Biomedical subjects

J M Hallenbeck

Publications and source records attributed to J M Hallenbeck.

At least 19 recordsLinked to original sources

PubMed1992

Comparison of stimulated tissue factor expression by brain microvascular endothelial cells from normotensive (WKY) and hypertensive (SHR) rats.

The amounts of tissue factor (TF) expressed by brain microvascular endothelial cells (BMECs) from normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were compared after stimulating the cells with different doses of lipopolysaccharide (LPS), thrombin, phorbol myristic acid (PMA), Ca(2+)-ionophore (A23187), or tumor necrosis factor (TNF) and interleukin-1 (IL-1). Treatment of cultured BMECs from WKY and SHR with all of these factors dose-dependently increased their total amount of TF; no substantive differences in the levels of enhanced TF expression were observed between WKY and SHR BMECs. We conclude that stimulated endothelium from rats with hypertension, a major stroke risk factor, is not hyperresponsive with respect to TF expression when compared to normotensive controls.

Animals↗

PubMed1992

Laser-Doppler flowmetry in monitoring regulation of rapid microcirculatory changes in spinal cord.

We established a rabbit model for continuous on-line monitoring of spinal cord microcirculation using laser-Doppler flowmetry (LDF). We tested the suitability of this model for studying rapid, nonequilibrium microcirculatory blood flow (BF) states induced by pharmacological treatments, hemorrhage, and asphyxia. Effective BF regulation was observed at systemic arterial pressure levels of 50 mmHg. Autoregulatory vasodilation began 1 min after the onset of severe hypotension, whereas more immediate vasodilation took place after asphyxia (hypercarbia). Pathological situations were studied in a simple model of spinal cord (SC) ischemia-reperfusion after 10 (n = 7) and 25 min (n = 7) of ischemia and 2 h of reperfusion. After 25 min of ischemia, delayed hypoperfusion (BF -35 +/- 7%, P less than 0.01) took place in association with tissue edema. LDF offered sensitive, stable, and reproducible estimates of microcirculation with high temporal resolution, thus permitting on-line evaluation of rapid, nonequilibrium BF responses and delayed states of spinal cord BF dysregulation.

Animals↗

PubMed1992

Effect of lidocaine on somatosensory evoked response and cerebral blood flow after canine cerebral air embolism.

BACKGROUND AND PURPOSE: Victims of air embolism often recover rapidly on hyperbaric treatment then deteriorate again, even if hyperbaric treatment is continued. In previous animal experiments, lidocaine has been shown to improve recovery of somatosensory evoked response amplitude after air embolism. However, animals in these experiments rarely deteriorated. We have shown that the induction of air embolism and transient hypertension in canines produces deterioration despite hyperbaric treatment, and we decided to test the effect of lidocaine on somatosensory evoked potential recovery and cerebral blood flow in this model. METHODS: Dogs were treated with repeated doses of lidocaine or equivalent volumes of saline during hyperbaric therapy after internal carotid air embolism and transient hypertension. The investigators were unaware of treatment group assignment during the experiments. The amplitude of the median nerve somatosensory evoked potential and cerebral blood flow measured with carbon-14-labeled iodoantipyrine autoradiography were used to assess effect of therapy. RESULTS: Lidocaine-treated dogs recovered 60 +/- 10% (mean +/- 95% confidence limits) of the baseline somatosensory evoked potential amplitude 220 minutes after air embolism; saline-treated dogs recovered 32 +/- 10% (a significant difference at p less than 0.01). Lidocaine-treated dogs also had higher cerebral blood flow values than saline-treated dogs 220 minutes after air embolism. CONCLUSIONS: Lidocaine ameliorated the delayed deterioration of evoked potential associated with air embolism and hypertension in this canine model. The improved cerebral blood flow may be a mechanism of action of lidocaine or an associated effect of improved neuronal survival.

Animals↗

PubMed1992

Release of proinflammatory and prothrombotic mediators in the brain and peripheral circulation in spontaneously hypertensive and normotensive Wistar-Kyoto rats.

