Cerebral blood flow and neurologic outcome when nimodipine is given after complete cerebral ischemia in the dog

Ten minutes of complete cerebral ischemia was produced in 26 dogs by temporary ligation of the aorta and the venae cavae. Twenty dogs received nimodipine, a calcium entry blocker, 10 micrograms kg-1 i.v. 2 min after the ischemic period, followed by 1 microgram kg-1 min-1 for 2-3 h. Six dogs received only the solvent used for nimodipine. Fourteen dogs received nimodipine for 3 h and were subsequently evaluated neurologically up to 48 h postischemia. In the 12 other dogs, CBF and metabolism were followed for 2 h postischemia while either nimodipine or the solvent only was infused. The results were compared to previously published results for untreated dogs and dogs given nimodipine before the ischemic event. Nimodipine had the same effect on postischemic CBF whether started before or after the ischemic event, nearly doubling the flow when compared with untreated controls, whereas the solvent alone caused only a slight increase in CBF over control. By contrast, nimodipine initiated in the preischemic period significantly improved the neurologic outcome, but when initiated in the postischemic period the results were equivocal, such that the outcome was not significantly different from either the untreated group or the group in which nimodipine was initiated preischemia. Metabolic measurements did not give any indication of a specific effect of nimodipine, nor could the metabolic results be used as an indicator of neurologic outcome. The results are consistent with a beneficial effect of nimodipine following complete cerebral ischemia; however, evaluation of neurologic functional effects will require a more sensitive model.     

Nicardipine increases cerebral blood flow but does not improve neurologic recovery in a canine model of complete cerebral ischemia

The effects of the calcium entry blocker nicardipine on CBF, CMRO2, and neurologic outcome following 10 min of complete cerebral ischemia were examined in dogs. In CBF and CMRO2 studies, the CBF in the untreated group (seven dogs) and the nicardipine group (seven dogs; 20 micrograms kg-1 at 30 min postischemia and a subsequent infusion of 2 micrograms kg-1 min-1 for 90 min) initially increased to 300-400% and then returned to preischemic values at 30 min postischemia. Thereafter the CBF in the untreated group significantly decreased to 50% of preischemic values for the following 90-min period (hypoperfusion), while the CBF in the nicardipine group did not differ from preischemic values. The CMRO2 in both groups decreased to approximately 50-80% of preischemic values after 15 min postischemia and did not differ between the groups throughout the study. In neurologic outcome studies, 18 dogs were divided into three groups (of six dogs each): untreated; saline infusion only, posttreated; nicardipine as in CBF and CMRO2 studies, pretreated; nicardipine 20 micrograms kg-1 at 2 min preischemia and a subsequent infusion of 2 micrograms kg-1 min-1 from immediately postischemia to 120 min postischemia. Nicardipine treatment initiated either before or after ischemia failed to improve neurologic outcome at 48 h postischemia. Thus, the increase of postischemic global CBF by nicardipine is not accompanied by neurologic recovery in a canine model of complete cerebral ischemia.     

Nimodipine does not affect cerebral lactate levels following complete ischemia in dogs

Nimodipine is known to improve postischemic cerebral blood flow (CBF) and neurologic outcome in experimental animals. Whether or not the two observations are related is unknown. This study searched for a possible improved rate of brain metabolic recovery in animals treated with nimodipine postischemia. Complete cerebral ischemia was produced for 11 min in 16 dogs, followed by reperfusion for 70 min. Prior to ischemia, glucose was administered (0.75 g X kg-1) in 12 dogs. Half of the glucose-treated dogs were given i.v. nimodipine, beginning 5 min postischemia (10 micrograms X kg-1 bolus followed by 1 microgram X kg-1 X min-1). The other half were given only saline postischemia. The remaining four dogs were given no glucose and received saline only postischemia. In all dogs, serial brain biopsies were taken at 2, 20, 40, and 70 min postischemia. In 5 dogs, the integrity of the blood-brain barrier (BBB) was tested by injection of Evans blue dye and postmortem examination of the brains. Brain biopsies were assayed for concentrations of phosphocreatine, ATP, ADP, AMP, glucose, lactate, and pyruvate. In all dogs, there was rapid restoration of a normal brain energy state following reperfusion. Brain lactate had returned to near normal in all dogs by 70 min postischemia, and the rate of lactate depletion was not different between groups. The integrity of the BBB was only minimally affected. A portion of the brain lactate was converted to pyruvate rather than crossing the BBB.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of the calcium antagonist nimodipine on the delayed hypoperfusion following incomplete ischemia in the rat

