Postischemic Cerebral Blood Flow Research Articles

Postischemic Cerebral Blood Flow and Neuroeffector Mechanisms

The influence of neuroeffector mechanisms in the regulation of postischemic cerebral blood flow was investigated by microsphere determination in 8 cats after chronic unilateral vascular deafferentation by trigeminal ganglionectomy. The animals were subjected to 90 min of reperfusion following 10 min of global ischemia induced by 4-vessel occlusion and systemic hypotension. Cortical hyperemia 30 min after reperfusion was attenuated by up to 48% in cortical gray matter ipsilateral to the side of trigeminal ganglionectomy (p less than 0.01). Axon reflex mechanisms involving the release of neuropeptides from peripheral sensory nerve fibers, such as substance P (SP), calcitonin gene-related peptide (CGRP) and neurokinin A (NKA), mediate this response. SP and NKA cause vasodilation by endothelium-dependent mechanisms (endothelium-dependent relaxing factor), whereas CGRP relaxes vascular smooth muscle by direct receptor interactions. Studies were therefore undertaken to determine the extent to which endothelium-dependent mechanisms mediate the hyperemia following global cerebral ischemia. In 7 intact cats, the postischemic response of pial arterioles to the topical application of acetylcholine (ACh; 10(-7) M), an endothelial-dependent vasodilator, was measured using a closed cranial window technique. Although ACh increased pial arteriolar caliber by 17% under resting conditions, the same dose elicited a vasoconstrictor response (87% of pre-ACh diameter 30 min after reperfusion) for the first 60 min of reperfusion after 10 min of ischemia. ACh-induced vasodilation was restored by 75 min (105%), but was less than control even at 120 min (109 vs. 117%; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Protective Effect of Nimodipine against Ischemic Neuronal Damage in Rat Hippocampus without Changing Postischemic Cerebral Blood Flow

The purpose of the present study was to investigate the neuroprotective action of nimodipine. Furthermore, the influence of nimodipine on postischemic local CBF (LCBF) was examined. Forebrain ischemia of the rat was performed for 10 min by bilateral carotid clamping, administration of trimethaphan, and blood withdrawal to obtain an MABP of 40 mm Hg. LCBF was measured after 10 min of postischemic recirculation by injecting [14C]iodoantipyrine in saline solution. Nimodipine (0.1, 0.3, and 1.0 mg/kg) was suspended in miglyol oil and applied orally 60 min prior to ischemia. Histological evaluation was performed 7 days after ischemia. Hippocampal neuronal damage was determined as the percentage of necrotic neurons. After preischemic application of nimodipine, neuronal damage was significantly reduced in the hippocampal CA1 subfield. Postischemic LCBF was not affected by treatment with nimodipine. These findings show that nimodipine is able to protect neurons against ischemic damage. The neuroprotective effect of nimodipine was not mediated by a postischemic cerebral vasodilation, but by a direct action on the neurons.

The effect of the excitatory amino acid receptor antagonist dizocilipine maleate (MK-801) on hemispheric cerebral blood flow and metabolism in dogs: modification by prior complete cerebral ischemia