BACKGROUND AND PURPOSE: We reported previously that stroke risk factors prepared the brain stem for the development of ischemia and hemorrhage and induced the production of tumor necrosis factor following an intrathecal injection of lipopolysaccharide, a prototypic monocyte-activating stimulus. This study evaluates whether blood or brain cells of hypertensive rats produce more proinflammatory and prothrombotic mediators than do blood or brain cells of normotensive rats. METHODS: Levels of tumor necrosis factor, platelet-activating factor, 6-ketoprostaglandin F1 alpha, and thromboxane B2 in the cerebrospinal fluid and blood of spontaneously hypertensive and normotensive Wistar-Kyoto rats were monitored before and after a challenge with lipopolysaccharide. RESULTS: Little or no activity from these mediators was found in the cerebrospinal fluid or blood of saline-injected control animals. Intravenous administration of lipopolysaccharide (0.001, 0.1, and 1.8 mg/kg) produced dose-dependent increases in blood levels of all mediators in hypertensive rats. In normotensive rats the levels were less than in hypertensive rats and were not clearly dose-related. When lipopolysaccharide was injected intracerebroventricularly, more tumor necrosis factor was measured in the cerebrospinal fluid than in the blood, suggesting local synthesis of this cytokine. Levels of tumor necrosis factor and platelet-activating factor in the cerebrospinal fluid were higher in hypertensive than in normotensive rats. The thromboxane A2/prostacyclin ratio was not altered significantly between the two rat strains. CONCLUSIONS: It is suggested that the higher incidence of brain stem ischemia and hemorrhage after the intrathecal injection of lipopolysaccharide in hypertensive rats than in normotensive rats might be related to the higher levels of the two cytotoxic factors tumor necrosis factor and platelet-activating factor produced in response to such challenge.

Animals↗

PubMed1992

Blood flow and vascular permeability during motor dysfunction in a rabbit model of spinal cord ischemia.

BACKGROUND AND PURPOSE: Delayed deterioration of neurological function after central nervous system ischemia is a well-documented clinical problem. The purpose of our study was to elucidate the role of spinal cord blood flow and spinal cord-blood barrier integrity in the evolution of delayed neurological deterioration after transient spinal cord ischemia in rabbits. METHODS: Anesthetized rabbits were subjected to lumbar spinal cord ischemia (25 minutes) and variable periods of reperfusion (30 minutes to 48 hours after ischemia). Regional spinal cord blood flow was monitored by carbon-14-labeled iodoantipyrine autoradiography; vascular permeability was assessed by quantitative microhistofluorescence of Evans blue-albumin in frozen sections of spinal cord. Hindlimb motor function was assessed by standard scoring system and tissue edema by wet/dry weight method. RESULTS: Hindlimb motor function indicated complete paralysis during ischemia and partial gradual recovery upon reperfusion (up to 8 hours), followed by progressive deterioration to severe deficits over 48 hours. Severe vascular permeability disruption was noticed early (30 minutes) after reperfusion, but almost complete recovery reestablished at 8 hours was followed by a secondary progressive increase in vascular permeability. Blood flow was reduced by 20-30% (p less than 0.01) 4 hours after ischemia in the gray matter, but hyperemia (200-300%, p less than 0.01) was observed 12-24 hours after ischemia. Spinal cord water content increased by 5.7% (p less than 0.05) 24 hours after ischemia. CONCLUSIONS: This study demonstrates that delayed neurological and motor deterioration after spinal cord ischemia is associated with severe progressive breakdown of spinal cord-blood barrier integrity that develops late (hours) after the injury. Our data suggest that no ischemic insult in early or late reperfusion is associated with delayed motor deterioration.

Animals↗

PubMed1992

The onset of postischemic hypoperfusion in rats is precipitous and may be controlled by local neurons.

