Incomplete Cerebral Ischemia Research Articles

Neuronal damage in the striatum following forebrain ischemia: lack of effect of selective lesions of mesostriatal dopamine neurons

Transient periods of global cerebral ischemia lead to selective neuronal damage in the striatum. We investigated the effects of unilateral 6-hydroxydopamine lesions of the mesostriatal dopamine (DA) system on the density and distribution of neuronal necrosis in the rat striatum following ischemia induced by bilateral occlusion of the common carotid arteries combined with hypotension. After both 12 and 15 min of ischemia, which caused slight and extensive striatal damage, respectively, there was no difference in the density of neuronal necrosis in the striatum between DA-lesioned and sham-operated animals. We conclude that the DA system alone does not modulate injury following complete cerebral ischemia, but may contribute significantly to damage following conditions such as during hypoglycemia and incomplete cerebral ischemia.

Ganglionic Blockade Improves Neurologic Outcome from Incomplete Ischemia in Rats

The authors investigated the effects of nitrous oxide (N2O), ganglionic blockade, and combined infusion of epinephrine and norepinephrine (0.1 microgram.kg-1.min-1 each) on neurologic outcome and brain histopathology in a model of incomplete cerebral ischemia in the rat. Thirty-eight Sprague-Dawley rats were assigned to one of four groups: group 1 (n = 10) received 70% N2O in O2; group 2 (n = 12) received 70% N2O in O2, plus ganglionic blockade; and group 3 (n = 10) received 70% N2O in O2, plus ganglionic blockade and catecholamine infusion. In groups 1-3, ischemia was produced by right carotid occlusion combined with hemorrhagic hypotension (35 mmHg) for 30 min. Group 4 (n = 6) received 70% N2O in O2 and hemorrhagic hypotension without carotid occlusion for 30 min. At the end of ischemic and nonischemic hypotension, the carotid artery was unclamped and the blood slowly reinfused. Neurologic outcome was evaluated for a 5-day period with a graded deficit score (0 = normal to 39 = stroke-related death). Brain histopathology was evaluated in coronal section at the level of the caudate nucleus according to a 6-point scale, from 0 = normal to 5 = total hemispheric infarction. Arterial blood gases, pH, and body temperature were kept constant in all groups. Compared to N2O alone (group 1), treatment with ganglionic blockade (group 2) decreased plasma catecholamines by 75% and significantly improved neurologic outcome from incomplete cerebral ischemia (P less than 0.05). Administration of exogenous epinephrine and norepinephrine in the presence of N2O and ganglionic blockade (group 3) worsened neurologic outcome compared to group 2 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Selective dysfunction of the vagal component of the baroreflex following cerebral Ischemia: protection by ifenprodil and flunarizine

Baroreflex sensitivity assessed from the phenylephrine-induced reflex bradycardia was significantly decreased following 5 min global incomplete cerebral ischemia in pentobarbitalized dogs. Although bilateral vagotomy in the cervical region decreased baroreflex sensitivity by about 50% in sham-operated animals, it hardly affected the baroreflex in animals subjected to ischemia. The extent of the decrease in she influence of vagotomy on the baroreflex was dependent on the severity of ischemia in the dorsal medulla oblongata. In animals vagotomized before ischemia, no significant decrease in baroreflex sensitivity was observed following ischemia. Pretreatment with ifenprodil or flunarizine, 1 mg/kg i.V., 5 min prior to ischemia prevented the post-ischemic decrease in baroreflex sensitivity. Vagotomy decreased baroreflex sensitivity during the reperfusion period in these treated animals. These results suggest that the post-ischemic attenuation of reflex bradycardia may be due to a selective dysfunction of the vagal component of baroreflex, which can be prevented by the cerebroprotective agents.

