Biomedical subjects

A L Betz

Publications and source records attributed to A L Betz.

At least 19 recordsLinked to original sources

PubMed1992

Attenuated development of ischemic brain edema in vasopressin-deficient rats.

Brain edema formation was investigated in the vasopressin-deficient Brattleboro rat using a middle cerebral artery occlusion model of early ischemic injury. Water and sodium accumulation after 4 h of ischemia were attenuated 36 and 20%, respectively, in the Brattleboro strain as compared to the control Long-Evans strain. This effect was independent of differences in animal size and state of hydration. In addition, measurements of cerebral blood flow indicated that Brattleboro and Long-Evans rats had equal levels of ischemia following middle cerebral artery occlusion. Systemic treatment of Brattleboro rats with vasopressin normalized their serum electrolyte concentrations and osmolarity but did not alter sodium or water accumulation in the ischemic brain. In contrast, intraventricular administration of vasopressin in Brattleboro rats increased edema formation to that seen in control rats. The reduced water and sodium accumulation in Brattleboro rats subjected to middle cerebral artery occlusion may be related to alterations in blood-brain barrier permeability since the blood-to-brain sodium flux was 36% less in the ischemic tissue of the Brattleboro as compared to the Long-Evans strain. These results support the hypothesis that central vasopressin is a regulator of brain volume and electrolyte homeostasis. Furthermore, our findings suggest a role for central vasopressin in the development of ischemic brain edema.

Aminoisobutyric Acids↗

PubMed1992

Middle cerebral artery occlusion in rats: a neurological and pathological evaluation of a reproducible model.

Middle cerebral artery occlusion (MCAO) in rats produces an infarct of varying size. We examined three factors that may influence this variability: animal weight, vascular anatomy, and extent of occlusion in rats undergoing MCAO. We also developed a four-point neurological evaluation scale and validated its usefulness by comparing it with a four-grade pathological determination of the size of the infarct. Of 82 animals subjected to a standard MCAO, 34 developed small cortical infarcts (pathological grades I-II; infarct size less than 25 mm2, 6-17% of the ipsilateral cortex surface area), and 48 large infarcts (pathological grades III-IV, infarct size greater than 25 mm2, 20-56% of surface area). We were able to predict the size of infarction from the neurological evaluation in 83% of the animals, and this accuracy reached 91% when grades I and II and III and IV were considered together (P less than 0.001). In 41 animals subjected to a more extensive vascular occlusion, 89% exhibited large infarcts. Four vascular patterns were identified but none played a significant role in the incidence or size of the cortical stroke. However, rats weighing less than 300 g showed a smaller lesion size than did rats greater than 300 g. Our proposed new MCAO technique appears useful in reproducing large-sized infarcts of the frontoparietal cortex.

Animals↗

PubMed1992

An overview of the multiple functions of the blood-brain barrier.

The BBB formed by brain capillary endothelial cells is now recognized as more than an impermeable wall. It has specific transport systems that facilitate the uptake of important nutrients and hormones and active pumps that help to regulate the concentrations of ions and metabolites in the brain's ISF. Enzymes present in the endothelial cell metabolize neurotransmitters, drugs, and toxins before they can enter the brain and disrupt its function. Many of these properties are likely to be under regulation either by neurotransmitters and hormones released in the brain or by those present in the systemic circulation. As a result of this constellation of diverse functions, the brain capillary endothelial cell is able to efficiently supply the brain with the metabolites that it requires while contributing to the maintenance of the brain's ionic homeostasis and protecting it from circulating toxins.

Animals↗

PubMed1991

Oleic acid reversibly opens the blood-brain barrier.

This study examined the effect of intracarotid oleic acid infusion on blood-brain barrier permeability. Oleic acid was infused for 30 s at a rate of 6 ml/min into the right internal carotid artery at concentrations of 10(-6), 10(-5), 2 x 10(-5) and 5 10(-5) M. Extensive Evans blue-albumin extravasation was observed 15 min after the administration of 2 x 10(-5) M oleic acid. The permeability surface area product for alpha-aminoisobutyric acid (AIB), determined 1-11 min following the infusion of oleic acid was increased 10-fold following infusion of 10(-5) M oleic acid and 20-fold following the administration of 5 x 10(-5) M oleate. The blood-brain barrier opening to AIB proved to be reversible 80-90 min after the infusion of 2 x 10(-5) M oleic acid. The possible mechanisms of the oleic acid effect are discussed.

Aminoisobutyric Acids↗

PubMed1991

Blood to brain sodium transport and interstitial fluid potassium concentration during early focal ischemia in the rat.