BACKGROUND AND PURPOSE: Reperfusion following transient global cerebral ischemia is characterized by an initial hyperemic phase, which precedes hypoperfusion. The pathogenesis of these flow derangements remains obscure. Our study investigates the dynamics of postischemic cerebral blood flow changes, with particular attention to the role of local neurons. METHODS: We assessed local cortical blood flow continuously by laser Doppler flowmetry to permit observation of any rapid flow changes after forebrain ischemia induced by four-vessel occlusion for 20 minutes in rats. To investigate the role of local cortical neurons in the regulation of any blood flow fluctuations, five rats received intracortical microinjections of a neurotoxin (10 micrograms ibotenic acid in 1 microliter; 1.5-mm-depth parietal cortex) 24 hours before ischemia to induce selective and localized neuronal depletion in an area corresponding to the sample volume of the laser Doppler probe (1 mm3). Local cerebral blood flow was measured within the injection site and at an adjacent control site. RESULTS: Ischemia was followed by marked hyperemia (235 +/- 23% of control, n = 7), followed by secondary hypoperfusion (45 +/- 3% of control, n = 7). The transition from hyperemia to hypoperfusion occurred not gradually but precipitously (maximal slope of flow decay: 66 +/- 6%/min; n = 7). In ibotenic acid-injected rats, hyperemia was preserved at the injection site, but the sudden decline of blood flow was abolished (maximal slope of flow decay: 5 +/- 3%/min compared with 53 +/- 8%/min at the control site; n = 5, p less than 0.001) and no significant hypoperfusion developed (103 +/- 20% of control at 60 minutes). CONCLUSIONS: These data suggest that the rapid transition to cortical hypoperfusion after forebrain ischemia may be triggered locally by a neuronal mechanism but that this mechanism does not underlie the initial hyperemia.

Animals↗

PubMed1992

Polymorphonuclear leukocytes and monocytes/macrophages in the pathogenesis of cerebral ischemia and stroke.

BACKGROUND: The extent to which polymorphonuclear leukocytes and monocytes/macrophages contribute to the pathobiology of cerebral ischemia and stroke is an issue of long-standing contradiction and controversy. Recent developments in the ability to selectively modify leukocyte adhesion with antiadhesion antibodies and the potential clinical application of this therapeutic approach have spurred a resurgence of experimental studies examining the role of leukocytes in cerebral ischemia and stroke. SUMMARY OF REVIEW: We review studies examining leukocyte accumulation, initiation of thrombosis, and exacerbation of ischemic brain injury in stroke, and we examine other proposed contributions of leukocytes to cerebrovascular pathophysiology. CONCLUSIONS: The importance of specific characteristics of a given ischemia model and of underlying stroke risk factors in determining the degree of leukocyte involvement and effectiveness of therapies directed against these cells is discussed.

Brain Ischemia↗

PubMed1992

Effects of treatment with dexamethasone on recovery from experimental cerebral arterial gas embolism.

Dexamethasone is often recommended as an adjunct to recompression in the treatment of serious central nervous system decompression accidents. We studied the effects of prophylactic and therapeutic administration of dexamethasone combined with hyperbaric treatment in anesthetized dogs that were subjected to carotid air embolism and a brief episode of arterial hypertension. To assess recovery we measured somatosensory evoked potential (SSEP) amplitude, intracranial pressure, brain water, and cerebral blood flow. Three groups were studied: pre-air treatment (dexamethasone 1 mg/kg 3-4 h before carotid air embolism, and 1 mg/kg immediately after air embolism); post-air treatment (2 mg/kg immediately after air embolism); and control (equivalent volumes of saline pre- and post-air). There was a slight improvement in SSEP early in the course of hyperbaric therapy in the pre-air treated group; the post-air group never differed from control. No differences in intracranial pressure or brain water were found among groups. No blood flows below those lethal to neurons occurred in treated animals but 4 of 7 control animals had low flows. Although prophylactic treatment with dexamethasone produces some improvement in recovery, we cannot confirm that dexamethasone is an effective adjunct to recompression when administered therapeutically.

Animals↗

PubMed1991

Lipopolysaccharide-induced production of tumor necrosis factor activity in rats with and without risk factors for stroke.

Rats produced more TNF activity in cerebrospinal fluid (CSF) than in blood after intracerebroventricular (i.c.v.) injection of lipopolysaccharide (LPS). After intravenous (i.v.) LPS, blood TNF levels exceeded CSF levels. Thus, brain cells appear to produce TNF in response to LPS. Rats with the stroke-risk factors hypertension or combined hypertension and genetic stroke-proneness produce more TNF in response to a provocative dose of LPS i.v. than control animals free of these risk factors. The possible relevance to stroke vulnerability is discussed.

