Impaired pial arteriolar reactivity to hypercapnia during hyperammonemia depends on glutamine synthesis

Takahiko Hirata, Raymond C Koehler, Tetsu Kawaguchi, Saul W. Brusilow, Richard J. Traystman

Research output: Contribution to journalArticle

Abstract

Background and Purpose: Acute hyperammonemia causes glutamine and water accumulation in astrocytes and loss of the cerebral blood flow response selectively to CO2. We tested whether extraparenchymal pial arterioles not subjected directly to mechanical compression by swollen astrocyte processes also lose hypercapnic reactivity and whether any such loss can be attenuated by inhibiting glutamine synthesis during hyperammonemia. Methods: Pentobarbital anesthetized rats were pretreated intravenously with either saline vehicle, methionine sulfoximine (0.83 mmol/kg), which inhibits glutamine synthetase and potentially γ-glutamylcysteine synthetase, or buthionine sulfoximine (4 mmol/kg), which inhibits γ-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.

Original languageEnglish (US)
Pages (from-to)729-736
Number of pages8
JournalStroke
Volume27
Issue number4
StatePublished - Apr 1996

Fingerprint

Hyperammonemia
Hypercapnia
Methionine Sulfoximine
Glutamine
Buthionine Sulfoximine
Astrocytes
Cerebrovascular Circulation
Glutamate-Cysteine Ligase
Sodium Acetate
Arterioles
Glutamate-Ammonia Ligase
Water
Pentobarbital
Microspheres
Ammonium Compounds
Intravenous Infusions
Nitric Oxide
Ions
Pressure
ammonium acetate

Keywords

  • ammonia
  • carbon dioxide
  • cerebral arteries
  • cerebral blood flow
  • glutamine synthetase

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Neuroscience(all)

Cite this

Hirata, T., Koehler, R. C., Kawaguchi, T., Brusilow, S. W., & Traystman, R. J. (1996). Impaired pial arteriolar reactivity to hypercapnia during hyperammonemia depends on glutamine synthesis. Stroke, 27(4), 729-736.

Impaired pial arteriolar reactivity to hypercapnia during hyperammonemia depends on glutamine synthesis. / Hirata, Takahiko; Koehler, Raymond C; Kawaguchi, Tetsu; Brusilow, Saul W.; Traystman, Richard J.

In: Stroke, Vol. 27, No. 4, 04.1996, p. 729-736.

Research output: Contribution to journalArticle

Hirata, T, Koehler, RC, Kawaguchi, T, Brusilow, SW & Traystman, RJ 1996, 'Impaired pial arteriolar reactivity to hypercapnia during hyperammonemia depends on glutamine synthesis', Stroke, vol. 27, no. 4, pp. 729-736.
Hirata, Takahiko ; Koehler, Raymond C ; Kawaguchi, Tetsu ; Brusilow, Saul W. ; Traystman, Richard J. / Impaired pial arteriolar reactivity to hypercapnia during hyperammonemia depends on glutamine synthesis. In: Stroke. 1996 ; Vol. 27, No. 4. pp. 729-736.
@article{59ef0dac98b04e9dbf03339628c1b854,
title = "Impaired pial arteriolar reactivity to hypercapnia during hyperammonemia depends on glutamine synthesis",
abstract = "Background and Purpose: Acute hyperammonemia causes glutamine and water accumulation in astrocytes and loss of the cerebral blood flow response selectively to CO2. We tested whether extraparenchymal pial arterioles not subjected directly to mechanical compression by swollen astrocyte processes also lose hypercapnic reactivity and whether any such loss can be attenuated by inhibiting glutamine synthesis during hyperammonemia. Methods: Pentobarbital anesthetized rats were pretreated intravenously with either saline vehicle, methionine sulfoximine (0.83 mmol/kg), which inhibits glutamine synthetase and potentially γ-glutamylcysteine synthetase, or buthionine sulfoximine (4 mmol/kg), which inhibits γ-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.",
keywords = "ammonia, carbon dioxide, cerebral arteries, cerebral blood flow, glutamine synthetase",
author = "Takahiko Hirata and Koehler, {Raymond C} and Tetsu Kawaguchi and Brusilow, {Saul W.} and Traystman, {Richard J.}",
year = "1996",
month = "4",
language = "English (US)",
volume = "27",
pages = "729--736",
journal = "Stroke",
issn = "0039-2499",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Impaired pial arteriolar reactivity to hypercapnia during hyperammonemia depends on glutamine synthesis

AU - Hirata, Takahiko

AU - Koehler, Raymond C

AU - Kawaguchi, Tetsu

AU - Brusilow, Saul W.

AU - Traystman, Richard J.

PY - 1996/4

Y1 - 1996/4

N2 - Background and Purpose: Acute hyperammonemia causes glutamine and water accumulation in astrocytes and loss of the cerebral blood flow response selectively to CO2. We tested whether extraparenchymal pial arterioles not subjected directly to mechanical compression by swollen astrocyte processes also lose hypercapnic reactivity and whether any such loss can be attenuated by inhibiting glutamine synthesis during hyperammonemia. Methods: Pentobarbital anesthetized rats were pretreated intravenously with either saline vehicle, methionine sulfoximine (0.83 mmol/kg), which inhibits glutamine synthetase and potentially γ-glutamylcysteine synthetase, or buthionine sulfoximine (4 mmol/kg), which inhibits γ-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.

AB - Background and Purpose: Acute hyperammonemia causes glutamine and water accumulation in astrocytes and loss of the cerebral blood flow response selectively to CO2. We tested whether extraparenchymal pial arterioles not subjected directly to mechanical compression by swollen astrocyte processes also lose hypercapnic reactivity and whether any such loss can be attenuated by inhibiting glutamine synthesis during hyperammonemia. Methods: Pentobarbital anesthetized rats were pretreated intravenously with either saline vehicle, methionine sulfoximine (0.83 mmol/kg), which inhibits glutamine synthetase and potentially γ-glutamylcysteine synthetase, or buthionine sulfoximine (4 mmol/kg), which inhibits γ-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.

KW - ammonia

KW - carbon dioxide

KW - cerebral arteries

KW - cerebral blood flow

KW - glutamine synthetase

UR - http://www.scopus.com/inward/record.url?scp=0029975974&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0029975974&partnerID=8YFLogxK

M3 - Article

C2 - 8614939

AN - SCOPUS:0029975974

VL - 27

SP - 729

EP - 736

JO - Stroke

JF - Stroke

SN - 0039-2499

IS - 4

ER -