Regional cerebral blood flow (CBF) was measured autoradiographically in the recovery period following 15 min of forebrain ischemia in rats pretreated with either nimodipine (0.1 mg kg-1) or vehicle. The results showed that although nimodipine increased postischemic CBF, the flow enhancement was regionally heterogeneous, sometimes resulting in zones of gross hypoperfusion and overt hyperemia within the same structures. This patchy improvement of delayed postischemic hypoperfusion was not accompanied by recovery of sensory evoked responses, and return of EEG activity was not enhanced.     

Sequential cerebral blood flow changes in short-term cerebral ischemia in gerbils

Using quantitative autoradiography, we studied sequential changes in regional cerebral blood flow during and after 2 minutes of bilateral common carotid artery occlusions in 18 gerbils. Occlusion (n = 4) led to severe ischemia in the forebrain (regional cerebral blood flow less than 5% of control [n = 4]) and midbrain (regional cerebral blood flow less than 10% of control), but was morphologically nonlethal. Reperfusion of the brain was complete, and regional cerebral blood flow was not different from control 1 minute after ischemia (n = 4), but hypoperfusion (regional cerebral blood flow 30-50% of control) occurred at 5 minutes (n = 3) and was pronounced at 1 hour (n = 4); at this stage blood flow was inhomogeneous. Hypoperfusion had disappeared at 4 hours (n = 3). Our results indicate that the well-documented sequence of cerebral blood flow changes (i.e., ischemia, initial recovery of blood flow, and delayed hypoperfusion) takes place even after nonlethal cerebral ischemia.     

The effects of nimodipine on cerebral blood flow and metabolism

Nimodipine, a calcium entry blocker, was administered in increasing doses of 0.1-3.0 micrograms kg-1 min-1 to six dogs after they had recovered consciousness from a surgical preparation that was conducted under general anesthesia and while they were under the influence of total spinal anesthesia. CBF was measured with a sagittal sinus outflow technique and CMRO2 was calculated as the product of CBF and the arteriovenous O2 difference. Nimodipine did not influence either CBF or CMRO2. There was a decrease in the cortical pyruvate level at the end of the study, but no significant change in phosphocreatine, ATP, lactate, or energy charge when compared with six control dogs. It has previously been reported that nimodipine increases the CBF in global ischemia with a potentially beneficial effect on the neurological outcome. With no effect on normal CBF or metabolism, this suggests that nimodipine may be useful in a variety of ischemic situations without fear of either a steal phenomenon or untoward effects on intracranial pressure.     

Correlations between cerebral arterial velocities, blood flow, and delayed ischemia after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Elevated middle cerebral erythrocyte velocities and tissue hypoperfusion have been correlated with delayed ischemia after subarachnoid hemorrhage, but few studies have compared serial arterial velocities with cerebral blood flow and neurological deficits. METHODS: Serial measurements of middle cerebral velocities, using transcranial Doppler ultrasonography, were performed in 34 patients after subarachnoid hemorrhage and correlated with cerebral blood flow, measured in 20 of the 34 using single-photon emission computed tomography with technetium-99m hexamethylpropylene amine oxime and neurological evidence of delayed ischemia. RESULTS: In 16 patients without delayed ischemia, eight had evidence of vasospasm (greater than 120 cm/sec), but only one of seven had hypoperfusion, suggesting that vasospasm might be more common than hypoperfusion in this group (p = 0.1). In 10 patients with delayed ischemia and a lateralizing deficit, both asymmetrical middle cerebral vasospasm (eight of nine with vasospasm) and hypoperfusion (six of six studied) were concordant with the clinically ischemic hemisphere (p less than 0.05). Vasospasm occurred with nonlateralized delayed ischemia in seven of eight patients and with hypoperfusion in five of six, affecting the anterior cerebral territory in three. CONCLUSIONS: Concordant vasospasm and hypoperfusion were most often present in patients with delayed ischemia and lateralizing neurological deficits. Discordant results reflect inherent limitations and the different levels of the circulation monitored by the two techniques.     