Superoxide dismutase does not prevent delayed hypoperfusion after incomplete cerebral ischaemia in the rat

Local cerebral blood flow (1CBF) was measured autoradiographically 60 minutes after 15 minutes of forebrain ischaemia in rats treated with superoxide dismutase (SOD) before (50 mg.kg-1 body weight) or at the end of the ischaemia period (4 mg.kg-1 body weight). Incomplete forebrain ischaemia was produced by a combination of common carotid artery occlusion and bleeding to a mean arterial blood pressure of 50 mmHg. During ischaemia the 1CBF values in cortical areas were less than 3% of the preischaemic values and treatment with SOD prior to ischaemia did not influence 1CBF during ischaemia. Sixty minutes after termination of cerebral ischaemia the 1CBF values were decreased to between 40 and 60% of values found in control animals. Neither form of treatment improved the postischaemic cerebral blood flows. The results imply that postischaemic flow disturbances in the brain may not be due to extracellular superoxide production.

Preischemic Hyperglycemia and Postischemic Alteration of Rat Brain Pyruvate Dehydrogenase Activity

Transient cerebral ischemia in normoglycemic animals is followed by a decrease in glucose utilization, reflecting a postischemic cerebral metabolic depression and a reduction in the activity of the pyruvate dehydrogenase complex (PDHC). Preischemic hyperglycemia, which aggravates ischemic brain damage and invariably causes seizure, is known to further reduce cerebral metabolic rate. To investigate whether these effects are accompanied by changes in PDHC activity, the postischemic cerebral cortical activity of this enzyme was investigated in rats with preischemic hyperglycemia (plasma glucose 20-25 mM). The results were compared with those obtained in normoglycemic animals (plasma glucose 5-10 mM). The activated portion of PDHC and total PDHC activity were measured in neocortical samples as the rate of decarboxylation of [14C]pyruvate in crude brain mitochondrial homogenates after 5 min, 15 min, 1 h, 6 h, and 18 h of recirculation following 15 min of incomplete cerebral ischemia. In normoglycemic animals the fraction of activated PDHC, which rises abruptly during ischemia, was reduced to 19-25% during recirculation compared with 30% in sham-operated controls. In hyperglycemic rats the fraction of activated PDHC was higher during the first 15 min of recirculation. However, after 1 and 6 h of recirculation, the fraction was reduced to values similar to those measured in normoglycemic animals. Fifteen of 26 rats experienced early (1-4 h post ischemia) seizures in the recovery period. The PDHC activity appeared unchanged prior to these early postischemic seizures. We conclude that the accentuated depression of postischemic metabolic rate observed in hyperglycemic animals is not coupled to a corresponding postischemic depression of PDHC.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain Lactate and Neurologic Outcome Following Incomplete Ischemia in Fasted, Nonfasted, and Glucose-loaded Rats

The neurologic outcomes following incomplete cerebral ischemia in rats treated by fasting, nonfasting, or glucose administration (6 ml/kg of 50% glucose solution intraperitoneal) were compared. Rats were anesthetized with 1.4% inspired isoflurane in air and incomplete ischemia was produced by temporary unilateral carotid occlusion and hypotension of 30 mmHg for 30 min. The rats were recovered and neurologic outcome was scored every 8 h for 3 days using a 6-point scale ranging from 0 (normal) to 5 (death associated with stroke). Brain histopathology was scored using a four-point scale on 19 of 30 rats surviving the 3-day postischemic neurologic examination and was correlated with neurologic deficit scores. Fasted rats had plasma glucose concentrations of 79 +/- 7 mg/100 ml (mean +/- SE) during ischemia and a significantly better neurologic outcome (P less than 0.001) than glucose-loaded rats (plasma glucose = 496 +/- 43 mg/100 ml). Nonfasted rats had blood glucose values (292 +/- 28 mg/100 ml) and deficit scores not significantly different from fasted but better than glucose-loaded rats (P = 0.054). Brain histology showed the greatest neuronal damage in caudate followed by hippocampus and cortical tissue. Histopathologic evaluation showed a correlation of r = 0.87 (P less than 0.01) with neurologic outcome. In separate experiments brain samples were collected at the end of the ischemic period in each of the experimental groups and regional tissue lactate and brain phosphocreatine and adenosinetriphosphate (ATP) concentrations were measured. Ischemic tissue lactate was similar in fasted, nonfasted, and glucose-loaded rats in caudate and hippocampus but was significantly higher in glucose loaded rats in cortical and thalamic tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Midazolam and flumazenil in neuroanaesthesia

