Phenylephrine-induced hypertension reduces ischemia following middle cerebral artery occlusion in rats

We studied the influence of phenylephrine-induced hypertension on the area of ischemia during brief middle cerebral artery occlusion. Rats were anesthetized with 1.2 minimal alveolar concentration (MAC) isoflurane, and the middle cerebral artery was occluded via a subtemporal craniectomy. Immediately thereafter, in one group (n = 9) arterial blood pressure was increased 30-35 mm Hg above the preocclusion level by intravenous infusion of phenylephrine. In a second, control, group (n = 10) there was no manipulation of blood pressure. Local cerebral blood flow was determined autoradiographically 15 minutes after occlusion. The areas (expressed as a percentage of the total coronal cross-sectional area) in which local cerebral blood flow decreased to three ranges (0-6 ml/100 g/min [rapid neuronal death probable], 6-15 ml/100 g/min [delayed neuronal death probable], and 15-23 ml/100 g/min [electrophysiologic dysfunction with prolonged survival probable]) were measured. The areas in which local cerebral blood flow decreased to the two more severely ischemic ranges were smaller in the phenylephrine group than in the control group. For example, in the coronal section in the center of the middle cerebral artery distribution, local cerebral blood flow was 0-6 ml/100 g/min in 6.7 +/- 1.4% of the section in normotensive rats but was in that range in only 1.7 +/- 0.6% of the section during phenylephrine-induced hypertension (p less than 0.05). For the 6-15 ml/100 g/min range, the areas were 6.8 +/- 0.8% and 3.8 +/- 0.7%, respectively (p less than 0.05). For the 15-23 ml/100 g/min range, there were no differences between groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reperfusion after cerebral ischemia: influence of duration of ischemia

The influence of the duration of ischemia on the pattern of cerebral blood flow in recirculation was studied in anesthetised rats. Severe incomplete cerebral ischemia (mean ischemic flow = 5.8 +/- 0.4 ml/100 g/min) was produced by four-vessel occlusion and recirculation permitted after 15, 30 or 60 minutes ischemia. All three groups showed an immediate hyperemia followed by hypoperfusion. Hyperemia was maximal following 15 minutes ischemia and least pronounced following 60 minutes ischemia (p = 0.0249). Hypoperfusion started most quickly following 15 minutes ischemia and was delayed following 60 minutes ischemia (p less than 0.001). In established hypoperfusion there was no difference in flow between the three groups. The possible mechanisms of these changes in flow are discussed.     

Calcium channel blockers correct acidosis in ischemic rat brain without altering cerebral blood flow

We compared the effects of intravenous infusions of 40 micrograms/kg/min verapamil (n = 5), 0.5 microgram/kg/min nimodipine (n = 5), and 5 ng/kg/min prostacyclin (n = 6) and no treatment (n = 6) on local cerebral pH and local cerebral blood flow in middle cerebral artery-occluded rats 90 minutes after the ischemic insult. Local cerebral pH and local cerebral blood flow were determined simultaneously by a double-label autoradiographic technique. The infusions were started 15 minutes after completion of the occlusion and ended at decapitation 90 minutes after completion of the occlusion. Cortical pH for four regions in the ischemic middle cerebral artery territory of rats receiving verapamil or nimodipine was normalized (mean +/- SEM 6.90 +/- 0.02 and 7.01 +/- 0.01, respectively, for the parietal, sensorimotor, frontal, and auditory cortexes), while mean +/- SEM pH in rats receiving prostacyclin was 6.79 +/- 0.01; in untreated rats, mean +/- SEM pH in the same brain regions was 6.72 +/- 0.01. Local cerebral pH in the verapamil- or nimodipine-treated rats was thus significantly different from that in untreated rats (p less than 0.05). Local cerebral blood flow in treated rats was not different from that in untreated ones. Our findings suggest that calcium channel blockers correct ischemic cerebral acidosis by metabolic mechanisms rather than by changes in blood flow.     