The effect of the N-methyl- d-aspartate (NMDA) receptor antagonist dizocilipine maleate (MK-801) on cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO 2), intracranial pressure and systemic variables was examined in 6 normal dogs (Group I). In 6 additional dogs (Group II), the effects of a prior 11 min episode of complete cerebral ischemia on the response to dizocilipine was studied. CBF was measured with a sagittal sinus outflow technique and CMRO 2 was calculated as the product to CBF and the arterial to sagittal sinus O 2 content difference. Dizocilipine was administered as a 150 μg/kg i.v. bolus followed by a 75 μg·kg −1·h −1 infusion for 90 min. Plasma dizocilipine levels were >25 ng/ml for the duration of the infusion. The CSF levels were approximately half the plasma levels. Five minutes after initiation of dizocilipine treatment, Group I dogs experienced a 63% increase in heart rate ( P < 0.01) and an 8% decrease in the mean arterial blood pressure ( P < 0.05). Over the same time interval, CBF increased by 85% ( P < 0.01) and intracranial pressure nearly doubled ( P < 0.05). In addition, dizocilipine treatment in all Group I animals resulted in EEG quasiperiodic bursts of δ-waves and polyspikes on a background of β-activity. With the exception of the intracranial pressure, the above changes in systemic and cerebral variables persisted for the duration of the drug infusion. Intracranial pressure was no longer significantly elevated after 80 min of drug infusion. Hemispheric CMRO 2 was unchanged by dizocilipine in Group I dogs. There was a decrease in the cortical glucose level the end of the study, but no significant change in phosphocreatine, ATP, lactate, or energy charge when compared with 6 laboratory normals. An identical dose of dizocilipine administered after an 11 min episode of complete cerebral ischemia resulted in no significant changes in either cerebral or systemic variables. The absence of systemic effects in Group II dogs suggests that dizocilipine administration in normal dogs results in a centrally mediated activation of the peripheral sympathetic nervous system. The uncoupling of CBF and CMRO 2 observed following dizocilipine treatment is similar to that reported for two other known NMDA antagonists, ketamine and phencyclidine. If administration of dizocilipine results in improved histopathological and neurological outcome following an episode of complete cerebral ischemia, this improvement is unrelated to changes in postischemic CBF or hemispheric CMRO 2.

Post-ischemic neurologic recovery and cerebral blood flow using a compression model of complete "bloodless" cerebral ischemia in dogs.

Complete "bloodless" cerebral ischemia was produced in 14 dogs by increasing intracranial pressure above systolic blood pressure (compression ischemia) for 10 min after the onset of an isoelectric EEG. Six dogs were observed for 48 h post-ischemia to assess neurologic recovery, and in 6 other dogs, acute post-ischemic cerebral blood flow was determined for 2 h. In 2 additional dogs, pre-ischemic and intra-ischemic cerebral blood volume (CBV) was measured using 111In-labeled red blood cells. Compression ischemia resulted in 2 of 6 dogs that were normal at 48 h post-ischemia, 3 dogs had moderate cerebral injury, and 1 dog died. These results were similar to results from previous studies in our laboratory in which complete "stagnant" cerebral ischemia of a comparable duration was produced in dogs using aortic and caval cross-clamping. Restoration of cerebral perfusion pressure following compression ischemia was accompanied by an initial phase of cerebral hyperemia followed by a delayed period of hypoperfusion similar to that observed following stagnant ischemia. The CBV studies in 2 dogs revealed that compression ischemia decreased CBV to 12% and 14% of pre-ischemic control values, respectively. The authors conclude, contrary to previous reports, that compression ischemia, although producing near bloodless ischemia, does not improve the brain's tolerance to ischemia.

Effects of nimodipine on the production of thromboxane A2 following total global cerebral ischemia.

To clarify the contribution of vasoconstrictor prostaglandins to the hypoperfusion state typically following total global cerebral ischemia, 14 mongrel dogs were subjected to 11 minutes of global cerebral ischemia. They were then randomly assigned to receive either no treatment or an intravenous bolus of the calcium channel blocker nimodipine, 10 micrograms/kg, 15 minutes after ischemia followed by a continuous infusion of nimodipine, 1.0 micrograms/kg/min. Thromboxane (Tx) A2 production, as measured by cerebral venous levels of TxB2 (the stable metabolite of TxA2) increased similarly in the two groups. In contrast to previous studies, mean postischemic cerebral blood flow did not increase sufficiently in the nimodipine-treated group to achieve statistical significance. These data suggest that the improved neurological outcome associated with nimodipine treatment following global cerebral ischemia does not relate to reduced levels of the prostaglandin precursor arachidonate.

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)

The effect of nimodipine on post-ischemic cerebral glucose utilization and blood flow in the rat.

