Glutamine-dependent inhibition of pial arteriolar dilation to acetylcholine with and without hyperammonemia in the rat - PubMed (original) (raw)

Glutamine-dependent inhibition of pial arteriolar dilation to acetylcholine with and without hyperammonemia in the rat

Tetsu Kawaguchi et al. Am J Physiol Regul Integr Comp Physiol. 2005 Jun.

Abstract

Glutamine has been shown to influence endothelial-dependent relaxation and nitric oxide production in vitro, possibly by limiting arginine availability, but its effects in vivo have not been well studied. Hyperammonemia is a pathophysiological condition in which glutamine is elevated and contributes to depressed CO(2) reactivity of cerebral arterioles. We tested the hypothesis that acute hyperammonemia decreases pial arteriolar dilation to acetylcholine in vivo and that this decrease could be prevented by inhibiting glutamine synthetase with L-methionine-S-sulfoximine (MSO) or by intravenous infusion of L-arginine. Pial arteriolar diameter responses to topical superfusion of acetylcholine were measured in anesthetized rats before and at 6 h of infusion of either sodium or ammonium acetate. Ammonium acetate infusion increased plasma ammonia concentration from approximately 30 to approximately 600 microM and increased cerebral glutamine concentration fourfold. Arteriolar dilation to acetylcholine was intact after infusion of sodium acetate in groups pretreated with vehicle or with MSO plus methionine, which was coadministered to prevent MSO-induced seizures. In contrast, dilation in response to acetylcholine was completely blocked in hyperammonemic groups pretreated with vehicle or methionine alone. However, MSO plus methionine administration before hyperammonemia, which maintained cerebral glutamine concentration at control values, preserved acetylcholine dilation. Intravenous infusion of L-arginine during the last 2 h of the ammonium acetate infusion partially restored dilation to acetylcholine without reducing cerebral glutamine accumulation. Superfusion of 1 or 2 mM L-glutamine through the cranial window for 1 h in the absence of hyperammonemia attenuated acetylcholine dilation but had no effect on endothelial-independent dilation to nitroprusside. We conclude that 1) hyperammonemia reduces acetylcholine-evoked dilation in cerebral arterioles, 2) this reduction depends on increased glutamine rather than ammonium ions, and 3) increasing arginine partially overcomes the inhibitory effect of glutamine.

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Figures

Fig. 1

Fig. 1

Cerebral tissue concentration (±SD) of glutamine (top), glutamate (middle), and arginine (bottom) after a 6-h infusion of sodium acetate in groups pretreated with vehicle (n = 5) and L-methionine-_S_-sulfoximine (MSO) + L-methionine (Met; n = 6) and after a 6-h infusion of ammonium acetate in groups pretreated with vehicle (n = 5), Met (n = 6), MSO/Met (n = 6), and L-arginine (Arg; n = 5). *P < 0.05 from vehicle-sodium acetate group; +P < 0.05 from MSO/Met-ammonium acetate group. Arginine concentration in the L-arginine group was greater than in the Met-ammonium acetate group but was not significant from the other groups.

Fig. 2

Fig. 2

Mean arterial blood pressure (top), intracranial pressure (middle), and cerebral perfusion pressure (bottom) (±SD) during ACh superfusion before (0 h) and at 6 h of infusion of sodium acetate in groups pretreated with vehicle (n = 8) and MSO/Met (n = 8) and after 6 h of infusion of ammonium acetate in groups pretreated with vehicle (n = 8), Met (n = 6), MSO/Met (n = 8), and Arg (n = 8). *P < 0.05 from 0-h value within group; +P < 0.05 from vehicle-ammonium acetate group at same time point.

Fig. 3

Fig. 3

Percent change in baseline pial arteriolar diameter (3SD) after 6 h of infusion of sodium acetate in groups pretreated with vehicle (n = 8) and MSO/Met (n = 8) and after 6 h infusion of ammonium acetate in groups pretreated with vehicle (n = 8), Met (n = 6), MSO/Met (n = 8), and Arg (n = 8). *P < 0.05 from vehicle-sodium acetate group; +P < 0.05 from vehicle-ammonium acetate group.

Fig. 4

Fig. 4

Percent change in pial arteriolar diameter (±SD) during 30 M ACh superfusion before (0 h) and at 6 h of infusion of sodium acetate in groups pretreated with vehicle (n = 8) and MSO/Met (n = 8) and after 6 h of infusion of ammonium acetate in groups pretreated with vehicle (n = 8), Met (n = 6), MSO/Met (n = 8), and Arg (n = 8). *P < 0.05 from 0-h value within group;+P < 0.05 from vehicle-ammonium acetate group at same time point.

Fig. 5

Fig. 5

Percent change in pial arteriolar diameter (±SD) during 10 μM ACh superfusion vs. glutamine concentration in outflow of cranial window after 1 h of superfusion with 0 (n = 7), 0.3 (n = 6), 1 (n = 7), and 2 mM (n = 7) glutamine in inflow. *P < 0.05 from diameter at 0 mM inflow glutamine; P < 0.05 from diameter at 0.3 mM inflow glutamine.

Fig. 6

Fig. 6

Percent change in pial arteriolar diameter (±SD) during 3 μM sodium nitroprusside superfusion vs. glutamine concentration in outflow of cranial window after 1 h of superfusion with 0 (n = 7), 0.3 (n = 6), 1 (n = 7), and 2 mM (n = 7) glutamine in inflow. There was no significant effect of glutamine.

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