Autoradiographic analysis on second-messenger systems and local cerebral blood flow in ischemic gerbil brain

Alterations of the second-messenger systems, adenylate cyclase (AC) and protein kinase C (PKC), and local cerebral blood flow (lCBF) were evaluated during experimental cerebral ischemia in gerbils employing a quantitative autoradiographic method, which permitted these three parameters to be measured in the same brain. Ischemia was induced by occlusion of the right common carotid artery for 6 h. Animals attaining more than 5 in their ischemic scores were utilized for further experiments. At the end of ischemia, lCBF was measured by the [14C]iodoantipyrine method. The AC and PKC activities were estimated by the autoradiographic technique developed in our laboratory using [3H]forskolin (FK) and [3H]phorbol-12,13-dibutyrate (PDBu), respectively. The lCBF fell below 10 ml/100 g/min in most cerebral regions on the ligated side. The greatest reduction in FK binding was noted in the olfactory tubercle, caudate-putamen, and globus pallidus, followed by the hippocampus and cerebral cortices. The FK binding tended to be low at lCBF less than 20 ml/100 g/min in the cerebral cortices. However, the PDBu binding was relatively well preserved in each cerebral structure, and no significant correlation between lCBF and PDBu binding was noted in the cerebral cortices. The AC system may thus be vulnerable to ischemic insult over extensive brain regions, while the PKC system may be relatively resistant to ischemia.     

Cerebrovascular effects of angiotensin converting enzyme inhibition involve large artery dilatation in rats.

BACKGROUND AND PURPOSE: The aim of the study was to selectively examine the effects of converting enzyme inhibition on the large brain arteries by using concomitant inhibition of carbonic anhydrase to cause severe dilatation of mainly parenchymal resistance vessels. METHODS: Cerebral blood flow was measured using the xenon-133 injection technique in three groups of Wistar rats either during carbonic anhydrase inhibition with acetazolamide (treatment A, n = 8), during carbonic anhydrase inhibition followed by converting enzyme inhibition with captopril 40 minutes later (treatment B, n = 10), or during carbonic anhydrase inhibition preceded by converting enzyme inhibition 20 minutes earlier (treatment C, n = 7). RESULTS: After treatment A, cerebral blood flow rose rapidly and stabilized within 20 minutes at an average of 220 ml/100 g.min; flow remained stable until at least 60 minutes. After treatment B, cerebral blood flow increased by a further 17.4%, from an average of 219 ml/100 g.min to an average of 257 ml/100 g.min (p less than 0.01). After treatment C, cerebral blood flow stabilized at an average of 238 ml/100 g.min, with flow from 20 to 60 minutes always being higher (from 5% to 17%) than during carbonic anhydrase inhibition alone (p less than 0.02). Thus the additional inhibition of converting enzyme resulted in higher cerebral blood flow than during inhibition of carbonic anhydrase alone. CONCLUSIONS: These results suggest that converting enzyme inhibition reduced resistance of large brain arteries and support the hypothesis that there is some angiotensin II-induced tone in large cerebral arteries.     

Bimodal treatment with nimodipine and low-molecular-weight dextran for focal cerebral ischemia in the rat

We compared the effects of intravenous treatment with combined low-molecular-weight dextran and nimodipine (n = 9), or placebo (n = 10), on local cerebral blood flow after occlusion of the left middle cerebral and common carotid artery in the rat. Treatment for a total of 4 hours with low-molecular-weight dextran (5 mg/kg/min) and nimodipine (0.25 microgram/kg/min) produced a decrease in hematocrit from 46 +/- 1 to 33 +/- 1% at the end of the study and a statistically significant increase in local cerebral blood flow, when compared to the control group, in 6 regions of interest: the territories of the right middle (p = 0.01), right anterior (p = 0.007), and left anterior cerebral arteries (p = 0.001); the superior (p = 0.03) and inferior border zone (p = 0.003); and white matter in the right hemisphere (p = 0.04). The ischemic volume, defined as brain volume with a cerebral blood flow of less than the critical level of 25 ml/min/100 gm was determined as a percentage of total brain volume for the control and treatment groups. The group treated with low-molecular-weight dextran and nimodipine showed a 31% decrease in ischemic volume (p = 0.03). These results indicate that a bimodal approach with low-molecular-weight dextran and nimodipine can be safely used in a model of acute stroke and has a beneficial effect on local cerebral blood flow and ischemic volume when compared with control subjects. After 4 hours, the potential exists that this treatment is therapeutic, assuming that the ischemic volume progresses to infarction.     