Of the numerous benzodiazepines currently available, only a few are used in anaesthetic practice. Midazolam is utilised as a premedicant, sedative, and an induction agent and produces minimal depression of ventilation or of the cardiovascular system. The anticonvulsant activity is similar to that of diazepam. In neuroanaesthesia midazolam may be an acceptable alternative to other intravenous induction agents like barbiturates or etomidate in patients with compromised intracranial compliance. Midazolam produces dose-related reductions in cerebral blood flow and cerebral oxygen consumption. However, midazolam does not necessarily prevent increases in intracranial pressure during induction of anaesthesia. In the electroencephalogram (EEG) midazolam produces a reduction in alpha-activity, an increase in theta-delta-activity and low-voltage beta-activity. Midazolam like other benzodiazepines does not affect early components of auditory and somatosensory evoked responses, whereas late cortical responses may be suppressed. Flumazenil, a specific benzodiazepine antagonist, has been demonstrated to be effective in reversing benzodiazepine-induced sedation. In the EEG midazolam-induced changes vanish almost instantaneously. Flumazenil is also effective in restoring the amplitudes of cortical auditory and somatosensory evoked responses. However, as has been demonstrated in head-injured patients and animal experiments after incomplete cerebral ischaemia, increases in cerebral blood flow and intracranial pressure cannot be excluded after flumazenil administration. When utilising flumazenil for wake-up procedures in midazolam-sedated patients with pathological intracranial compliance, flumazenil has to be titrated very carefully in low doses over prolonged periods.

Leukocyte involvement in cerebral ischemia and reperfusion injury

Leukocytes have been postulated to contribute to cerebral ischemia and reperfusion injury. The present study implies that leukocytes have a deleterious effect in the brain following ischemia. We compared the alteration of cortical electrical activity following transient, incomplete cerebral ischemia in control and leukopenic rats by monitoring somatosensory evoked potentials and electroencephalographic activity. There was complete cessation of electroencephalographic activity, and the cortical peak of the evoked potential was abolished during ischemia in the control animals. However, when the animals were rendered leukopenic, there was maintenance of electroencephalographic activity with reduced amplitude and preservation of the cortical peak of the evoked response during the ischemic period. This indicates that when the animals are made leukopenic, even under ischemic conditions, the neurophysiologic functioning is still maintained to a certain extent.

Decrease in Perfusion of Cerebral Capillaries during Incomplete Ischemia and Reperfusion

The effect of unilateral, incomplete cerebral ischemia on CBF, unidirectional flux of alpha-aminoisobutyric acid (AIB) and sodium, and number of perfused capillaries during ischemia and reperfusion was measured in the cortex of gerbils with symptomatic ischemia. Three hours of unilateral carotid occlusion reduced the CBF to the ipsilateral cortex by 81%, with a smaller 30% decrease in the contralateral cortex. Following 11 min of reperfusion, CBF in the ipsilateral cortex returned to the preischemic value, while the contralateral blood flow decreased to 50% of control. The transfer constants for AIB and sodium in the ipsilateral cortex were reduced by 67 and 53%, respectively, after 3 h of ischemia, with no change in the contralateral cortex. The transfer constant for AIB remained decreased by 48% during the first 20 min of reperfusion, while that for sodium returned to its control value. The number of perfused capillaries was reduced 54% by 3 h of ischemia and remained decreased by 20% after 11 min of reperfusion. These data indicate that 3 h of unilateral carotid occlusion reduces the number of perfused capillaries in the ipsilateral cortex during the ischemic period. Further, the early reperfusion phase is characterized by a mismatch between capillary perfusion and CBF. Finally, early in the postischemic phase, sodium transport undergoes a selective stimulation, probably as a result of stimulation of ion transport.