The authors hypothesized that pretreatment with the calcium entry blocker nimodipine would preserve cerebral glucose utilization and maintain favorable brain blood flow after cerebral ischemia. Three groups of pentobarbital anesthetized rats were studied: control (group 1), ischemia (group 2), and ischemia plus nimodipine pretreatment, 1 mg X kg-1 ip, 1 h prior to ischemia (group 3). Forebrain ischemia was induced with bilateral carotid clamping, administration of trimethaphan, and blood withdrawal to obtain a mean arterial pressure of 50 mmHg. The carotid clamps were released and blood re-infusion was begun 9 min after the onset of an isoelectric EEG signal. Ten minutes later, determination of regional cerebral glucose utilization (rCGU) was begun by injecting 3H-2-deoxyglucose in saline. After 60 min of reperfusion, regional cerebral blood flow (rCBF) was determined by the indicator fractionation method, using 14C-iodoantipyrine. The brain was divided into hemisphere, diencephalon, cerebellum, and brainstem. Tissue radioactivities were determined by standard techniques. Compared to group 1, hemispheric rCGU (mean +/- SEM, mumoles X 100 g-1) was significantly (P less than 0.05) reduced in groups 2 and 3 (40 +/- 3 vs. 27 +/- 2 and 22 +/- 2). Hemispheric rCGU was not significantly different in groups 2 and 3. Group 2 exhibited significantly (P less than 0.05) reduced rCBF (mean +/- SEM, ml X 100 g-1 X min-1) in the hemispheres compared to control (85 +/- 6 vs. 135 +/- 17). However, nimodipine pretreatment prevented this post-ischemic hypoperfusion in group 3 (133 +/- 18).(ABSTRACT TRUNCATED AT 250 WORDS)

Beagle pup model of perinatal asphyxia: nimodipine studies.

Calcium antagonists may be of significant benefit in the pharmacotherapy of cerebral ischemia, possibly by improving postischemic cerebral blood flow (CBF). This study evaluated the effects of the calcium antagonist nimodipine on CBF in a newborn beagle pup model of perinatal asphyxia lasting 5 minutes. Immediately after the asphyxial episode, nimodipine (2 micrograms/kg/min) or saline was infused for 10 minutes, following which [14C]iodoantipyrine determinations of CBF were performed. In noninsulted pups, nimodipine caused both significant decreases in CBF to cortical and deep gray structures as well as a decrease in mean arterial blood pressure (MABP) (p less than 0.05). In insulted pups, nimodipine similarly decreased MABP (p less than 0.001) and CBF to cortical and deep gray matter regions. Nimodipine appeared to have no effect on arterial blood gases and EEG tracings in either insulted or noninsulted pups. Although nimodipine may be shown to improve neurologic outcome in asphyxiated newborn infants, the limits of this study do not show the mechanism to be that of improving CBF.

Effect of lidoflazine on cerebral blood flow and neurologic outcome when administered after complete cerebral ischemia in dogs.

This study tested the hypothesis that lidoflazine, a calcium entry blocking drug, will improve post-ischemic neurologic outcome when administered after a period of complete cerebral ischemia, and that the improvement in outcome is related to an increase in post-ischemic cerebral blood flow (CBF). Complete cerebral ischemia was produced in 31 dogs by temporary ligation of the aorta and venae cavae. In six dogs, 10 min of complete cerebral ischemia was followed by an infusion of lidoflazine 1.0 mg X kg-1 iv over 10 min. CBF and cerebral metabolic rate for oxygen (CMRO2) were measured pre-ischemia, and for 90 min post-ischemia. The results from these six dogs were compared with results previously obtained from eight untreated dogs under similar, but not identical, conditions. The CBF measured post-ischemia in the dogs administered lidoflazine did not differ from the CBF measured post-ischemia in the untreated dogs. Both groups showed an initial hyperemia post-ischemia, followed by significant decreases in CBF from control values by 35 min post-ischemia. The post-ischemic CMRO2 also did not differ between lidoflazine treated and untreated groups. In 25 dogs, 11 min of complete cerebral ischemia was followed by an iv infusion of either lidoflazine 1.0 mg X kg-1 or saline placebo. The same iv infusions were repeated at 8 and 16 h post-ischemia. Seven dogs were excluded from data analysis for failure to meet pre-established protocol criteria. Neurologic injury was evaluated in the remaining dogs at 48 h post-ischemia by an observer blinded to the treatment groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Canine cerebral function and blood flow after complete cerebral ischemia: effect of head position.