Endogenous platelet activating factor does not modulate blood flow and metabolism in normal rat brain

Both platelet activating factor and eicosanoids participate in the cerebrovascular response to ischemia. Eicosanoids also modulate cerebrovascular tone under normal physiologic circumstances, but a similar role for platelet activating factor has not been investigated. Therefore, using 16 rats, we studied the effects of the platelet activating factor receptor blockers BN 52021 (10 mg/kg, n = 4 or 30 mg/kg, n = 2) and WEB 2086 (5 mg/kg, n = 6) on global cerebral blood flow and the cerebral metabolic rate for oxygen and compared them with the effect of indomethacin (10 mg/kg, n = 4). Neither antagonist altered cerebral blood flow (112 +/- 16 and 107 +/- 14 ml/100 g/min at baseline versus 108 +/- 16 and 105 +/- 18 ml/100 g/min after BN 52021 and WEB 2086, respectively). In contrast, indomethacin significantly (p less than 0.05) decreased cerebral blood flow from 106 +/- 8 to 69 +/- 4 ml/100 g/min. No treatment altered the cerebral metabolic rate for oxygen compared with baseline. These data suggest that in normal rat brain, concentrations of platelet activating factor, unlike those of eicosanoids, are subthreshold and do not modulate cerebral blood flow or the cerebral metabolic rate for oxygen.     

Chronic cerebral blood flow changes following experimental subarachnoid hemorrhage in rats

Experimental subarachnoid hemorrhage was induced in 52 adult male Wistar rats by microsurgical transclival basilar artery puncture. Telencephalic blood flow measured in 24 rats with subarachnoid hemorrhage was compared with that in 23 sham-operated rats and 10 unoperated control rats using the [14C]butanol indicator fractionation technique. Telencephalic blood flow was significantly less in the rats with subarachnoid hemorrhage than in the sham-operated rats 3 (78.7 +/- 6.9 [n = 7] and 112.0 +/- 8.5 [n = 8] ml/100 g/min, respectively; p less than 0.01), 7 (74.9 +/- 5.1 [n = 9] and 112.6 +/- 4.6 [n = 8] ml/100 g/min, p less than 0.001), and 14 (81.9 +/- 6.0 [n = 8] and 104.1 +/- 5.4 [n = 7] ml/100 g/min, p less than 0.01) days after surgery. Telencephalic blood flow in unoperated controls (114.7 +/- 4.9 ml/100 g/min) did not differ significantly from sham-operated rats. Clinically, the 52 rats with subarachnoid hemorrhage were indistinguishable from 32 sham-operated rats. Postmortem examinations in 10 rats used in a preliminary investigation demonstrated significant blood clot in the basal cisterns 2 hours after basilar artery puncture. Intracranial pressure was slightly elevated (2.3 mm Hg over baseline) 30 minutes after the hemorrhage (n = 7), but when measured 3 (n = 3) or 7 (n = 3) days after surgery it had returned to baseline. Histologic examination of the brains from 10 rats subjected to subarachnoid hemorrhage 7 (n = 5) or 14 (n = 5) days before sacrifice revealed no evidence of cerebral ischemia or vasculopathic changes in the cerebral arteries.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tirilazad mesylate does not improve early cerebral metabolic recovery following compression ischemia in dogs.