Comparison of Methohexital and Isoflurane on Neurologic Outcome and Histopathology Following Incomplete Ischemia in Rats

Using a rat model of incomplete cerebral ischemia the effects of isoflurane (iso) and methohexital (metho) were compared with those of 70% nitrous oxide controls (N2O). Two levels of incomplete cerebral ischemia were produced by right carotid occlusion plus hypotension for 30 min: moderate = 30 mmHg, FIO2 = 0.30; severe = 25 mmHg, FIO2 = 0.20. The iso doses (1 and 2 MAC) and metho doses (0.01 and 0.1 mg.kg-1.min-1) were tested at each ischemic level. These iso and metho doses were selected because without ischemia they produced similar decreases in cerebral oxygen consumption (CMRO2) compared with that produced in N2O controls. In the absence of ischemia, the electroencephalogram (EEG) was suppressed by 0.01 mg.kg-1.min-1 metho and 1 MAC iso and showed burst-suppression with 0.1 mg.kg-1.min-1 metho and 2 MAC iso. The EEG was further depressed by ischemia under all anesthetic conditions. Neurologic outcome was evaluated for 3 days following incomplete cerebral ischemia by using a graded deficit score (0 = normal, 5 = death associated with stroke). Following moderate ischemia all four anesthetic treatments improved outcome compared with N2O controls, but after severe ischemia only 2 MAC iso significantly improved outcome. Neurohistopathology was evaluated on a scale of 0 to 40, 24 h after ischemia. The neurohistopathology score was significantly improved by all four anesthetic treatments compared with N2O following moderate ischemia and was better with 2 MAC iso compared with 0.1 mg.kg-1.min-1 metho after both moderate and severe ischemia. These results show that both iso and metho improve outcome from cerebral ischemia compared with that associated with N2O, but only 2 MAC iso resulted in an improved outcome following severe ischemia. This difference in outcome between the two anesthetics may be related to greater neuronal depression with iso, which may occur with little difference in cerebral metabolic depression.

Blood-brain barrier sodium transport limits development of brain edema during partial ischemia in gerbils.

Sodium derived from the blood is known to accumulate in brain tissue during the early stages of incomplete ischemia. Our present studies were undertaken to determine the relation between blood-brain barrier sodium transport and the development of ischemic brain edema. Incomplete cerebral ischemia was produced in gerbils by ligation of the left common carotid artery under ether anesthesia. Following recovery from the anesthetic, the gerbis were evaluated for the presence of neurologic symptoms and were divided into symptomatic (n = 77) and asymptomatic (n = 94) groups. Tissue water, sodium, and potassium contents, tissue plasma volume, and brain uptake of 22Na were measured in both groups 1.5, 3, 6, 12, and 24 hours after carotid ligation. There was a progressive accumulation of sodium and water in the ipsilateral cerebral cortex of the symptomatic group compared with either the corresponding contralateral cortex of the same gerbils or with the asymptomatic group. Net changes in brain sodium and potassium concentrations appeared to be the main determinants of fluid accumulation. Brain edema was not due to opening of the blood-brain barrier because the unidirectional transport of 22Na remained low and was even reduced by 35-55% in the ischemic cortex. Nevertheless, this sodium transport activity appeared to be rate-limiting in the development of brain edema during the first 3 hours of ischemia because the rate of sodium accumulation in the tissue was the same as the rate of 22Na transport from the blood to the brain. We conclude that blood-brain barrier sodium transport is an important factor in the formation of ischemic brain edema.

The interaction of nitrous oxide and isoflurane with incomplete cerebral ischemia in the rat.