Animals↗

PubMed1991

Platelet-activating factor in stroke and brain injury.

Platelet-activating factor, an endogenous phospholipid of proinflammatory, hemostatic, and vasoactive properties, is synthesized by neurons and in injured brain. Platelet-activating factor is released together with eicosanoids such as thromboxane A2, prostacyclin, and leukotrienes. Its effects in neurons are mediated through a specific receptor coupled to phospholipase C and phosphoinositol metabolism. The cerebrovascular effects of platelet-activating factor include disruption of the blood-brain barrier, edema formation, and vasospasm. It has also been described to possess direct toxicity to neuronal cells in culture. Discovery and development of several highly potent and selective antagonists to platelet-activating factor receptors facilitated experimental studies underscoring the role of this factor as an endogenous mediator in cerebral disorders, particularly cerebral ischemia and trauma. Significant biochemical, microvascular, functional, and behavioral recovery has been demonstrated using these antagonists in an array of experimental models of focal and global ischemia in the central nervous system (CNS). Clearly, studies of platelet-activating factor in experimental models of CNS ischemia and reperfusion injury open a new perspective on phospholipid metabolism in stroke and offer an exceptionally promising therapeutic prospect. Data supporting this factor as a mediator of specific pathological sequelae in stroke and neuroinjury are surveyed in this review. We discuss the mechanisms and significance of platelet-activating factor-mediated effects and propose directions for future studies.

Animals↗

PubMed1991

Extracellular matrix permits the expression of von Willebrand's factor, uptake of di-I-acetylated low density lipoprotein and secretion of prostacyclin in cultures of endothelial cells from rat brain microvessels.

Microvascular endothelial cells from the adult rat brain were cultured on Matrigel and found to express many differentiated properties including secretion of prostacyclin (PGI2) and von Willebrand's factor (vWF). Brain microvascular endothelial cells (BMECs) were purified by dextran and percoll gradients after enzymatic treatment and cultured under various conditions. BMECs that were plated on Matrigel stained positively for factor VIII-related antigen and incorporated Di-I-acetylated low density lipoprotein, whereas BMEC plated on fibronectin, gelatin, or uncoated dishes did not express any of the above properties which are characteristic of endothelial cells. vWF was measured by a sensitive ELISA in the culture media of BMECs plated on different types of matrices. Specificity of the anti-human vWF antibodies for the rat vWF was verified by immunoabsorption on a solid phase, sodium dodecyl sulfate, and Western blot analysis. BMECs also secreted vWF into the culture media only when the cells were plated on Matrigel, and this secretion was augmented after a 6 h incubation with an interleukin-1 tumor necrosis factor-alpha mixture, but not by lipopolysaccharide. From different matrices tested, only Matrigel permitted the secretion of PGI2 by BMECs. Cells also proved to be sensitive to mechanical stimulation and became refractory to secretagogue if the mechanical stimulation was serially repeated. Under the best conditions, stimulation of the cells with bradykinin (1 microM) substantially increased PGI2 secretion. These data indicate that growth of BMECs on Matrigel in vitro permits the expression of classical endothelial cell markers in a manner similar to the behavior of these cells in situ.

Acetylation↗

PubMed1991

Cortical microcirculation in a new model of focal laser-induced secondary brain damage.