BACKGROUND AND PURPOSE: Tirilazad mesylate (U74006F) has been reported to improve recovery following cerebral ischemia. We conducted a randomized blinded study to determine if the drug would improve immediate metabolic recovery after complete cerebral compression ischemia. METHODS: Mongrel dogs were anesthetized with pentobarbital and fentanyl and treated with either vehicle (citrate buffer, n = 8) or tirilazad (1.5 mg/kg i.v. plus 0.18 mg/kg/hr, n = 8). Normothermic complete cerebral compression ischemia was produced for 12 minutes by lateral ventricular fluid infusion to raise intracranial pressure above systolic arterial pressure. Cerebral high-energy phosphate concentrations and intracellular pH were measured by phosphorus magnetic resonance spectroscopy. Cerebral blood flow was measured with radiolabeled microspheres, and oxygen consumption was calculated from sagittal sinus blood samples. Somatosensory evoked potentials were measured throughout the experiment. RESULTS: During ischemia, both groups demonstrated complete loss of high-energy phosphates and a fall in intracellular pH (vehicle, 5.76 +/- 0.23; tirilazad, 5.79 +/- 0.26; mean +/- SEM). At 180 minutes of reperfusion, there were no differences between groups in recovery of intracellular pH (vehicle, 6.89 +/- 0.07; tirilazad, 6.88 +/- 0.18), phosphocreatine concentration (vehicle, 89 +/- 16%; tirilazad, 94 +/- 24% of baseline value), oxygen consumption (vehicle, 2.6 +/- 0.2 ml/min/100 g; tirilazad, 1.8 +/- 0.5 ml/min/100 g), or somatosensory evoked potential amplitude (vehicle, 11 +/- 6%; tirilazad, 7 +/- 4% of baseline value). Forebrain blood flow fell below baseline levels at 180 minutes of reperfusion in the tirilazad-treated animals but not in the vehicle-treated dogs (vehicle, 28 +/- 4 ml/min/100 g; tirilazad, 18 +/- 5 ml/min/100 g). CONCLUSIONS: We conclude that tirilazad pretreatment does not improve immediate metabolic recovery 3 hours following 12 minutes of normothermic complete ischemia produced by cerebral compression.     

Evaluation of cerebral hemodynamics with perfusion CT]

We report on the evaluation of cerebral ischemic lesions with perfusion CT. Cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) of 52 patients mostly with ischemic cerebrovascular disease were analysed using the box-modulation transfer function method with 30 ml of contrast medium intravenously injected at 5 ml/sec. CBF, CBV and MTT of the middle cerebral artery (MCA) territory were 43.5 +/- 4.6 ml/100 g/min, 1.9 +/- 0.2 ml/100 g and 2.9 +/- 0.6 seconds at the unaffected side, and 37.7 +/- 7.3 ml/100 g/min, 2.1 +/- 0.3 ml/100 g, 3.7 +/- 0.9 seconds at the lesion side with stenosis or occlusion in the main MCA trunks or internal carotid artery, respectively. A statistically significant difference was shown in CBF and MTT values. Furthermore, there was a close correlation in CBF values of MCA territories between Xe-CT and perfusion CT (r = 0.645, n = 76, p < 0.0001). MTT showed a positive correlation with CBV in those subjects when MTT was below 4.1 seconds (r = 0.526, p < 0.0001, n = 83). MTT also showed a negative correlation with CBF in those patients when MTT indicated more than 4.1 seconds (r = 0.818, p < 0.001, n = 21). These results suggest that the progression of cerebral ischemia may be classified in 4 stages using perfusion CT. The stages are as follows: stage 0; normal CBF without prolonged MTT and increased CBV, stage 1; relatively increased CBV, stage 2; significantly prolonged MTT, and stage 3; significantly decreased CBF with prolonged MTT.     

Age-related vulnerability to cerebral ischemia in spontaneously hypertensive rats.