During partial ischemia, sodium and potassium ions exchange across the blood-brain barrier, resulting in a net increase in cations and brain edema. Since this exchange is likely mediated by specific transporters such as Na,K-ATPase in the capillary endothelium and because brain capillary Na,K-ATPase activity is stimulated by increased extracellular potassium in vitro, this study was designed to determine if the rate of blood to brain sodium transport is increased in ischemic tissue having an elevated interstitial fluid potassium concentration ([K]ISF) in vivo. Sprague-Dawley rats were studied between 2-3 h after occlusion of the right middle cerebral artery. To identify where cortical tissue with an elevated [K]ISF could be sampled for transport studies, the regional pattern of cerebral blood flow and [K]ISF was obtained in a group of 17 rats using hydrogen clearance and potassium-selective microelectrode techniques. We observed severely elevated [K]ISF (greater than 10 mM) when CBF was less than 20 ml 100 g-1 min-1 and mildly elevated levels at CBF between 20-45 ml 100 g-1 min-1. In a second group of seven rats, permeability-surface area products (PS products) for 22Na and [3H]alpha-aminoisobutyric acid ([3H]AIB) were determined in ischemic cortex with elevated [K]ISF and in nonischemic cortex. The PS products for AIB were similar in both tissues (2.2 +/- 0.7 and 2.1 +/- 0.4 microliters/g/min) while the PS products for sodium was significantly increased in the ischemic tissue (1.5 +/- 0.2 and 2.4 +/- 1.1 microliters/g/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoisobutyric Acids↗

PubMed1991

Effect of aspartame-derived phenylalanine on neutral amino acid uptake in human brain: a positron emission tomography study.

The possible effects of elevation of the plasma phenylalanine level secondary to the ingestion of aspartame on brain amino acid uptake in human subjects have been investigated by means of positron emission tomography (PET). 1-[11C]Aminocyclohexanecarboxylate [( 11C]ACHC) is a poorly metabolized synthetic amino acid that crosses the blood-brain barrier by the same carrier that transports naturally occurring large neutral amino acids. Quantitative test-retest PET studies were performed on 15 individuals. Seven received two identical baseline scans, whereas eight received a baseline scan followed by a scan performed approximately 40-45 min following ingestion of an orange-flavored beverage containing 34 mg/kg of body weight of the low-calorie sweetener aspartame, a dose equivalent to the amount in 5 L of diet soft drink consumed all at once by the study subjects, weighing an average of 76 kg. The 40-45-min interval was selected to maximize the detection of possible decreases in ACHC uptake resulting from increased competition for the carrier, because the plasma phenylalanine level is known to peak at this time. We observed an 11.5% decrease in the amino acid transport rate constant K1 and a smaller decrease in the tissue distribution volume of ACHC (6%). Under conditions of normal dietary use, aspartame is thus unlikely to cause changes in brain amino acid uptake that are measurable by PET.

Amino Acids↗

PubMed1991

Xanthine oxidase is not a major source of free radicals in focal cerebral ischemia.

Xanthine oxidase (XO) has been proposed as an important source of free radicals during ischemia. This enzyme normally exists as a dehydrogenase (XD), but it is converted to XO in some ischemic tissues. Recently, treatment of animals with the XD and XO inhibitor allopurinol or with free radical scavengers before cerebral ischemia has been shown to reduce brain injury. Therefore, we studied conversion of XD to XO in three ischemic and nonischemic brain regions during focal cerebral ischemia resulting from permanent occlusion of the middle cerebral artery (MCAO) in anesthetized rats. In nonischemic brain, 16-22% of the enzyme was in the XO form. After 24 h of ischemia this value was not significantly different (10-15%). Neither the total activity of XO nor that of XD changed, indicating that there was no irreversible conversion of XD to XO. To further explore the possible role of XO, we examined the effect of various doses of allopurinol (5, 20, or 100 mg/kg given 1 h before MCAO or 100 mg/kg given 48, 24, and 1 h before MCAO) on uric acid accumulation, brain edema formation, and cerebral blood flow (CBF) 24 h after MCAO. All but the lowest dose of allopurinol greatly reduced the appearance of uric acid in the ischemic brain; however, only the highest dose of allopurinol had any beneficial effect on brain edema. This reduction in brain edema occurred without a significant improvement in CBF. Thus XO is probably not an important source of free radicals in this model of focal cerebral ischemia.

Allopurinol↗

PubMed1991

Effect of indomethacin on edema following single and repetitive cerebral ischemia in the gerbil.