No correlation between cerebral blood flow and neurologic recovery after reversible total cerebral ischemia in the dog

This study was conducted to determine if regional cerebral flow during the first day after total cerebral ischemia was correlated with neurologic deficit and eventual survival. Dogs were subjected to 11 min of total cerebral ischemia (TCI) produced by an arterial and venous double balloon occlusion method. Recovery was allowed for up to 7 days after reperfusion, whereupon it was reassessed in survivors. Blood flow, determined by the radiolabeled microsphere method, was determined before TCI and at times up to 24 h after reperfusion. Blood flow during reperfusion after TCI followed the expected pattern of immediate hyperperfusion followed by prolonged hypoperfusion. TCI of 11 min duration resulted in a 50% mortality rate by 1 week. No positive correlation between magnitude or duration of hypoperfusion and neurologic deficit or mortality was found. It was concluded that improved postischemic blood flow cannot be used as a criterion for assessing drug therapy without reference to metabolic demand. The observation of a statistical correlation between dogs that survived and lower hematocrit was reported. It was suggested that the prolonged hypoperfusion encountered after TCI was not pathological, but rather served as a mechanism to limit oxygen exposure to the brain during a vulnerable period and, thus, was part of a controlled attempt at recovery of function by the central nervous system.     

Nimodipine attenuates both increase in cytosolic free calcium and histologic damage following focal cerebral ischemia and reperfusion in cats

To clarify the mechanism of its effect on ischemic stroke, we investigated the effect of nimodipine, a dihydropyridine calcium antagonist, on changes in cytosolic free calcium, cortical blood flow, and histologic changes following focal cerebral ischemia and reperfusion in 14 cats. Using indo-1, a fluorescent intracellular Ca2+ indicator, we simultaneously measured changes in the Ca2+ signal ratio (400:506 nm), reduced nicotinamide adenine dinucleotide fluorescence (464 nm), and reflectance (340 nm) during an ultraviolet excitation (340 nm) directly from the cat cortex in vivo. In six cats treated with vehicle only, the calcium signal ratio increased from 5 minutes after middle cerebral artery occlusion to 30 minutes into reperfusion. The elevation of cytosolic free calcium was significantly attenuated by nimodipine, which was administered by intravenous infusion in eight cats starting 5 minutes after occlusion. Nimodipine had no effect on cortical blood flow during ischemia but induced a hyperperfused state following reperfusion. Nimodipine did not modify changes in the mitochondrial oxidation-reduction state. Nimodipine proved to have beneficial effects on recovery of the electroencephalogram following reperfusion as well as on the extent of focal histologic damage. Our results suggest that nimodipine, when administered during the early stage of focal ischemia, can favorably modify the outcome of stroke by reducing the Ca2+ entry during both the ischemic and reperfusion periods.     

Failure of deferoxamine, an iron chelator, to improve neurologic outcome following complete cerebral ischemia in dogs

Eleven minutes of complete cerebral ischemia was produced in 17 dogs by temporary ligation of the venae cavae and aorta. Immediately prior to the ischemic episode, 7 dogs received deferoxamine, an iron chelator, 50 mg/kg i.v., and 10 dogs received an equivalent volume of saline placebo i.v. Five dogs failed to meet preestablished protocol criteria and were excluded from data analysis. Neurologic recovery was evaluated by an observer blind to the treatment groups in the remaining 12 dogs at 48 hours postischemia. The neurologic effects of complete cerebral ischemia were compared between dogs treated with deferoxamine and those receiving placebo treatment. One of 6 deferoxamine-treated dogs was normal and 5 were moderately to severely damaged. Similarly, 1 of 6 placebo-treated dogs was normal and 5 were moderately to severely damaged. The authors conclude that deferoxamine does not provide cerebral protection in this model of complete cerebral ischemia.     