BACKGROUND AND PURPOSE: We sought to determine the effects of aging on regional cerebral blood flow and ischemic brain damage in transient cerebral ischemia in rats. METHODS: Five adult (5-6 months) and five aged (18-22 months) female spontaneously hypertensive rats were subjected to 20 minutes of bilateral carotid occlusion and 60 minutes of recirculation under amobarbital anesthesia (100 mg/kg i.p.). Regional cerebral blood flow in the hippocampus and striatum was measured using the hydrogen clearance method. Nine adult and 14 aged rats were subjected to 20 minutes of bilateral carotid occlusion or were sham-operated under ether anesthesia. Seven days after 20 minutes of cerebral ischemia, the rats' brains were perfusion fixed. Ischemic damage in the hippocampus and striatum was graded (0 [normal] to 3 [majority of neurons damaged]). RESULTS: After 20 minutes of bilateral carotid occlusion, striatal cerebral blood flow decreased to 9.1 +/- 1.5 and 3.9 +/- 2.0 ml/100 g/min in aged and adult rats, respectively, and hippocampal cerebral blood flow decreased to 8.6 +/- 2.4 and 5.7 +/- 2.4 in aged and adult rats, respectively. Although these ischemic cerebral blood flow values were not significantly different between the two age groups, scores for ischemic damage in the hippocampus CA-1 subfield and striatum were significantly higher in aged than in adult rats (p less than 0.05, Kruskal-Wallis' h test with Bonferroni correction). CONCLUSIONS: We conclude that aging may be a primary factor in the development of greater ischemic neuronal damage observed in aged hypertensive rats.     

Age-related differences in recovery of blood flow and metabolism after cerebral ischemia in swine

We tested two hypotheses: 1) that cerebral blood flow, oxygen consumption, and evoked potentials recover to preischemic values at 120 minutes of reperfusion more completely in 1-2-week-old piglets than in 6-10-month-old pigs after complete ischemia; and 2) that recovery of cerebral blood flow, oxygen consumption, and electrical function in piglets and pigs at 120 minutes of reperfusion is better after incomplete than after complete ischemia. During 30 minutes of ischemia produced by intracranial pressure elevation, cerebral blood flow determined by the microspheres technique was decreased to 0-1 ml/min/100 g with complete ischemia, to 1-10 ml/min/100 g with severe incomplete ischemia, or to 10-20 ml/min/100 g with moderate incomplete ischemia. During reperfusion after complete ischemia, both piglets and pigs demonstrated hyperemia but delayed hypoperfusion occurred in more brain regions in pigs, oxygen consumption returned to preischemic values in piglets but not in pigs (70 +/- 10% of preischemic values), and evoked potentials recovered better in piglets than in pigs (24 +/- 4% and 9 +/- 4% of preischemic values, respectively). Both piglets and pigs had fewer brain areas with hyperemia and hypoperfusion and improved oxygen consumption and electrical function during recovery from incomplete than from complete ischemia. We speculate that piglets tolerate complete ischemia better than pigs because of decreased reperfusion injury and that both groups recover better from incomplete than complete ischemia because of improved substrate supply during ischemia.     

Conjugated superoxide dismutase reduces extent of caudate injury after transient focal ischemia in cats.

We tested the efficacy of preischemic and postischemic systemic treatment with 30,000 units polyethylene glycol-conjugated superoxide dismutase in a reperfusion model of focal cerebral ischemia. Forty-one anesthetized cats underwent 2 hours' occlusion of the left middle cerebral artery and both common carotid arteries followed by 4 hours of reperfusion. Cats were blindly assigned to one of three groups: treatment with vehicle (10% polyethylene glycol in saline, n = 17), pretreatment with drug 3 hours before ischemia (n = 12), and posttreatment with drug at the time of reperfusion (n = 12). Size of the ischemic injury was calculated from 2,3,5-triphenyltetrazolium chloride staining. Injury in the caudate nucleus was significantly reduced with pretreatment (28 +/- 6% of ipsilateral caudate volume, mean +/- SEM) compared with the vehicle (56 +/- 8%). Posttreatment did not significantly ameliorate caudate injury (46 +/- 10%). Between the first and second hours of ischemia ipsilateral caudate blood flow determined using microspheres increased significantly from 11 +/- 4 to 16 +/- 5 ml/min/100 g with pretreatment, but blood flow remained constant throughout ischemia with vehicle (8 +/- 2 ml/min/100 g) and posttreatment (10 +/- 3 ml/min/100 g). The size of cortical injury (vehicle, 17 +/- 5%; pretreatment, 11 +/- 3%; posttreatment, 17 +/- 5% of hemispheric volume) did not differ significantly among groups. Somatosensory evoked potential recovery did not differ among groups. We conclude that pretreatment with conjugated superoxide dismutase can ameliorate the extent of injury in an end-artery region, such as the caudate nucleus, in a reperfusion model of focal ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Microsphere analysis of local cerebral and extracerebral blood flow after complete ischemia of the cat brain for one hour

