nitroarginine and Brain-Edema

Brain edema is a common fatal complication in acute liver failure. It is related to an acute change in brain osmolarity secondary to the glial accumulation of glutamine. Since high cerebral blood flow (CBF) precedes cerebral herniation in fulminant hepatic failure we first determined if an increase in brain water and glutamine are prerequisite to a rise in CBF in a model of ammonia-induced brain edema. Secondly, we determined if such a cerebral hyperperfusion is mediated by nitric oxide synthase (NOS).. Male rats received an end-to-side portacaval anastomosis (PCA). At 24 h, they were anesthetized with ketamine and infused with ammonium acetate (55 microM/kg per min). Studies were performed at 60, 90, 120, 150 and 180 min after starting the ammonia infusion and once the intracranial pressure had risen three-fold (mean 210'). Brain water (BW) was measured using the gravimetry method and CBF with the radioactive microsphere technique. Glutamine (GLN) in the CSF was sampled via a cisterna magna catheter. The neuronal NOS was specifically inhibited by 1-2-trifluoromethylphenyl imidazole (TRIM, 50 mg/kg intraperitoneally) and in separate studies nonspecifically by N-omega-nitro-L-arginine (L-NNA, 2 microg/kg per min intravenously). At 90', brain water was significantly increased (P < 0.015) as compared to the 60' group while CBF was significantly different at 150'. A significant correlation was observed between values of CBF and brain water (r = 0.88, n = 36, P < 0.001). Administration of either TRIM or L-NNA did not prevent the development of cerebral hyperperfu. sion and edema.. We observed that cerebral hyperemia follows an initial rise in brain water content, rather than in the cerebrospinal fluid concentration of glutamine. The rise in CBF further correlated with brain water accumulation and was of critical importance for the development of intracranial hypertension. The unique mechanism for the rise in CBF in hyperammonemia was not prevented by NOS inhibition indicating that NO is not the mediator of high CBF and intracranial hypertension.

Topics: Ammonia; Anesthesia, General; Animals; Arteries; Body Water; Brain; Brain Edema; Cerebrovascular Circulation; Enzyme Inhibitors; Glutamine; Hyperemia; Intracranial Pressure; Male; Nitric Oxide Synthase; Nitroarginine; Oxygen; Pentobarbital; Rats; Rats, Sprague-Dawley; Veins

The involvement of nitric oxide (NO) in the development of ischemic cytotoxic edema was investigated by inhibiting nitric oxide synthase (NOS) activity with N omega-nitro-L-arginine (NLA). Bilateral carotid artery occlusion (15 min) alone or with release (15 and 60 min) served as a model for edema induction. NLA, N omega-nitro-D-arginine methyl ester (D-NAME) or Ringer's solution were administered 4 hr prior to ischemia or sham operation. Treatment with a stable nitroxide radical, 4-hydroxy-2,2, 6,6-tetramethylpiperidine-L-oxyl (TPL), was used to assess free radical involvement in edema. Accumulation of tissue water was evaluated by measuring specific gravity (SG) of brain cortex and histological examination. There was a greater reduction of cortical SG in early reperfusion (15 min) and a lesser decrease in SG (60 min later) in NLA-than in D-NAME- or Ringer's-treated gerbils. The NLA effect was confirmed by histological examination of the brain tissue. TPL treatment (pre- and postischemic) ameliorated the formation of edema to the same degree as NLA. The findings indicate a biphasic NLA modulation of cytotoxic edema most likely mediated through absence or presence of NO-derived free radicals.

Topics: Animals; Brain Edema; Brain Ischemia; Enzyme Inhibitors; Female; Gerbillinae; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine

We investigated whether treatment with the nitric oxide synthase inhibitor N-nitro-L-arginine (L-NA) and the free radical scavenger superoxide dismutase influences cerebral blood flow changes, brain edema, and cerebrospinal fluid pleocytosis in early experimental pneumococcal meningitis. Compared to untreated infected rats, superoxide dismutase given 3 hours after infection significantly attenuated the increase of brain water content, intracranial pressure, and cerebrospinal fluid white blood cell count, but did not modulate the increase in regional cerebral blood flow. N-Nitro-L-arginine treatment (5 mg/kg intravenously, followed by 5 mg/kg/hour) reversed the increase in regional cerebral blood flow; prevented an increase in brain water content, intracranial pressure, and cerebrospinal fluid nitrite concentrations; and reduced cerebrospinal fluid white blood cell count. With a closed cranial window preparation, N-nitro-L-arginine prevented pneumococci-induced dilatation of pial arterioles. When the effective dose was increased twofold, the effects of N-nitro-L-arginine became more pronounced but resulted in the death of 4 of 5 rats, probably due to hemodynamic side effects. In primary cultures of rat cerebral endothelial cells, nitrite concentrations increased after pneumococcal stimulation, which could be prevented by N-nitro-L-arginine and cycloheximide. These data suggest that (a) nitric oxide accounts for regional cerebral blood flow changes and pial arteriolar dilatation in the early phase of experimental pneumococcal meningitis; (b) both superoxide radical and nitric oxide are involved as mediators of brain edema and meningeal inflammation; and (c) cerebral endothelial cells can be stimulated by pneumococci to release nitric oxide presumably via the inducible nitric oxide synthase.

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Arterioles; Brain Edema; Cells, Cultured; Cerebral Arteries; Cerebrospinal Fluid; Cerebrovascular Circulation; Endothelium, Vascular; Inflammation; Intracranial Pressure; Leukocyte Count; Male; Meningitis, Pneumococcal; Nitric Oxide; Nitric Oxide Synthase; Nitrites; Nitroarginine; Rats; Rats, Wistar; Superoxide Dismutase

The present study was designed to determine the effect of nitro-L-arginine, the inhibitor of nitric oxide synthesis, on the evolution of cytotoxic brain edema during focal cerebral ischemia.. Diffusion-weighted and contrast-enhanced, perfusion-sensitive magnetic resonance imaging was performed in anesthetized, mechanically ventilated rats at 30 minutes and 1, 2, and 3 hours after occlusion of the middle cerebral artery combined with coagulation of the basilar artery. At the onset of ischemia, the animals were infused intravenously with 0.5 mL of either 0.9% NaCl or nitro-L-arginine (30 mg/kg). The severity of cytotoxic edema was evaluated based on changes in the water apparent diffusion coefficient (ADC) derived from diffusion-weighted images. The size of the area affected by ischemia was evaluated 3 hours after occlusion using 2,3,5-triphenyltetrazolium chloride (TTC) staining.. The percentage decrease of ADC in the striatum of rats pretreated with nitro-L-arginine was significantly smaller (P < .05) than in the control group at 30 minutes and 1 and 2 hours of ischemia. The ADC in the injured cortex of nitro-L-arginine-treated rats did not differ significantly from the ADC value measured in the contralateral cortex until 3 hours after the occlusion. However, at 3 hours of ischemia the percentage decrease of ADC in both the striatum and the cortex of either group of rats was similar. This transient attenuation of ADC drop during ischemia after nitro-L-arginine pretreatment occurred concurrently with a transient improvement of blood supply to the ischemic regions. The percentage of hemispheric area with abnormal TTC staining after 3 hours of ischemia did not differ between control and nitro-L-arginine-treated rats.. Nitro-L-arginine delays the development of ischemic injury by retarding cytotoxic brain edema. This effect is, at least partially, mediated by an improvement in blood supply to the ischemia tissues.

Topics: Animals; Arginine; Brain Edema; Brain Ischemia; Cerebral Cortex; Corpus Striatum; Hemodynamics; Male; Nitric Oxide; Nitroarginine; Rats; Rats, Sprague-Dawley

In order to investigate whether or not nitric oxide (NO) formation underlies the cellular mechanisms of ischemic brain damage, we examined the effects of N omega-nitro-L-arginine (L-NNA), a NO synthase inhibitor, on ischemic brain edema and subsequent infarction in rats with middle cerebral artery occlusion (MCAo). For this purpose, administrations of L-NNA (1 mg/kg, i.p.) to each animal were done at the time of 5 min, 3, 6 and 24 h after MCAo, respectively. It was shown from this study that L-NNA significantly mitigated ischemic cerebral edema, and histological examinations revealed that this compound markedly reduced infarction size that occurred following MCAo. These results strongly suggest that NO formation is at least partly involved in the pathogenetic mechanisms of ischemic brain edema and subsequent cerebral infarction.

Topics: Animals; Arginine; Brain Chemistry; Brain Edema; Brain Ischemia; Cerebral Arteries; Cerebral Infarction; Male; Nitric Oxide; Nitroarginine; Potassium; Rats; Rats, Sprague-Dawley; Sodium