To study the causes of spatial and temporal evolution of progressive neuro-injury in focal brain ischemia, models with consistent lesion topography are required. In such models, continuous monitoring of the microcirculation in a penumbral area undergoing progressive damage could be possible. We used a fixed-pulse (1.0 s, 40 W) Nd-YAG laser (NYL) to produced discrete brain lesions in rats and monitored the cerebral blood flow (CBF) with laser-Doppler flowmetry (LDF) in nonirradiated areas directly adjacent to the maturing lesion. We also examined the time evolution of the lesion topography over a 4 day period. The lesion volume determined by histopathological methods increased from 3.1 +/- 0.5 to 4.5 +/- 0.5 mm3 (p less than 0.05) during the first 2 h. Simultaneously, LDF indicated severe hypoperfusion (-60 +/- 21%, p less than 0.01) at a zone (1 mm distance from the laser lesion) where progressive neuronal degeneration and increased tissue water content (80.0 +/- 3.3% versus 76.8 +/- 2.1% in normal tissue, n = 7, p less than 0.05) were also observed. At a 4 mm distance from the lesion, hyperemic CBF responses were observed, but no histopathological signs or edema. Secondary brain damage progressed up to 4 days (lesion volume of 6.0 +/- 0.7 mm3). The NYL-induced brain lesion produced a highly reproducible focal injury and progressive neuronal death in a spatial relationship with microcirculatory failure and edema formation. The model allows prospective study of tissue state at a discrete zone, which is separate from the initial injury, but susceptible to secondary brain damage.

Animals↗

PubMed1991

Priming by platelet-activating factor of endotoxin-induced lung injury and cardiovascular shock.

Platelet-activating factor (PAF) is a glycerophospholipid known for its unusual potent vasoactive and proinflammatory activities. The present study examined whether PAF might serve as a priming factor in endotoxin-induced tumor necrosis factor-alpha (TNF alpha) synthesis, cardiovascular shock, and lung injury in anesthetized rats. Intravenous infusion of PAF (1 pmol/kg/min for 60 minutes, n = 5) alone or endotoxin (0.1 micrograms/kg i.v. bolus, n = 5) failed to alter blood pressure, serum TNF alpha and thromboxane B2, platelet and leukocyte count, and hematocrit, nor was lung histology, myeloperoxidase activity, and water content changed. In contrast, the combined administration of PAF and endotoxin markedly elevated serum TNF alpha (1,359 +/- 362 pg/ml, n = 5, p less than 0.01) and thromboxane B2 (43 +/- 5 pg/100 microliters, n = 8, p less than 0.01) along with hypotension, hemoconcentration, leukopenia, and thrombocytopenia. Most notably, the combined regimen caused neutrophil aggregation, adhesion, and accumulation into the lung parenchyma along with platelet-fibrin deposits in postcapillary venules, pulmonary edema, and increased lung myeloperoxidase activity. The role of PAF in this process was confirmed by 1) the prevention of the priming effect by pretreatment with the PAF antagonist BN 50739 (n = 5), and 2) the failure of lyso-PAF, the cardinal nonactive PAF-metabolite, to prime for endotoxin-induced production of TNF alpha (n = 4). These data suggest that PAF could serve as a key mediator in priming for endotoxin-induced tissue injury, especially the typical pulmonary pathophysiology of adult respiratory distress syndrome, a severe pathological outcome of septic shock, burns, and multiple organ injury.

Animals↗

PubMed1991

Allopurinol pretreatment improves evoked response recovery following global cerebral ischemia in dogs.

The reperfusion of previously ischemic tissue may lead to the formation of highly reactive free radicals that promote tissue injury. Xanthine oxidase has been implicated as one source of these free radicals. We examined the role of xanthine oxidase in brain injury using a cerebrospinal fluid compression model of global cerebral ischemia with 15 minutes of ischemia and 4 hours of reperfusion. Seven dogs were pretreated with the xanthine oxidase inhibitor allopurinol (50 mg/kg for 5 days). Neurophysiological recovery was monitored with cortical somatosensory evoked potentials. As an attempt to correlate brain recovery with the mechanism of protection, free brain malondialdehyde was measured at the end of reperfusion by high-performance liquid chromatography. Brain water content was measured by wet-dry weights. Compared with seven untreated control dogs, allopurinol pretreatment significantly improved recovery of somatosensory evoked potentials after 4 hours of reperfusion. However, the amount of free malondialdehyde in the allopurinol-treated dogs was 32% greater than that in the controls. Brain water content was similar in the two groups. These results suggest that xanthine oxidase contributes to brain injury after ischemia and reperfusion. However, tissue damage caused by xanthine oxidase may be mediated through mechanisms other than free radical production.

Allopurinol↗

PubMed1991

Cerebral air embolism treated by pressure and hyperbaric oxygen.