In rats with incomplete cerebral ischemia the effects of 70% N2O alone, isoflurane alone (0.5 and 1 MAC), and the combination of N2O + isoflurane on neurologic outcome, neurohistopathology, and EEG were compared. Moderate and severe ischemia were produced by right carotid artery occlusion combined with hemorrhagic hypotension (moderate ischemia, MAP = 30 mmHg, FIO2 = 0.30; severe ischemia, MAP = 25 mmHg, FIO2 = 0.20). Neurologic outcome was evaluated using a graded deficit score from 0 to 5 (0 = normal, 5 = death associated with stroke), and neurohistopathology was evaluated using a 40-point scale from 0 = normal to 40 = total hemisphere infarct at the level of the caudate nucleus in coronal section. Compared with N2O alone, isoflurane (0.5 and 1 MAC) improved neurologic outcome following moderate ischemia (P less than 0.05). Isoflurane also decreased histopathologic damage following moderate ischemia (N2O control = 33 +/- 1 vs. 0.5 MAC isoflurane = 11 +/- 4 and 1 MAC isoflurane = 12 +/- 3, P less than 0.05), whereas only 0.5 MAC isoflurane decreased histopathologic damage following severe ischemia (N2O control = 38 +/- 1 vs. 0.5 MAC isoflurane = 25 +/- 5; P less than 0.05) Adding N2O to 0.5 MAC isoflurane attenuated the neurologic protective effect of isoflurane alone and increased histopathologic damage following both moderate and severe ischemia (moderate = 23 +/- 5, severe = 37 +/- 2; both P greater than 0.05 compared with N2O controls). The effect of adding 70% N2O to isoflurane on cerebral blood flow (CBF) and cerebral oxygen consumption(CMRO2) was also evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral Metabolic Depression and Brain Protection Produced by Midazolam and Etomidate in the Rat

Midazolam and etomidate have been shown to depress cerebral metabolism and may protect the brain during ischemia. However, it has been reported that etomidate may produce EEG spiking activity and seizures, which could adversely affect outcome. We compared the effects of midazolam and etomidate on EEG, cerebral blood flow (CBF), and cerebral cortical oxygen consumption (CMRO2) as well as neurologic outcome following incomplete cerebral ischemia in the rat. CBF was measured with radioactive microspheres and cortical CMRO2 was calculated by multiplying cortical CBF by the arterial-sagittal sinus oxygen content. Incomplete ischemia was produced by unilateral carotid artery occlusion combined with hemorrhagic hypotension. In low doses (0.02 mg/kg/min i.v.), both midazolam and etomidate depressed EEG, decreased CMRO2, and improved outcome from ischemia compared to nitrous oxide control rats. At a higher dose (0.2 mg/kg/min i.v.), midazolam further depressed EEG and CMRO2 and again improved outcome compared to N2O controls. In contrast, high dose etomidate (0.2 mg/kg/min) produced spiking EEG activity without further depression of CMRO2 and a worsening of outcome following cerebral ischemia. These results support previous reports that midazolam and etomidate may protect the brain from incomplete cerebral ischemia but suggest that EEG spiking activity associated with high dose etomidate may be associated with a worse outcome.

Differential effects of isoflurane and nitrous oxide on cerebral blood flow, metabolism and electrocorticogram after incomplete cerebral ischemia in the rat