Summary In normothermic anesthetized cats complete cerebral circulatory arrest for one h was produced and followed by blood recirculation of the brain for 30 min to 4h. Total and local blood flow of the brain, kidney, heart and liver were measured before and after ischemia using radioactive labelled microspheres. Before ischemia blood flow of the brain was 39.1±2.3 ml/100 g/min, of the kidney 307.2±28.3 ml/100 g/min, of the heart 241.1±32.5 ml/100 g/min and of the liver 87.8±25.6 ml/100 g/min (means±SEM). Regional flow rates within the brain varied between 35 and 51 ml/100 g/min.Reactive hyperemia was present in the brain 30 min after the beginning of recirculation following ischemia for 1h. Local cerebral flow rates increased three to five times above the control flow, depending on the respective region. Mean cerebral blood flow returned to or slightly below normal, 2 to 4h after ischemia, but there was considerable redistribution of flow rates within the brain. The filter capacity of the brain for microspheres of 15 and 50 diameter did not change after ischemia indicating that postischemic blood recirculation was not accompanied by an opening of arteriovenous shunts.This work was supported by the Deutsche Forschungsgemeinschaft     

Functional recovery of cortical neurons as related to degree and duration of ischemia

Simultaneous recordings of spontaneous single cell activity and local cerebral blood flow were obtained from 72 cortical neurons and adjacent brain in 54 cats before, during, and after ischemia induced by reversible occlusion of the middle cerebral artery. In most cells spontaneous electrical activity ceased at flow values of about 0.18 ml/gm/min (range, 0.06 to 0.22 ml/gm/min). No signal was obtained from 28 neurons during reperfusion following ischemia of varying degree and duration. Overall, neurons exposed to a residual flow of 0.14 ml/gm/min or less for more than 45 minutes had a poorer prognosis compared to any other combination of degree and duration of ischemia. A discriminant curve was estimated to define the border line between recovering and nonrecovering cells. Regions showing irreversible neuronal failure contained selective neuronal necrosis or areas of infarction by histological examination. Reperfusion restored neuronal function in 44 cells. In this group of neurons, there was a joint interaction of duration of ischemia, ischemic residual flow, and recovery time: cells exposed to moderate ischemia (0.09 to 0.22 ml/gm/min) for up to 20 minutes recovered rapidly; most neurons subjected either to extreme ischemia (less than 0.09 ml/gm/min) of short duration (less than 20 minutes) or to moderate ischemia (0.09 to 0.22 ml/gm/min) for longer periods (20 to 141 minutes) required from 19 to 50 minutes for recovery. A few resistant neurons tolerated less than 0.09 ml/gm/min for more than 20 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hydroxyethyl starch 200/0.5 reduces infarct volume after embolic stroke in rats.