BACKGROUND AND PURPOSE: Repetitive periods of cerebral ischemia result in more severe injury than a single period of ischemia of similar total duration. We investigated the possibility of prostaglandin mediation of this increased injury by attempting to modify brain edema formation with indomethacin pretreatment. METHODS: Under halothane/N2O anesthesia, groups of gerbils underwent bilateral carotid occlusion to induce forebrain ischemia. Group I underwent a single 15-minute period of carotid occlusion. Group II underwent three 5-minute periods of occlusion at hourly intervals. Groups III and IV were similar to groups I and II, respectively, but received 0.2 mg/kg indomethacin before carotid occlusion. Cortical and cerebellar water and sodium contents were determined in control animals (n = 6) at time zero and in experimental animals 24, 48, and 72 hours after ischemia (n = 6-10 gerbils/group at each time point). RESULTS: Cortical water and sodium contents in group II peaked 48 hours after insult (82.15 +/- 0.31% and 420 +/- 14 meq/kg dry wt, respectively) and were significantly higher than control and group I values at both 24 and 48 hours. Cortical water did not change from control in group I animals. Indomethacin pretreatment significantly attenuated increases in water and sodium content seen at 48 hours in gerbils undergoing repetitive ischemia (peak 80.02 +/- 0.45% and 300 +/- 39 meq/kg dry wt), but did not affect mortality. CONCLUSIONS: Indomethacin lessens edema after repetitive cerebral ischemia, suggesting that elevations of cyclooxygenase products are responsible, at least in part, for severe brain edema following repetitive ischemia.

Animals↗

PubMed1991

Interaction between free radicals and excitatory amino acids in the formation of ischemic brain edema in rats.

Both oxygen free radicals and excitatory amino acids have been implicated as important cellular toxins in ischemic brain. Recent in vitro studies suggest that there may be a mutual interaction between these two mediators. We explored the relation between oxygen free radicals and excitatory amino acids in the development of ischemic brain edema in vivo. Male Sprague-Dawley rats were treated with the free radical scavenger dimethylthiourea 1 hour before ischemia or with the excitotoxin antagonist MK-801 30 minutes before ischemia produced by occlusion of the middle cerebral artery. Groups of seven or eight animals were treated with vehicle, low-dose (375 mg/kg) dimethylthiourea, high-dose (750 mg/kg) dimethylthiourea, low-dose (0.5 mg/kg) MK-801, high-dose (2.0 mg/kg) MK-801, or both high-dose dimethylthiourea and low-dose MK-801. After 4 hours of ischemia, brain water content was determined. In eight vehicle-treated controls, mean +/- SEM water content of tissue in the center of the ischemic zone was 83.29 +/- 0.18%. A significant reduction of brain edema was observed in all drug-treated groups: for example, 50.2% (p less than 0.001) in the high-dose dimethylthiourea group, 53.7% (p less than 0.001) in the low-dose MK-801 group, and 66.4% (p less than 0.001) in the combined dimethylthiourea and MK-801 group. Combined treatment with dimethylthiourea and MK-801 provided no significant additive effect over that resulting from treatment with MK-801 alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMed1990

Potassium activation of the Na,K-pump in isolated brain microvessels and synaptosomes.

Brain capillary endothelial cells play an important role in ion homeostasis of the brain through the transendothelial transport of Na and K. Since little is known about the regulation of ion transport in these cells, we determined the effect of extracellular potassium concentration ([K]o) on the kinetics of the Na,K-pump in isolated cerebral microvessels using both K uptake and Na efflux as measures of pump activity. In addition, we studied K activation of K uptake into synaptosomes under similar conditions to compare this neuronal system to the capillary. When microvessels were preloaded with 22Na by 30 min incubation in K-free buffer, efflux of 22Na into buffer with varying [K]o was dependent on [K]o and inhibited by 7 mM ouabain. This activation of Na efflux was half maximal at 4.2 mM [K]. Ouabain-sensitive K uptake was also half maximally stimulated by a similar [K] in both Na loaded and non-loaded microvessels. In contrast, K uptake into synaptosomes was half maximal at 0.47 mM K. These results demonstrate that both active Na efflux and K uptake into microvessels in vitro are dependent on [K]o in the physiological range. In contrast, synaptosomal K uptake is near maximal at 3 mM K. This suggests that increases in brain [K]o may stimulate ion transport across the cerebral capillary, but will have little effect on Na,K-pump activity in neurons.

Animals↗

PubMed1990

Myo-inositol transport into endothelial cells derived from nervous system microvessels.