Differential effects of isoflurane (ISOF) and N2O on cerebral blood flow, metabolism and electrocorticogram (ECoG) were examined in rats subjected to 15 min-incomplete cerebral ischemia. In the first study, regional cerebral blood flow (rCBF) and ECoG were measured during and after ischemia. In the second study, local cerebral blood flow (LCBF) and glucose utilization (LCGU) were determined at 60 min after reperfusion. In the N2O group, rCBF in both the cerebral cortex and hippocampus decreased significantly to less than 10% of the pre-ischemic value during ischemia, and it increased to 170% at 10 min after reperfusion. The ECoG became flat during ischemia and reappeared at 21 min after reperfusion. In the ISOF group, rCBF decreased significantly to 25% during ischemia and returned to the preischemic value after reperfusion. The ECoG became flat during ischemia and reappeared at 14 min. In the N2O group, LCBFs decreased significantly to 40-50% of the pre-ischemic values in the forebrain. LCGUs decreased significantly to 30-50% in all structures of the forebrain. In the ISOF group, LCBFs decreased significantly to 60-80% in the forebrain, but were not different in other structures. LCGUs did not differ from pre-ischemic values in all structures except for in the thalamus and habenula. These results may indicate cerebral protective effects of ISOF on incomplete cerebral ischemia in rats.

Acute ultrastructural response of hypoxic hypoxia with relative ischemia in the isolated brain.

The acute cortical response to surgical brain isolation and subsequent extracorporal normoxic or 30 min hypoxic (PaO2 = 20 mm Hg) perfusions (hypoxic hypoxia with relative ischemia) was evaluated. Cerebral blood flow, arterial pH and CO2 were maintained constant during both perfusions; only the arterial oxygen content was changed. The isolated brain model used in this and previous investigations produces no qualitative ultrastructural changes in the neocortex following brain isolation and normoxic perfusion. However, the acute cortical structural response to 30 min of hypoxic hypoxia with relative ischemia demonstrated a number of important observations. Hypoxic hypoxia produced ultrastructural responses common to cerebral ischemia such as nuclear chromatin clumping, nucleolar condensation and cytoskeletal breakdown. Although neuronal abnormalities seen after 30 min of hypoxic hypoxia were similar to those acute neuronal changes observed following complete cerebral ischemia without recirculation, they differed three ways: (a) mitochondrial swelling and microvacuolation were observed in many cortical pyramidal neurons. (b) Glycogen particles within astroglial processes were observed even after a 30-min period of hypoxic hypoxia. (c) Perivascular astroglial swelling was minimal despite considerable perineuronal swelling. In contrast, incomplete cerebral ischemia produces mitochondrial changes similar to those in hypoxic hypoxia but also causes the depletion of tissue glycogen and perivascular glial swelling. Thus, hypoxic hypoxia with relative ischemia produces a unique acute ultrastructural response compared to either complete or incomplete cerebral ischemia.

S-Adenosyl-L-Methionine Ameliorates Ischemic Brain Metabolism in Spontaneously Hypertensive Rats

Effects of S-adenosyl-L-methionine (SAM) on the metabolism in ischemic brain were investigated. The ischemic model employed was an incomplete cerebral ischemia of the spontaneously hypertensive rat (SHR) produced by the occlusion of both common carotid arteries. One hundred mg/kg of SAM was administered (i.p.) 6 times from the beginning of occlusion at 30 min intervals. At 3 hr after the onset of occlusion, animals were killed by microwave irradiation and creatine phosphate (CrP), ATP, glucose, lactate and γ-aminobutyric acid (GABA) contents in the brain were measured. SAM significantly mitigated both the reductions in CrP, ATP and glucose levels and the increase in GABA level due to the cerebral ischemia. In another set of experiments with the same experimental schedule, water content in the brain was examined. SAM significantly suppressed the increase in water content due to the cerebral ischemia. These results indicate ameliorating effects of SAM on the metabolism in ischemic brain.

S-adenosyl-L-methionine ameliorates ischemic brain metabolism in spontaneously hypertensive rats.

Effects of S-adenosyl-L-methionine (SAM) on the metabolism in ischemic brain were investigated. The ischemic model employed was an incomplete cerebral ischemia of the spontaneously hypertensive rat (SHR) produced by the occlusion of both common carotid arteries. One hundred mg/kg of SAM was administered (i.p.) 6 times from the beginning of occlusion at 30 min intervals. At 3 hr after the onset of occlusion, animals were killed by microwave irradiation and creatine phosphate (CrP), ATP, glucose, lactate and gamma-aminobutyric acid (GABA) contents in the brain were measured. SAM significantly mitigated both the reductions in CrP, ATP and glucose levels and the increase in GABA level due to the cerebral ischemia. In another set of experiments with the same experimental schedule, water content in the brain was examined. SAM significantly suppressed the increase in water content due to the cerebral ischemia. These results indicate ameliorating effects of SAM on the metabolism in ischemic brain.