BACKGROUND AND PURPOSE: We evaluated isovolumic hemodilution with hydroxyethyl starch 200/0.5 in a rat model of focal cerebral ischemia. This compound avoids the unfavorable viscosity and erythrocyte aggregation abnormalities of low molecular weight dextran during administration over a period of several days. METHODS: Sprague-Dawley rats, anesthetized with 0.5-1% halothane and 70% N2O, were subjected to silicon cylinder (treated and control groups) or sham (sham group) embolization of the cerebral circulation. Thirty minutes after embolization, the treated group (n = 5) was infused with 11 ml/kg of 10% hydroxyethyl starch 200/0.5, and the control (n = 5) and sham (n = 4) groups were infused with saline for 1 hour. In the treated group, 7.1 ml/kg of blood was withdrawn. After 24 hours, the animals were reanesthetized, and cerebral blood flow was determined with [14C]iodoantipyrine. Alternative brain slices were either incubated with 2,3,5-triphenyltetrazolium chloride for infarct volume determination or frozen for ischemic volume and cerebral blood flow determination using autoradiography. RESULTS: The hematocrit in the treated group was reduced from (mean +/- SEM) 46 +/- 1% to 35 +/- 2% at 1.5 hours (p < 0.01). Cortical blood flow was within the normal range of 115-185 ml/min/100 g, except for the ischemic cortex in the embolized groups, treated and control. The ischemic and infarct volume of the treated group was reduced by 74% (p < 0.05) and 89% (p < 0.05), respectively, from the control group. The treated and sham ischemic and infarct volumes were not statistically different. CONCLUSIONS: These data suggest that hydroxyethyl starch 200/0.5 could be an effective treatment for ischemic stroke when administered early, because it reduces infarct and ischemic volumes from control values to levels indistinguishable from those of the sham group.     

Monoclonal leukocyte antibody does not decrease the injury of transient focal cerebral ischemia in cats.

BACKGROUND AND PURPOSE: We tested the hypothesis that inhibition of leukocyte function by administration of monoclonal antibody 60.3 (MoAb 60.3) improves electrophysiological recovery and decreases injury volume following transient focal cerebral ischemia in cats. METHODS: Halothane-anesthetized cats underwent 90 minutes of left middle cerebral artery and bilateral common carotid artery occlusion followed by 180 minutes of reperfusion. Cats were assigned to receive either 2 mg/kg MoAb 60.3 (n = 8) directed at the CDw18 leukocyte antigen complex or an equal volume of diluent (sterile saline; n = 10) at 45 minutes of ischemia in a blinded fashion. RESULTS: Blood flow to the left temporoparietal cortex decreased to less than 5 ml/min/100 g with ischemia, but was minimally affected on the right side. Postischemic hyperemia occurred in the left caudate nucleus, whereas blood flow in other brain regions returned to control. No region demonstrated delayed hypoperfusion, and there were no differences between groups. Somatosensory evoked potential recorded over the left cortex was ablated during ischemia and recovered to less than 10% of baseline amplitude at 180 minutes of reperfusion in both groups. Left hemispheric injury volume, as assessed by 2,3,5-triphenyltetrazolium chloride staining, was not affected by drug treatment (mean +/- SE values: MoAb 60.3, 37 +/- 5%; placebo, 38 +/- 7% of hemisphere). CONCLUSIONS: Inhibition of leukocyte function with MoAb 60.3 does not afford protection from severe focal ischemia and reperfusion in cats.     

The novel dihydronaphthyridine Ca2+ channel blocker CI-951 improves CBF, brain pHi, and EEG recovery in focal cerebral ischemia