It has been reported that animals exposed to relatively "bloodless" cerebral ischemia have improved cerebral function post-ischemia. This suggests the possibility that large variations in cerebral blood volume during complete ischemia might affect outcome following reperfusion. The purpose of this study was to determine whether changes in dog head position (and therefore cerebral blood volume) during complete cerebral ischemia produced by occluding the aorta and venae cavae affect post-ischemic cerebral blood flow (CBF), cerebral metabolic oxygen requirements (CMRO2), or neurologic outcome. Two dogs were transfused with 111In-labeled red blood cells. Gamma camera images taken during complete cerebral ischemia showed 45-degree head-up dogs to have 30% of the cranial blood volume of a 10-degree head-down dog. CBF and CMRO2 90 min post-ischemia were not significantly different between the head-up and head-down groups in the 14 dogs studied. There was also no significant difference in neurologic outcome at 48 h post-ischemia between head-up and head-down dogs. The authors conclude that head position during complete cerebral ischemia has a major effect on cranial blood volume, but no effect on post-ischemic CBF, CMRO2, or neurologic outcome.

Sodium 5-(3'-pyridinylmethyl)benzofuran-2-carboxylate (U-63557A) potentiates protective effect of intravenous eicosapentaenoic acid on impaired CBF in ischemic gerbils.

Eicosapentaenoic acid (EPA) has been reported to improve postischemic cerebral blood flow (CBF). The present study was designed to determine whether sodium 5-(3'-pyridinylmethyl)benzofuran-2-carboxylate (U-63557A), a selective thromboxane synthetase inhibitor, could potentiate the effects of EPA on CBF in ischemic gerbils. Ischemia was produced by bilateral carotid artery occlusion for 15 minutes followed by reperfusion for 2 hours. Immediately after ischemia, gerbils were given either an intravenous bolus of 0.167 mg of EPA followed by a continuous infusion of EPA at 1 mg/hr, or U-63557A (10 mg/kg intraperitoneally), or U-63557A and EPA, or a saline infusion. Regional CBF was measured by the hydrogen clearance method, and brain water by the specific gravity technique. Brain prostaglandins were measured by radioimmunoassay. Preischemic CBF's ranged from 27.4 to 29.5 ml/100 gm/min for the four animal groups. After ischemia and 2 hours of reperfusion, CBF in the saline-infused gerbils was significantly decreased to 19.2 ml/100 gm/min. Gerbils treated with either EPA or U-63557A alone had a CBF of 23.7 and 21.6 ml/100 gm/min, respectively. Postischemic CBF in animals treated with both U-63557A and EPA was 30.0 ml/100 gm/min, significantly higher than in saline-infused gerbils. Brain levels of 6-keto prostaglandin (PG)F1 alpha (the metabolite of PGI2) were significantly higher in gerbils treated with U-63557A and EPA compared to gerbils given EPA alone. This study indicates that U-63557A potentiates the effects of EPA on postischemic CBF. This is probably due to the ability of U-63557A to increase prostacyclin formation in the vessel wall.

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.

Nimodipine improves cerebral blood flow and neurologic recovery after complete cerebral ischemia in the dog.

Ten minutes of complete ischemia was produced in 11 dogs by temporary ligation of the aorta. Immediately before the ischemic episode, the dogs received nimodipine, a new calcium entry blocker, 10 micrograms kg-1, i.v., followed by an infusion of 1 microgram kg-1 min-1 for 2 h. Post-ischemic cerebral blood flow and metabolism were measured for 120 min in six dogs. Neurologic recovery was evaluated 48 h post-ischemia in five dogs. The results were compared to previously determined controls. Nimodipine nearly doubled cerebral blood flow in the delayed post-ischemic hypoperfusion period, compared to untreated dogs (approximately 45% versus 25% of pre-ischemic control values), but had no significant effect on metabolism. Nimodipine also improved neurologic recovery. Four of five treated dogs were normal and one was moderately damaged, whereas six of seven controls were either severely damaged or dead. This suggests that the delayed hypoperfusion state occurring after complete cerebral ischemia probably does contribute to the ultimate neurologic damage, and that nimodipine offers a potential protective effect.