The effects of a calcium antagonist, nimodipine, upon physiological responses of the cerebral vasculature and its possible influence upon focal cerebral ischaemia

The effects of a calcium antagonist, nimodipine, were tested on the response of the cerebral circulation to arterial pCO2 and blood pressure changes. The effects of reduced blood flow upon oedema formation and extracellular ion homeostasis under nimodipine preloading were studied. Both open and closed skull primate models were used, with alpha-chloralose anaesthesia. Nimodipine infusion increased basal blood flow in the open skull, but not the closed skull animals. Autoregulation to increased blood pressure was little affected. Responses to arterial pCO2 changes and autorerulation to reduced blood pressure were severely imparied. Residual blood flow after middle cerebral artery occlusion was significantly higher with nimodipine than in controls. The threshold levels of blood flow for the development of cortical oedema and for disturbance of ion homeostasis were, however, increased, suggesting that nimodipine interferes with cellular energy metabolism and increases the susceptibility of tissue to ischaemic damage.     

Nimodipine pretreatment improves cerebral blood flow and reduces brain edema in conscious rats subjected to focal cerebral ischemia

The effect of nimodipine pretreatment on CBF and brain edema was studied in conscious rats subjected to 2.5 h of focal cortical ischemia. An infusion of nimodipine (2 micrograms/kg/min i.v.) or its vehicle, polyethylene glycol 400, was begun 2 h before the ischemic interval and was continued throughout the survival period. Under brief halothane anesthesia, the animals' right middle cerebral and common carotid arteries were permanently occluded, and 2.5 h later, they underwent a quantitative CBF study ([14C]iodoantipyrine autoradiography followed by Quantimet 970 image analysis). Nimodipine treatment improved blood flow to the middle cerebral artery territory without evidence of a "vascular steal" and reduced the volume of the ischemic core (cortex with CBF of less than 25 ml/100 g/min) and accompanying edema by approximately 50% when compared with controls (p = 0.006 and 0.0004, respectively). Mild hypotension induced by nimodipine did not aggravate the ischemic insult. The ischemic core volumes, however, were 50-75% smaller than the 24-h infarct volumes generated in a similar paradigm that demonstrated 20-30% infarct reduction with continuous nimodipine treatment. These results suggest that nimodipine pretreatment attenuates the severity of early focal cerebral ischemia, but that with persistent ischemia, cortex surrounding the ischemic core undergoes progressive infarction and the early benefit of nimodipine treatment is only partly preserved.     

Postischemic canine cerebral blood flow appears to be determined by cerebral metabolic needs

Following a period of complete global cerebral ischemia and reperfusion there ensues a low flow state referred to as the delayed postischemic hypoperfusion state. It is unknown whether this low flow state contributes to neuronal injury or whether the magnitude of hypoperfusion correlates with the duration of ischemia. The latter question was addressed in 20 dogs in which complete global ischemia was induced by cerebrospinal fluid (CSF) compression for periods of 3, 9, 12, or 18 min. Following reperfusion, CBF (by sagittal sinus outflow) and CMRO2 were determined for 90 min, and results were correlated with the duration of ischemia. At 90 min postischemia the magnitude of decrease in CBF correlated crudely with the duration of ischemia (r = -0.67, p less than 0.01). For CMRO2 correlation of the magnitude of decrease with the duration of ischemia was more evident (r = -0.74, p less than 0.001). Furthermore, the postischemic ratio of CBF to CMRO2 was virtually identical for all dog groups regardless of the ischemic time. The adequacy of the ratio of CBF to CMRO2 was reflected by adequate oxygen levels in the sagittal sinus blood of all dogs. The authors conclude that the delayed postischemic hypoperfusion state is probably not an important determinant of neuronal injury since its magnitude appears to be primarily determined by the metabolic needs of the brain.     