Ornithine decarboxylase activity and immunohistochemical location in postischemic brain.

Ornithine decarboxylase, rate-limiting in polyamine formation, has been found to be necessary for the development of vasogenic edema after cryogenic cerebral injury and is postulated to be of importance in late ischemic brain edema formation. Ornithine decarboxylase activity and accompanying edema was studied after transient cerebral ischemia in Mongolian gerbils. Bilateral carotid artery occlusion was utilized to produce dense forebrain ischemia. After 4 h of reperfusion a significant elevation in ornithine decarboxylase activity was present (72.5 +/- 24.7 vs 8.5 +/- 2 pmoles/mg protein/h, p less than 0.05). Immunohistochemical localization of ornithine decarboxylase indicated its presence in cortical neurons of ischemic gerbils. This was typically located in the perinuclear cytoplasm and extended into proximal dendrites. Nonischemic animals did not contain ornithine decarboxylase immunoreactivity. These studies show the presence and location of ornithine decarboxylase in cerebral tissue subjected to transient ischemia. The increase in this marker of polyamine activity paralleled previous studies in this model of cerebral edema formation and reperfusion deficit in blood flow and evoked potential, suggesting that ornithine decarboxylase is a marker for and may be associated with those late metabolic events leading to progressive functional deterioration after incomplete cerebral ischemia.

Neurologic Outcome in Aged Rats After Incomplete Cerebral Ischemia

The effect of age on outcome after induced cerebral ischemia was tested in rats. Cerebral ischemia was produced by unilateral carotid ligation and hemorrhagic hypotension to 30 mm Hg (moderate ischemia) or 25 mm Hg (severe ischemia) in young (6 month) and old (26-28 month) rats anesthetized with 1 MAC halothane. Young rats had significantly better neurologic outcomes than old rats after similar ischemic challenges. This advantage disappears, however, when the inspired oxygen tension is altered to produce similar PaO2 in both age groups during ischemia. Measures of regional CBF with radioactive microspheres showed a 70% decrease in cortical blood flow in the ischemic cerebral hemisphere in both young and old rats. Plasma glucose concentrations increased from 150 to 250 mg/100 mL during ischemia in both age groups. Histologically, the brains showed similar signs of focal ischemic damage in striatum, hippocampus, and cortex in young and old rats. These results indicate that when blood pressure and respiratory factors are controlled experimentally during ischemia, young and aged rats have similar neurologic outcomes after cerebral ischemia.

Effects of new chemically and metabolically stable prostacyclin analogues (iloprost and ZK 96480) on early consequences of a transient cerebral oligemia, in the rat

Transient incomplete cerebral ischemia (oligemia) has been obtained in rats by associating mild systematic hypotension with bilateral carotid artery occlusion for 60 min. Continuous i.v drug administration for 3 days, performed with Alzet osmotic minipumps so that to deliver 167 ng.kg-1.min-1 Iloprost, 5 ng.kg-1.min-1 ZK 96480 or their respective vehicle, started 1 hour post-oligemia. Both compounds which are stable prostacyclin analogues reduced the edematous reaction and the post-oligemic accumulation of calcium in the brain tissue but above all they improved, mainly ZK 96480, the learning capacity of injured animals. These results indicate that regarding its therapeutic effect toward early consequences of a transient cerebral oligemia, ZK 96480 has the same profile as Iloprost at a dose 20-fold lower. Thus, these data encourage further clinical studies, in ischemic stroke, in which PGI 2 and Iloprost have been shown promising.