Myo-inositol, the precursor in the biosynthesis of inositol phospholipids and inositol phosphates, is found in many tissues at concentrations well above its concentration in the plasma, but the highest concentrations are in the central nervous system and the neuroretina. We describe an active, sodium gradient-dependent transport of myo-inositol into cultured endothelial cells derived from bovine retinal microvessels. Transport is inhibited by cytochalasin B, and phloridzin greater than phloretin. Mannitol, sorbitol, and fructose do not inhibit uptake, but D-galactose. inhibits uptake greater than L-glucose greater than D-glucose. The apparent Km of this transport system is 311 +/- 47 (S.D.) microM and the apparent Vmax is 40.8 +/- 2.8 (S.D.) pmol.mg protein-1.min-1. This transport system may be a key in the maintenance of this tissue concentrations as it could concentrate myo-inositol from the plasma into the extracellular spaces of the eye and central nervous system.

Animals↗

PubMed1990

Extravasation of albumin in ischaemic brain oedema.

Changes in brain water, sodium, potassium, and albumin contents and blood-brain barrier (BBB) permeability were determined between 1 hr and 42 days following occlusion of the middle cerebral artery in rats. Brain oedema was maximal 24 hrs, remained high for 3 days, and was resolved by 4 weeks. These changes in water content were accompanied by a parallel increase in sodium and decrease in potassium, however, the increase in sodium always exceeded the decrease in potassium so that there was a net gain in brain cations. BBB permeability to 3H-alpha-aminoisobutyric acid was normal for the first 4 hrs, but increased by 24 hr and returned to normal at 3 weeks. The time course for changes in brain albumin content was the same as that for BBB permeability and, at its greatest (3 days), the brain albumin was approximately 20% of the plasma albumin concentration. The relative contributions of the osmotic force produced by the increase in brain cations and the oncotic force produced by the increase in brain albumin to the observed change in water content were calculated. At all time points, the increase in brain cations accounted for nearly all of the observed brain oedema, while the increase in albumin played essentially no role in oedema development.

Aminoisobutyric Acids↗

PubMed1990

Effect of steroid therapy on ischaemic brain oedema and blood to brain sodium transport.

Dexamethasone has been shown in some studies to reduce ischaemic brain oedema, however, the mechanism is unknown. One possible mechanism is through inhibition of active transport of sodium across the blood-brain barrier (BBB) since some steroids, especially progesterone, inhibit sodium transport in isolated brain capillaries. Therefore, we measured brain oedema and BBB permeability to sodium and a passive permeability tracer, alpha-aminoisobutyric acid (AIB), 4 hr after middle cerebral artery occlusion (MCAO) in rats that had been treated 1 hr before MCAO with vehicle (control) or 2 mg/kg of either dexamethasone or progesterone. In controls, the water content of tissue in the center of the ischaemic zone was 82.4 +/- 0.2%. Brain oedema was significantly reduced following pretreatment with either dexamethasone (80.6 +/- 0.1, p less than 0.001) or progesterone (81.5 +/- 0.3, p less than 0.05). Both steroids also reduced BBB permeability to AIB by about 40% in normal brain but to a lesser extent in ischaemic brain. In contrast, steroid treatment had no effect on BBB permeability to sodium in either normal or ischaemic brain. We conclude that pretreatment with dexamethasone and progesterone reduces brain oedema accumulation during the early stages of ischaemia, however, this effect does not result from a reduction in BBB permeability to sodium.

Aminoisobutyric Acids↗

PubMed1990

Use of [11C]aminocyclohexanecarboxylate for the measurement of amino acid uptake and distribution volume in human brain.

A quantitative positron emission tomographic (PET) method to measure amino acid blood-brain barrier (BBB) transport rate and tissue distribution volume (DV) has been developed using 11C-labeled aminocyclohexanecarboxylate (ACHC), a nonmetabolized amino acid analogue. Dynamic PET data were acquired as a series of 15 scans covering a total of 60 min and analyzed by means of a two-compartment, two-parameter model. Functional images were calculated for the amino acid transport rate constants across the BBB and the amino acid DV in the brain. Results show [11C]ACHC to have an influx rate constant in gray matter of approximately 0.03-0.04 ml g-1 min-1, indicating a single-pass extraction fraction of approximately 5-7%. The intersubject coefficient of variation was approximately 15% while intrasubject variability of repeat scans was only slightly greater than 5%. Studies were performed in 15 young normal volunteer control subjects, 5 elderly controls, 7 patients with probable Alzheimer's disease, and one patient with phenylketonuria. Results indicate that [11C]-ACHC will serve as the basis of a method for measuring amino acid transport rate and DV in the normal and pathological human brain.

Adult↗

PubMed1990

Decrease in perfusion of cerebral capillaries during incomplete ischemia and reperfusion.