Effects of nimodipine on acute focal cerebral ischemia

Nimodipine is a calcium slow channel blocker with several pharmacologic properties suggesting the potential to favorably modify outcome in focal cerebral ischemia. Thirty adult cats underwent unilateral middle cerebral artery (MCA) occlusion for 4 hours. Seventeen cats were treated with an ipsilateral intracarotid infusion of nimodipine (1 microgram kg-1 min -1) beginning 15 minutes before MCA occlusion and continuing throughout the occlusion period. Eight nimodipine treated cats maintaining MAP greater than 90 mmHg were assigned to a Higher Pressure Nimodipine (HPN) group. The remaining nine treated cats with MAP less than 90 mmHg were assigned to the Lower Pressure Nimodipine (LPN) group. Thirteen cats were untreated, receiving an isovolumetric amount of vehicle through the ipsilateral carotid artery. Local cerebral blood flow (ICBF) was continuously monitored using thermal diffusion probes. The brains, assessed for colloidal carbon perfusion, fluorescein and Evans blue staining, electroencephalographic activity (EEG), and histological changes, revealed no significant differences by any of these methods between the HPN and control animals with the exceptions of: HPN treated cats exhibited a preservation of EEG activity at 15 minutes post-occlusion compared to the untreated cats, and Post-ischemic surface colloidal carbon perfusion was better preserved in the treated cats than in the untreated cats. Mild hypotension, as demonstrated by the LPN group, negated these two positive effects. Prior to MCA occlusion, ICBF was bilaterally significantly increased after nimodipine infusion in the HPN group as compared to vehicle infusion. Intra-arterially infused nimodipine did not reduce infarct size.     

Influence of granulocytopenia on canine cerebral ischemia induced by air embolism

We subjected nine dogs with severe granulocytopenia 4 days after the administration of mechlorethamine to 1 hour of cerebral ischemia induced by the controlled, incremental injection of air into the internal carotid artery. Cortical somatosensory evoked responses and cerebral blood flow determined by [14C]iodoantipyrine autoradiography were compared with those of six control dogs that had received mechlorethamine 1 day previously and were not yet granulocytopenic. Eleven additional control dogs received no mechlorethamine but had identical ischemic insults and were followed for 4 hours after ischemia. Both control groups had identical evoked response outcomes after 1 hour of recovery from ischemia. Granulocytopenic dogs had improved evoked response recoveries compared with either control group after 1 hour of recovery. No areas of very low blood flow were observed 1 hour after ischemia in the granulocytopenic dogs, but three of five dogs in the control group receiving mechlorethamine had such areas.     

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.     

Incomplete versus complete cerebral ischemia: improved outcome with a minimal blood flow

It has been reported that incomplete cerebral ischemia with cerebral blood flow less than 10% of control may be more damaging than an equal period of complete ischemia. In this study, the effects of severe, incomplete cerebral ischemia on neurological outcome and cerebral metabolism were studied in dogs anesthetized with nitrous oxide. The results were compared with those of a previous study concerned with the effects of complete ischemia. Dogs could sustain only 8 to 9 minutes of complete ischemia with return of normal neurological function, whereas maintenance of a cerebral blood flow rate less than 10% of control extended this limit to 10 6o 12 minutes. Following a 10-minute exposure, only dogs undergoing incomplete ischemia regained a normal cerebral oxygen consumption within 90 minutes; similarly, animals subjected to incomplete ischemia enjoyed a faster return of EEG activity than dogs exposed to complete ischemia of the same duration. Cerebral metabolite levels did not prove to be a good index of return of neurological function. Within periods of cerebral ischemia in which meaningful neurological recovery might be expected, we conclude that some blood flow is better than no flow.     

