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ABSTRACT: The importance of nitric oxide (NO) during focal cerebral ischemia remains controversial as studies have suggested both a neurotoxic and neuroprotective role. In the 7 d old rat pup, NG-nitro-L-arginine, a nitric oxide synthase inhibitor, reduced infarct volume in a model of unilateral carotid ligation with 2.5 h exposure to 8% O2. The current study examined whether NO is neurotoxic in a filament model of transient middle cerebral artery occlusion (MCAO) in the 14-18-d-old rat pup. We developed a reproducible filament model of transient MCAO in 14-18-d-old spontaneously hypertensive rats (35 g) by passing a no. 6-0 (0.07-mm) nylon filament via the carotid artery to occlude the middle cerebral artery for 4 h under normoxic conditions. After filament removal and reperfusion for 24 h, we determined infarct volume using the mitochondrial stain 2,3,5-triphenyltetrazolium chloride. NO synthesis was inhibited using NG-nitro-L-arginine methyl ester (L-NAME) at a dose of 3 mg/kg, intraperitoneally, 1 h before MCAO. We measured infarct volume in control (n = 7) and L-NAME (n = 7) groups. L-NAME reduced infarct volume by 55% (p < 0.01). In the control group, infarct volume (180 +/- 29 mm3) averaged 49 +/- 7% of the left hemisphere (359 +/- 16 mm3). In the L-NAME-treated group, infarct volume (77 +/- 19 mm3) was 22 +/- 5% of the left hemispheric volume (344 +/- 2 mm3). These findings support earlier studies that used models of neonatal hypoxic-ischemic brain injury and suggest a neurotoxic role of NO. They extend these observations by demonstrating a significant reduction in infarct volume in a stroke model in the immature rat pup.
Pediatric Research 12/1995; 38(5):652-6. · 2.70 Impact Factor
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ABSTRACT: Neonatal stroke remains a complex pathophysiologic process that is poorly understood and difficult to investigate. The primary animal model used to study this phenomenon is that of unilateral carotid artery ligation with 2-3 hours exposure to severe hypoxia. A new model of neonatal stroke was developed based on transient middle cerebral artery occlusion without craniectomy. In this model a #6-0 (0.07 mm) nylon filament is passed via the carotid artery to occlude reversibly the middle cerebral artery for 4 hours under conditions of normoxia in 14- to 18-day-old spontaneously hypertensive rat pups. After removal of the filament and reperfusion for 24 hours, the infarct volume was determined using the mitochondrial stain, 2,3,5-triphenyltetrazolium chloride. Using this technique, a neocortical and caudoputamenal infarct affecting 49% of hemispheric volume that measured 180 +/- 29 mm3 (hemisphere volume = 359 +/- 16 mm3, mean +/- SEM) was created in 90% of animals (n = 8) undergoing this procedure. This model has the advantage of being relatively noninvasive, of not requiring global exposure of brain to hypoxia, and of using temporary rather than permanent occlusion. This technique should improve the ability to study the acute and long-term pathophysiology of neonatal stroke, particularly the phenomenon of reperfusion injury, as well as its sequelae in the developing nervous system.
Pediatric Neurology 05/1995; 12(3):191-6. · 1.52 Impact Factor
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ABSTRACT: The role of nitric oxide (NO) in ischemic neuronal injury is unclear. In permanent focal ischemia models, NO release has been reported to be both neuroprotective, by virtue of actions to improve cerebral blood flow (CBF) within ischemic tissue, and neurotoxic. Very little attention has been given to determining the role of NO in transient focal ischemia. In the present studies, low-dose NO inhibition using NG-nitro-L-arginine methyl ester (L-NAME; 0.1 mg/kg bolus, 0.01 mg.kg-1.min-1 iv) reduced infarct volume after 180 min of middle cerebral arterial occlusion (MCAO) and 120 min of reperfusion as measured via 2,3,5-triphenyltetrazolium chloride by 55% (P < 0.0001). Similar reductions occurred whether L-NAME was given throughout MCAO-reperfusion or just 30 or 60 min before reperfusion. L-NAME reduced CBF in the area of infarction at 30 and 180 min of MCAO by 36 and 33% (P < 0.02). In contrast, 15 min into reperfusion, L-NAME increased CBF in the area of infarction by 69% (P < 0.03) and by 27% in the contralateral homologous right hemisphere. Although vascular effects are present, these findings suggest a neurotoxic role for NO primarily during reperfusion after transient focal ischemic injury.