Regional cerebral blood flow and glucose metabolism following transient forebrain ischemia.

Progressive brain damage after transient cerebral ischemia may be related to changes in postischemic cerebral blood flow and metabolism. Regional cerebral blood flow (rCBF) and cerebral glucose utilization (rCGU) were measured in adult rats prior to, during (only rCBF), and serially after transient forebrain ischemia. Animals were subjected to 30 minutes of forebrain ischemia by occluding both common carotid arteries 24 hours after cauterizing the vertebral arteries. Regional CBF was measured by the indicator-fractionation technique using 4-iodo-[14C]-antipyrine. Regional CGU was measured by the 2-[14C]deoxyglucose method. The results were correlated with the distribution and progression of ischemic neuronal damage in animals subjected to an identical ischemic insult. Cerebral blood flow to forebrain after 30 minutes of moderate to severe ischemia (less than 10% control CBF) was characterized by 5 to 15 minutes of hyperemia; rCBF then fell below normal and remained low for as long as 24 hours. Post-ischemic glucose utilization in the forebrain, except in the hippocampus, was depressed below control values at 1 hour and either remained low (neocortex, striatum) or gradually rose to normal (white matter) by 48 hours. In the hippocampus, glucose utilization equaled the control value at 1 hour and fell below control between 24 and 48 hours. The appearance of moderate to severe morphological damage in striatum and hippocampus coincided with a late rise of rCBF above normal and with a fall of rCGU; the late depression of rCGU was usually preceded by a period during which metabolism was increased relative to adjacent tissue. Further refinement of these studies may help identify salvageable brain after ischemia and define ways to manipulate CBF and metabolism in the treatment of stroke.

Postischemic cerebral blood flow and oxygen utilization rate in rats anesthetized with nitrous oxide or phenobarbital.

The present experiments were undertaken to measure postischemic regional cerebral blood flow (rCBF) and oxygen utilization rate (CMRo2) in rats anesthetized with either 70% N2O or phenobarbital (150 mg x kg-1). In previous studies we have found that extensive restitution of cerbral energy metabolites occurs after 30 min of complete cerebral ischemia irrespective of the type of anesthesia used. Following 30 min of pronounced, incomplete ischemia, however, a comparable restitution of cerebral energy state was obtained in deeply anesthetized (phenobarbital 150 mg x kg-1) but not in superfically anesthetized (70% N2O) rats. The objectives of the present investigation were (1) to study whether postischemic cerebral blood flow was higher in barbiturate-anesthetized animals during the initial recirculation period, and (2) to investigate if the protective effects of phenobarbital previously observed could be attributed to a decrease in CMRo2. In both groups of animals a considerable variability in postischemic rCBF was observed between different animals. However, no signs of gross inhomogeneity in blood flow were found and no consistent differences in flow values between the two groups of animals were observed. Since the measured postischemic CMRo2 were identical in both groups of animals and since cerebral venous oxygen contents were above normal the results leave little support to the assumption that, in the present model of transient, incomplete cerebral ischemia, failure of recovery of cerebral metabolism (N2O group) is primarily due to impaired recirculation, nor do they indicate that the protective effects of barbiturates is due to their ability to reduce rate of cerebral energy utilization.

Cerebral blood flow. A predictor of recovery from ischemia in the gerbil.

Cerebral ischemia was induced in gerbils by bilateral carotid ligation for periods of 10 to 40 minutes. Cerebral blood flow (CBF) was measured by hydrogen clearance. Following ischemia, ultimate clinical and electroencephalogram recovery could be predicted in every case within the first five minutes by recovery could be predicted in every case within the first five minutes by recovery of CBF to at least 100% of the control level. In animals without EEC recovery, the postischemic CBF was always less than 80% of control and progressively declined to zero. Residual flow during ischemia appeared to minimize the likelihood of brain death. The determination of ultimate brain death appeared to coincide with a major circulatory abnormality that is probably microvascular.