapnia. Thus, the loss of the CBF response is caused by a loss of CO2 reactivity in resistance arterioles and not simply an increase in resistance in downstream capillaries.
It is possible that compression of downstream capillaries caused an
autoregulatory dilation of upstream arterioles and that loss of
CO2 reactivity was secondary to an exhaustion of the
vasodilatory reserve of pial arterioles. Indeed, the 34±9% increase
in pial arteriolar diameter at 6 hours of ammonium acetate infusion
(Fig 1
) with normal levels of CBF (Fig 4
) may represent, at
least in part, an autoregulatory response to intraparenchymal vascular
compression. However, we found that pial arterioles still dilated in
response to hypoxia during acute hyperammonemia. This result is
consistent with the intact CBF response to hypoxia and
to hypotension previously reported in this model.19 Thus,
loss of vasodilation is specific for hypercapnia.
We have previously shown in this model of acute hyperammonemia that MSO inhibits cortical glutamine synthetase by 64%, prevents the 13-mmol/kg increase in cortical glutamine concentration, prevents the increase in tissue water content, prevents the increase in cisterna magna pressure, and prevents the loss of the CBF response to hypercapnia.3 11 The results with MSO in the present study confirm our previous findings on tissue water content, intracranial pressure, and CBF. The increases in tissue water content to 80.3% and in pressure under the cranial window to 13.6 mm Hg in vehicle-treated hyperammonemic rats are similar to the values obtained previously for water content (80.4%) and cisterna magna pressure (13 mm Hg). Thus, the model is reproducible and causes diffuse increases in intracranial pressure. Furthermore, the small decrease in plasma osmolarity with ammonium acetate infusion is inadequate to explain the increase in tissue water content.3
The major new finding with MSO in the present study is that MSO prevents loss of the pial arteriolar dilator response to hypercapnia. This result indicates that the loss of arteriolar reactivity is not attributable to ammonium ions per se but is dependent on glutamine synthesis and accumulation associated with hyperammonemia. It also indicates that upstream arterioles that are not in immediate contact with astrocytes, where glutamine synthetase is enriched,9 are functionally altered by a glutamine-dependent mechanism. There are several possible explanations for this result.
First, swollen astrocytes may reflect astrocyte dysfunction. Dysfunctional astrocytes may no longer control the extracellular constituents in a tight fashion. Treatment with MSO reduces the appearance of watery cytoplasm in astrocyte processes12 and may preserve astrocyte function. For example, a preliminary study with ion-sensitive microelectrodes indicates increased extracellular potassium activity that is attenuated by MSO pretreatment.25 Such alterations in potassium activity could modulate CO2 reactivity.26
Second, astrocytes may release nonionic substances that are vasoactive and can diffuse to the pial surface without significant metabolic degradation. However, regulation of vascular smooth muscle tone by astrocyte-derived substances has not been well studied.
Third, glutamine itself might alter vascular reactivity. Although glutamine is a neutral amino acid with no known vascular receptors, it might exert indirect effects. In cultured endothelial cells, glutamine but not ammonium chloride inhibits agonist-induced NO release by interacting with arginine in the signal transduction pathway linked to NO synthase,27 or possibly by inhibiting citrulline uptake,28 and recycling of citrulline to arginine.29 30 31 However, hypercapnic reactivity is not endothelium dependent,32 and it is unclear whether glutamine inhibits NO production in neurons sufficiently to reduce smooth muscle guanylate cyclase. Preliminary work by others33 suggests that glutamine can inhibit vasorelaxation elicited by transmural nerve stimulation. Whether such mechanisms can account for the complete loss of hypercapnic reactivity seen during acute hyperammonemia is unclear because NO synthase inhibition usually does not completely abolish hypercapnic reactivity.34
In addition to inhibiting glutamine synthetase
irreversibly,35 MSO can inhibit
-glutamylcysteine
synthetase reversibly.16
-Glutamylcysteine is the
precursor of glutathione. Administration of MSO has been reported to
decrease glutathione in kidney but not in whole brain.17
However, astrocytes have a relatively high glutathione turnover
rate,36 and it is possible that MSO could decrease
glutathione in this compartment. To control for this possibility, we
administered BSO, a reversible inhibitor of
-glutamylcysteine synthetase18 that can decrease
brain glutathione levels within 24 hours23 and augment
focal ischemia damage.37 We found that BSO did not
prevent the increase in tissue water content and intracranial
hypertension or the loss of pial arteriolar and CBF responsivity to
hypercapnia associated with hyperammonemia. Furthermore, we previously
found that BSO did not prevent swelling of perivascular astrocyte
processes in hyperammonemic rats.12 Therefore, the
positive physiological effects of MSO are not
attributable to potential inhibition of
-glutamylcysteine
synthetase.
In general, there was concordance among groups in the pial arteriolar diameter changes with the calculated changes in cerebrovascular resistance during hypercapnia. This observation is consistent with the premise that alterations occurred in both intraparenchymal and extraparenchymal resistance vessels. However, cerebrovascular resistance decreased somewhat during hypercapnia without a significant increase in pial arteriolar diameter in hyperammonemic rats pretreated with vehicle or BSO. Mean arterial blood pressure also decreased during hypercapnia. Because autoregulation remains intact in this experimental model,19 the small decrease in resistance may reflect an autoregulatory response in large arteries and arterioles38 proximal to the small-to-medium arterioles (11 to 60 µm) monitored in the present study.
In other brain regions, hyperammonemia attenuated the CBF response to hypercapnia and MSO improved the response. These results agree with our previous study.11 In the present study, we also found that BSO did not significantly improve the regional blood flow response to hypercapnia, again supporting the role of glutamine synthesis. Therefore, the role of glutamine accumulation during hyperammonemia is not restricted to cortical pial arterioles.
In summary, both the pial arteriolar dilatory and global CBF responses to hypercapnia were completely abolished within 6 hours of the elevation of plasma ammonia concentration to approximately 600 µmol/L. Lost reactivity was not attributable to vasoparalysis because pial arterioles still dilated during hypoxia. These pathophysiologic alterations depended on glutamine synthesis and accumulation rather than on ammonium ions per se. Because cerebral edema localized in astrocytes and moderate intracranial hypertension during acute hyperammonemia also depend on glutamine accumulation, changes in vascular reactivity may result indirectly from changes in astrocyte function. It is also possible that glutamine may affect vascular reactivity by modulating NO production.
| Selected Abbreviations and Acronyms |
|---|
|
| Acknowledgments |
|---|
| Footnotes |
|---|
Received September 14, 1995; revision received December 18, 1995; accepted January 16, 1996.
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T. Hirata, T. Kawaguchi, S. W. Brusilow, R. J. Traystman, and R. C. Koehler Preserved hypocapnic pial arteriolar constriction during hyperammonemia by glutamine synthetase inhibition Am J Physiol Heart Circ Physiol, February 1, 1999; 276(2): H456 - H463. [Abstract] [Full Text] [PDF] |
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