The American journal of physiology 07/1994; 267(1 Pt 2):H276-84.
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ABSTRACT: In a variety of recent studies, inhibitors of nitric oxide (NO) synthesis have ameliorated neuronal injury during permanent focal cerebral ischemia, suggesting that NO may contribute to ischemic damage. In other studies, however, these inhibitors increased infarct volume during permanent middle cerebral artery occlusion (MCAO). One complication in these studies was that high-dose NO synthase inhibitors increased mean arterial blood pressure (MAP) by 20-30 mm Hg. Thus, it is possible that variations in the effects of NO synthesis inhibitors on infarct volume could be related to effects of these inhibitors on MAP and cerebral perfusion during or after ischemia. The present study compared the effects of control (Ringer's lactate solution) versus low-dose NO inhibition (0.1 mg/kg bolus followed by 0.01 mg/kg/min) on cerebral infarct volume using L-NAME (NG-nitro-L-arginine methyl ester) administered during a 1-h baseline period, 3-h of MCAO, and 2 h of reperfusion in the spontaneously hypertensive rat. Infarct volume was determined using the TTC (2,3,5-triphenyltetrazolium chloride) method performed 5 h after onset of occlusion. L-NAME reduced infarct volume by 55%. In the control group (n = 7), infarct volume measured 116 +/- 4 (SEM) mm3 which was 29 +/- 1% of the left hemispheric volume (400.5 +/- 0.3 mm3). In the L-NAME group (n = 7), infarct volume measured 53 +/- 8 mm3 which was only 13 +/- 2% of the left hemispheric volume (400.4 +/- 0.5 mm3).(ABSTRACT TRUNCATED AT 250 WORDS)
Journal of Neurosurgical Anesthesiology 11/1993; 5(4):241-9. · 2.23 Impact Factor
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ABSTRACT: After transient cerebral ischemia, the brain is vulnerable to additional injury via hypoperfusion deficits. Eicosanoids with vasoconstrictor properties, such as thromboxane A2 (TxA2), may worsen postischemic hypoperfusion. The effect of temporary middle cerebral artery occlusion (MCAo) on brain TxB2 (the stable metabolite of TxA2) was evaluated in isoflurane-anesthetized rats. Microdialysis probes were placed in the caudate nucleus and temporal cortex. Each rat underwent one of the following ischemic regimens: groups I, II, and III--MCAo was maintained for 60, 120, and 180 min, respectively, followed by 120 min of reperfusion; group IV--a sham group in which MCAo and reperfusion were simulated; group V--7 h of MCAo only. Dialysate was measured for TxB2 by radioimmunoassay. Brain levels of TxB2 did not deviate from baseline during MCAo (or in the sham group). In contrast, during reperfusion, there was a significant increase in TxB2 following 180 min of MCAo but not after 60 or 120 min or MCAo (p < 0.05). These data indicate that, in this model of cerebral ischemia, TxB2 does not increase during MCAo. However, following a threshold duration of MCAo (180 min), the vasoconstrictor TxB2 may modulate postischemic hypoperfusion. These findings may have implications in the pharmacologic treatment of postischemic hypoperfusion and reperfusion brain injury.