We used pressure and hyperbaric oxygen to treat 2 patients with cerebral air embolism, occurring as the result of invasive medical procedures, and neither suffered any permanent damage detectable by clinical examination and MRI. This outcome contrasts with reports of infarct and disability among untreated victims of air embolism.

Adult↗

PubMed1990

Background review and current concepts of reperfusion injury.

We define the concept of reperfusion injury, and we present a background chronology of experimental work supporting and questioning this concept. We identify several new influences, such as current clinical interest in thrombolytic therapy for acute ischemia of heart and brain and the growing recognition of endothelium as a regulator of homeostasis. We propose that these influences will encourage a reexamination of reperfusion injury as a factor in the ultimate outcome of tissue exposed to reversible ischemia. We briefly discuss the major mechanisms presently implicated in reperfusion injury--loss of calcium homeostasis, free radical generation, leukocyte-mediated injury, and acute hypercholesterolemia.

Calcium↗

PubMed1990

No conversion of xanthine dehydrogenase to oxidase in canine cerebral ischemia.

Xanthine oxidase (XO) has been implicated as a source of free radicals mediating ischemia-reperfusion injury. Conversion of the non-free radical generating xanthine dehydrogenase (XD) to the free radical producing XO during ischemia has been demonstrated in several tissues. We examined the irreversible conversion of XD to XO in the dog brain after ischemia and after ischemia and reperfusion. Under pentobarbital sodium anesthesia and by use of a cerebrospinal fluid compression model of global cerebral ischemia, dogs were subjected to 30 min of ischemia (n = 8) or 30 min of ischemia and 60 min of reperfusion (n = 8). A cerebral perfusion pressure of 60 mmHg was maintained during reperfusion. Eight control dogs were not subjected to ischemia. After the dogs were killed their brains were rapidly removed and frozen in liquid nitrogen. XO and XD + XO activities were measured with a radioassay utilizing 8-[14C]hypoxanthine and separating substrate and products by thin-layer chromatography. Total XD + XO activity was significantly (P less than 0.05) decreased after ischemia and reperfusion (35.6 +/- 8.0 vs. 60.8 +/- 20.8 nmol.min-1.g protein-1 in controls, means +/- SD) but not after ischemia alone (48.2 +/- 20.4). XO/(XD + XO) was approximately 20% in all three groups. Irreversible XD to XO conversion is not an important mechanism leading to early tissue injury in global cerebral ischemia.

Animals↗

PubMed1990

Evidence for platelet-activating factor as a novel mediator in experimental stroke in rabbits.

Platelet-activating factor is a potent mediator of inflammation, which has untoward effects on cerebrovascular and neural elements. While several investigators have reported attenuation of ischemic damage after treatment with antagonists of platelet-activating factor, no study has proved endogenous production of platelet-activating factor in ischemia of the central nervous system. We hypothesized that endogenous production of platelet-activating factor participates in the early pathologic manifestations of deteriorating stroke. In 12 rabbits, we found tissue levels of platelet-activating factor measured by the release of serotonin from washed platelets to be elevated by approximately 20-fold in spinal cord injured by 25 minutes of ischemia and 2 hours of reperfusion (2.80 +/- 0.98 ng/g) compared with that in normal spinal cord (0.15 +/- 0.06 ng/g, p less than 0.01). Given during ischemia to seven rabbits, 10 mg/kg i.p. of a highly selective and potent antagonist of platelet-activating factor (BN 50739) accentuated the early postischemic hyperemia and prevented the delayed hypoperfusion measured by on-line laser-Doppler flowmetry (-35 +/- 7% of baseline [n = 7] without versus 33 +/- 14% with treatment, p less than 0.01) and the edema formation measured as the increase in tissue water content (4.4 +/- 0.7% without [n = 6] versus 2.1 +/- 0.6% with [n = 7]treatment, p less than 0.05) after 2 hours of reperfusion. This neurochemical and pharmacologic evidence emphasizes a new perspective of ischemia-induced phospholipid degradation and suggests an important role for platelet-activating factor in the early manifestations of stroke.

Animals↗