Effect of nimodipine on cerebral blood flow and metabolism in rats during hyperventilation

Nimodipine shws promise in the prevention and treatment of brain ischemia. We examined the interaction of nimodipine pretreatment in a dose sufficient to prevent postischemic hypoperfusion and hyperventilation. We studied four groups of rats: normocarbia plus vehicle (Group 1, n = 5), hypocarbia plus vehicle (Group 2, n = 4), normocarbia plus nimodipine (Group 3, n = 7), and hypocarbia plus nimodipine (Group 4, n = 6). Groups 3 and 4 received 1 mg/kg i.p. nimodipine, and Groups 1 and 2 received an equivalent amount of vehicle. Ventilation was left unaltered in Groups 1 and 3 or increased to lower PaCO2 to 21-24 mm Hg in Groups 2 and 4. Determination of regional cerebral glucose utilization (rCGU) was carried out using the [3H]2-deoxyglucose method, and regional cerebral blood flow (rCBF) was determined by the indicator fractionation method using [14C]iodoantipyrine. The brain regions studied were the cerebral hemispheres, the diencephalon, the cerebellum, and the brainstem. Hyperventilation in Groups 2 and 4 from approximately 38 to 22 mm Hg reduced rCBF to 60% of normocarbic levels (p less than 0.05). The slope and intercept of this response were similar in vehicle- and nimodipine-pretreated rats. Nimodipine modestly decreased mean arterial blood pressure by 20% and increased plasma glucose concentration by 60% (p less than 0.05). Although nimodipine tended to increase rCBF and decrease regional cerebrovascular resistance (rCVR), this was significant only for hemispheric rCVR (p less than 0.05). There was a borderline effect for nimodipine to increase rCGU, especially during hypocarbia.(ABSTRACT TRUNCATED AT 250 WORDS)     

鼠脑血管痉挛时尼莫地平对体感诱发电位的影响

目的 探讨蛛网膜下腔出血（SAH）后脑血管痉挛（CVS）对体感诱发电位（SEP）的影响,及尼莫地平（ND）的保护作用。方法 对单纯SAH组和ND处理组大鼠观察手术前后基底动脉管径,并检测24h内局部脑血流量（rCBF)、SEP潜伏期及脑组织内皮素-1（ET-1）含量的动态变化。结果 SAH组大鼠在诱导SAH后rCBF立即降低,并持续24h,同时有基底动脉痉挛;SAH后1h开始至24hSEP潜伏期逐渐延长,脑组织ET-1含量显著增加,ND处理组大鼠上述变化均较轻。结论 SAH后CVS可通过脑血流的降低,脑组织ET-1增加而导致SEP潜伏期延长,ND通过拮抗脑组织ET-1变化而对之具有保护作用。     

尼莫地平对大鼠急性脑缺血再灌注损伤早期保护作用的研究

目的探讨尼莫地平对急性脑缺血再灌注损伤的早期保护作用。方法线栓法复制大鼠急性脑缺血模型。30只雄性Wistar大鼠随机分为假手术、模型、尼莫地平3组。模型组采取缺血2h再灌注2h。尼莫地平组大鼠在缺血0时刻起每小时腹腔注射给药一次,剂量为5mg/kg。各组大鼠在手术4h后实验结束后,行腹主动脉采血,同时取完整脑组织。脑组织切片进行TTC染色,并比较各组脑组织梗死面积。检测各组大鼠血清及脑组织匀浆中SOD、MDA、NO含量。结果与模型组相比,尼莫地平组大鼠脑组织梗死面积显著减少。血清生化指标显示,模型组SOD含量显著低于假手术组,给予尼莫地平治疗后,SOD含量增加明显。模型组MDA、NO含量明显高于假手术组,尼莫地平组明显降低血清中MDA、NO。结论尼莫地平对大鼠急性脑缺血再灌注损伤有保护作用,这种保护作用与NO和氧化应激密切相关。