Journal of Neurosurgical Anesthesiology 01/1993; 5(1):41-7. · 2.23 Impact Factor
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ABSTRACT: Recent investigations have proposed that, after temporary ischemia, pentastarch may reduce microvascular permeability and reperfusion injury. However, this hypothesis has not been tested in the brain. Accordingly, after 180 min of temporary middle cerebral artery occlusion, the effect of pentastarch or albumin on blood-brain barrier permeability and cerebral injury was investigated in isoflurane-anesthetized rats. One of the following was maintained for the final 60 min of occlusion and throughout reperfusion: control-hematocrit was not manipulated; pentastarch-hematocrit was decreased to approximately 30% with pentastarch; or albumin-hematocrit was decreased (approximately 30%) with albumin. Part A (n = 21): 30 min of reperfusion was allowed, and blood-brain barrier permeability was determined with the indicator dye Evans Blue. Part B (n = 14): in different animals, 120 min of reperfusion was allowed, and cerebral injury (2,3,5-triphenyltetrazolium chloride stain) and edema (specific gravity) were assessed. Part C (n = 4): in different animals, the blood-brain barrier was evaluated by electron microscopy. Evans Blue (micrograms per gram brain tissue, mean +/- SD) was greater in the control (20.8 +/- 9.0) and albumin (15.5 +/- 7.3) groups versus the pentastarch (4.7 +/- 2.7) group (P less than 0.05). Brain injury (percent of hemisphere ipsilateral to occlusion) was less and specific gravity greater in the pentastarch (33 +/- 8 and 1.040 +/- 0.003 respectively) versus the albumin group (45 +/- 6 and 1.035 +/- 0.003). This study supports the hypothesis that during temporary cerebral ischemia, pentastarch decreases brain injury and edema.(ABSTRACT TRUNCATED AT 250 WORDS)
Anesthesiology 08/1992; 77(1):86-92. · 5.36 Impact Factor
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ABSTRACT: The affect of L-644,711, an anion transport inhibitor, on ischemic brain injury and edema was investigated. Spontaneously hypertensive rats were given one of the following doses of intrathecal L-644,711 during 180 min of middle cerebral artery occlusion and 120 min of reperfusion: control, vehicle only; dose I, 100 microg/kg: dose II, 200 microg/kg; dose III, 250 mug/kg; or dose IV, 320 microg/kg. Immediately after the 5-h period of ischemia and reperfusion, the brains were analyzed for brain injury with 2,3,5-triphenyltetrazolium chloride, and for edema by microgravimetry (specific gravity). There were no between-group differences in specific gravity (brain water content). Brain injury (% of the hemisphere ipsilateral to middle cerebral artery occlusion) was less (p <0.05) in rats that received the 250 (35 +/- 5%, mean +/- SD) or 320 microg/kg (36 +/- 6%) doses of L-644,711 vs. the control group (47 +/- 5%). L-644,711 has been hypothesized to affect brain injury by improving the neuronal acid-base state, inhibiting astroglial swelling, decreasing neutrophil aggregation, or reducing glutamate release. The microgravimetric data do not support astroglial swelling as a primary mechanism of decreased brain injury.
Journal of Neurosurgical Anesthesiology 12/1991; 3(4):258-64. · 2.23 Impact Factor
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ABSTRACT: The extent of cerebral injury and edema was determined in isoflurane-anesthetized rats (n = 32) after 180 min of middle cerebral artery occlusion (MCAO) and 120 min of reperfusion. One of the following was employed during the occlusion period only: 1) control, mean arterial pressure [MAP = 131 +/- 7 (SD) mmHg] and hematocrit (43 +/- 2%) were not manipulated; 2) hemodilution, the hematocrit was reduced to 30% with 5% albumin (MAP = 104 +/- 19 mmHg); 3) hemodilution-normotension, hemodilution was established, and MAP was maintained at 131 +/- 9 mmHg with phenylephrine; 4) hemodilution-hypertension, hemodilution was established, and MAP increased to 161 +/- 2 mmHg with phenylephrine. Brain injury was determined with 2,3,5-triphenyltetrazolium chloride, and cerebral edema was assessed by microgravimetry. Brain injury and cerebral edema were less in both phenylephrine groups, compared with the control and hemodilution groups (P less than 0.05). These results are consistent with the premise that if normotension is maintained, hemodilution reduces ischemic brain injury and edema. They also indicate that the addition of phenylephrine-induced hypertension to hemodilution therapy results in a further reduction of ischemic injury without exacerbating cerebral edema.
The American journal of physiology 08/1990; 259(1 Pt 2):H211-7.