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

Aminoisobutyric Acids↗

PubMed1990

Dimethylthiourea reduces ischemic brain edema without affecting cerebral blood flow.

Oxygen free radicals have been implicated as mediators of tissue damage in ischemic brain. We previously demonstrated that the hydroxyl radical scavenger 1,3-dimethyl-2-thiourea (DMTU) reduces infarct size after middle cerebral artery occlusion (MCAO) in rats. The present study was undertaken to determine whether this protection results from a preservation of the CBF. Adult male Sprague-Dawley rats were treated with DMTU (750 mg/kg i.p.) or saline vehicle 1 h before right MCAO. One-half 4, or 24 h after MCAO, animals were killed and samples were taken from the central, intermediate, and outer zones of the MCA distribution of each cortical mantle. Separate groups of animals were used to analyze these samples for water content (wet and dry weight), CBF [( 14C]butanol), or blood-brain barrier permeability [( 3H]alpha-aminoisobutyric acid). CBF was reduced in a graded fashion in the ischemic cortex: 0.169 +/- 0.020, 0.261 +/- 0.017, and 0.435 +/- 0.023 ml/g/min (mean +/- SEM, n = 8) after 4 h in the central, intermediate, and outer zones, respectively. Brain edema was present in a similar pattern, while blood-brain barrier permeability remained normal. Treatment with DMTU significantly reduced brain edema in the central and intermediate zones at both 4 and 24 h. However, CBF in the DMTU-treated animals was identical to that of the vehicle-treated animals. These results suggest that hydroxyl radicals play a role in the development of ischemic brain edema, but the mechanism does not appear to involve a direct effect on CBF.

Animals↗

PubMed1990

Effect of steroids on edema and sodium uptake of the brain during focal ischemia in rats.

Steroids reduce permeability of the blood-brain barrier and inhibit active sodium transport by brain capillaries in vitro. Since the rate of edema formation during the early stages of ischemia is related to the rate of sodium transport from blood to brain, this study was designed to determine whether steroids reduce ischemic edema formation by inhibiting blood-brain barrier sodium transport. Dexamethasone was compared with progesterone since the latter is a more potent inhibitor of sodium transport in isolated capillaries. Sprague-Dawley rats were treated with vehicle (n = 22) or 2 mg/kg of either dexamethasone (n = 22) or progesterone (n = 17) 1 hour before occlusion of the middle cerebral artery. After 4 hours of ischemia, brain water content and blood-brain barrier permeability to [3H] alpha-aminoisobutyric acid and sodium-22 were determined. In controls, mean +/- SEM water content of tissue in the center of the ischemic zone was 82.4 +/- 0.2%. Brain edema was significantly reduced following pretreatment with either dexamethasone (80.6 +/- 0.1%, p less than 0.001) or progesterone (81.5 +/- 0.3%, p less than 0.05). There was also a significant reduction in blood-brain barrier permeability to alpha-aminoisobutyric acid in normal brain following either treatment (e.g., 2.21 +/- 0.19 and 1.37 +/- 0.10 microliters/g/min, p less than 0.001, for control and dexamethasone treatments, respectively), but no effect on the permeability to sodium (e.g., 1.19 +/- 0.05 and 1.12 +/- 0.11 microliters/g/min for control and dexamethasone treatments, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Aminoisobutyric Acids↗

PubMed1990

Blood-to-brain sodium transport in ischemic brain edema.

Brain edema is a frequent complication of cerebral ischemia; however, its mechanism of formation is not well understood. Sodium is known to accumulate in brain during the early stages of partial ischemia. Therefore, the present studies were undertaken to determine the relation among BBB sodium transport, integrity of the BBB, and development of brain edema during the first 24 hr after the onset of cerebral ischemia. Partial cerebral ischemia was produced in gerbils by ligation of the left common carotid artery under ether anesthesia. After recovery from the anesthetic, animals were scored for the presence of symptoms, and those with scores greater than 10 of 25 (n = 87) were chosen for this study. Measurements of tissue water, sodium, and potassium contents, and brain uptake of 22Na and 3H-mannitol were made in each group at 1.5, 3, 6, 12, and 24 hr after carotid ligation. Accumulation of sodium and water in the ischemic compared with the nonischemic cerebral cortex was progressive. This edema formation was not of the vasogenic type because the permeability of the BBB to mannitol was unchanged. Blood-to-brain sodium transport was reduced by 30% to 40% at all time points in the ischemic cortex. Nevertheless, the remaining sodium transport activity appeared to play a role in the development of brain edema because Na accumulated in the tissue at a rate that was approximately the same as the rate of 22Na uptake from blood.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