The effects of the novel dihydronaphthyridine Ca2+ antagonist CI-951 on focal cerebral ischemia were assessed during MCA occlusion in 30 white New Zealand rabbits under 1.0% halothane anesthesia. In vivo brain pHi and focal CBF were measured with umbelliferone fluorescence. Baseline normocapnic brain pHi and CBF were 7.02 +/- 0.02 and 48.4 +/- 2.9 ml/100 g/min, respectively. In the severe ischemic regions, 15 min postocclusion brain pHi and CBF were 6.62 +/- 0.04 and 14.4 +/- 0.7 ml/100 g/min in controls vs. 6.60 +/- 0.02 and 12.9 +/- 2.3 ml/100 g/min, respectively, in animals destined to receive CI-951. Twenty minutes after MCA occlusion, CI-951 was administered at 0.5 microgram/kg/min and brain pHi and CBF were determined in both regions of severe and moderate ischemia for 4 h postocclusion. Control severe ischemic sites demonstrated no significant improvement in brain pHi and only mild increases in CBF over the next 4 h. CI-951 caused significant improvement in both of these parameters. Postocclusion 4 h brain pHi and CBF measured 6.69 +/- 0.04 and 18.5 +/- 3.2 ml/100 g/min in controls vs. 7.01 +/- 0.04 and 41.7 +/- 5.3 ml/100 g/min, respectively, in CI-951 animals (p less than 0.001). Similar improvements were observed in moderate ischemic sites. In animals that demonstrated postocclusion EEG attenuation, 75% of CI-951 animals had EEG recovery as compared to 18% in controls. CI-951 may be a useful therapeutic agent for focal cerebral ischemia if histological and outcome studies verify these data.     

Transport of sodium from blood to brain in ischemic brain edema

Brain water and sodium increase during ischemia, suggesting that the blood-brain barrier permeability to sodium is increased. To test this hypothesis we measured the permeability-surface area products of 22Na and [3H]sucrose in gerbils following 3 hours of unilateral ischemia. In animals with neurologic symptoms, unilateral carotid occlusion reduced the cerebral blood flow in the ipsilateral cerebral hemisphere to 13 +/- 4 ml/100 g/min (n = 6). The water content of the ischemic hemisphere increased from 79.0 +/- 0.6 to 80.8 +/- 0.2% (n = 7, p less than 0.001) and tissue sodium content increased from 231 +/- 17 to 359 +/- 23 mEq/kg (p less than 0.0001). However, there was a 40% reduction in the sodium permeability-surface area product of the ischemic hemisphere compared with the control side (1.65 +/- 0.44 vs 2.79 +/- 0.29 microliter/g/min, n = 6, p less than 0.001). The sucrose permeability-surface area product, a measure of blood-brain barrier integrity, was unchanged. Although ischemia was less severe in the diencephalon, the tissue water and sodium contents increased significantly on the ischemic side. In contrast to the cerebral hemisphere, however, the permeability-surface area products for both sodium and sucrose were unchanged in the ischemic diencephalon. These results suggest that the increase in tissue sodium seen in ischemic edema is not due to enhanced sodium uptake; we speculate that it results, in part, from a reduction in sodium and water clearance from the tissue.     

Threshold of regional cerebral blood flow for infarction in patients with acute cerebral ischemia

Threshold of regional cerebral blood flow (rCBF) for cerebral tissue survival in relation to time was studied in patients with acute cerebral ischemia with xenon-enhanced computed tomography (XeCT). Case 1: A 58-year-old man with right hemiparesis, total aphasia and a high intensity area of 1 cm 2 in the left insula on diffusion weighted image underwent XeCT CBF study before and after intra-arterial local thrombolytic therapy (IALT) on the occluded middle cerebral artery (MCA) 4 hours and 7 hours after stroke onset, respectively. Case 2: A 65-year-old woman with recurrent transient ischemic attacks (TIAs) caused by severe stenosis of the left MCA underwent XeCT CBF study 5 hours after onset of the last attack. XeCT was conducted by 5-min wash-in method. In Case 1 the rCBF in the pre-IALT MCA territory was 4 to 19 ml/100 g/min. The area where rCBF in the post-IALT increased to above 15 ml/100g/min were saved, but the other area where it remained in the 9 to 14 ml/100 g/min evolved into infarct on subsequent CT scan/MR (magnetic resonance) imaging. The patient was discharged with only mild motor dysphasia. In Case 2 the left corona radiata showed rCBF of 7 ml/100 g/min and this area evolved into infarct on MR imaging. The patient was discharged home with right hemiparesis. Our results showed validity of the rCBF threshold in acute cerebral ischemia reported by Jones et al. Residual rCBF in the acute stage of cerebral ischemic stroke can predict the fate of the lesion.