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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↗
PubMed1996

Hydroxyethyl starch solution attenuates blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats.

This study was performed to investigate whether a fraction of hydroxyethyl starch macromolecules, prepared from pentastarch and known as "Hes-Pz," with molecular weights of 100,000-1,000,000, protects against blood-brain barrier (BBB) disruption due to intracarotid injection of hyperosmolar mannitol. Rats were anesthetized with isoflurane, and retrograde catheterization of a unilateral eternal carotid artery was performed. Except for the Control group (n = 8), hemodilution was performed using lactated Ringer's solution LR group, n = 7), 6% hetastarch (HES group, n = 7), or 6% HES-Pz (HES-Pz group, n = 8) to reduce the hematocrit to about 23%. The BBB transfer coefficient (Ki) of 14C-alpha-aminoisobutyric acid was determined after a unilateral intracarotid injection of 25% mannitol. Blood pressure and hematocrit were similar in all groups. In the control group, Ki was increased significantly in the ipsilateral cortex (IC) where mannitol was injected (16.3 +/- 6.1 vs 4.1 +/- 1.4 microL.min-1) when compared with the contralateral cortex (CC). Ki was similar in the CC in all four groups. The Ki in the IC was significantly lower in the HES-Pz(6.4 +/- 3.5 microL.g-1.min-1) than in the Control, HES, or LR group (16.3 +/- 6.1, 19.0 +/- 12.9, 17.9 +/- 10.8 microL.g-1.min-1, respectively). Our data suggest that HES-Pz significantly attenuates disruption of the BBB caused by an injection of hyperosmolar mannitol.

Aminoisobutyric Acids↗
PubMed1983

Selection of experimental conditions for the accurate determination of blood--brain transfer constants from single-time experiments: a theoretical analysis.

Reliable blood-brain transfer constants can be determined from data obtained in single-time experiments (i.e., a single experimental time for tissue sampling). The accuracy of such measurements depends on factors such as the test molecule used and the experimental time chosen; therefore, the selection of optimal experimental conditions is important. In this presentation, a model of transport across the blood--brain barrier (BBB) was developed and used to determine appropriate experimental protocols for single-time experiments. Transfer numbers derived from published data with alpha-aminoisobutyric acid (AIB; a compound of low BBB permeability that is readily taken up by brain cells) and diethylenetriaminepentaacetic acid (DTPA; a compound of very low BBB permeability that is not taken up by brain cells) were inserted into the model and apparent blood-to-brain transfer constants (K1) were obtained. In addition, the two basic sets of transfer numbers were altered to mimic various experimental and pathological changes in blood--brain transport. The results of this analysis indicate that moderate to large transfer rates across the BBB (0.01-1.0 ml g-1 min-1) are more easily and reliably measured by AIB-like compounds. In contrast, compounds like DTPA are better test-molecules for measuring small changes in the BBB transfer rate (0.0001-0.001 ml g-1 min-1), provided an appropriate experimental time is chosen.

Aminoisobutyric Acids↗
PubMed1982

Fibroblasts from a patient with leprechaunism are resistant to insulin, epidermal growth factor, and somatomedin C.

Leprechaunism is a rare inherited disorder characterized by severe intrauterine growth retardation and insulin resistance. Cultured skin fibroblasts from an infant with Leprechaunism were previously reported to show decreased stimulation of DNA synthesis by insulin despite apparently normal binding of [125I]insulin and [125I]somatomedin C. We have now further investigated the growth of this patient's fibroblasts and compared their metabolic responses to insulin and various peptide growth factors with responses in normal foreskin-derived fibroblasts. The doubling time of Leprechaun fibroblasts was prolonged (90 vs. 29 h), and their morphology was abnormal. Stimulation of [3H]glucose uptake was minimal with low insulin levels (1--10 ng/ml) relative to controls, but was comparable at higher insulin concentrations (1--10 micrograms/ml). Stimulation of [3H] aminoisobutyric acid uptake by insulin, epidermal growth factor (EGF), multiplication-stimulating activity, and somatomedin C (Sm-C) in Leprechaun cells was diminished relative to control cells at all concentrations tested. Furthermore, stimulation of [3H]thymidine incorporation in Leprechaum cells by EGF, Sm-C, and fibroblast growth factor was also subnormal. Binding of [125I]EGF to Leprechaun fibroblasts was not decreased. It is concluded that fibroblasts from this patient are resistant to the metabolic effects of insulin, EGF, Sm-C, and fibroblast growth factor. Since receptors for three of these peptides are apparently normal, it is likely that the defect in these cells is at the postreceptor level, perhaps involving a metabolic pathway common to the action of multiple growth factors.

Aminoisobutyric Acids↗
PubMed1990

Aging and sex influence the permeability of the blood-brain barrier in the rat.

The aim of the present study was to investigate the existence of aging- and sex-related alterations in the permeability of the blood-brain barrier (BBB) in the rat, by calculating a unidirectional blood-to-brain transfer constant (Ki) for the circulating tracer [14C]-alpha-aminoisobutyric acid. We observed that: a) the permeability of the BBB significantly increased within the frontal and temporo-parietal cortex, hypothalamus and cerebellum in 28-30 week old rats, in comparison with younger animals; b) in several brain areas of female intact rats higher Ki values (even though not significantly different) were calculated at oestrus than at proestrus; c) in 1-week ovariectomized rats there was a marked increase of Ki values at the level of the frontal, temporo-parietal and occipital cortex, cerebellum and brain-stem. One can speculate that aging- and sex-related alterations in the permeability of the BBB reflect respectively changes in brain neurochemical system activity and in plasma steroid hormone levels.

Aging↗
PubMed1995

Systemic cytokine administration can affect blood-brain barrier permeability in the rat.

The aim of the present study was to clarify the effect of intracarotid injection of interleukin-1 beta (IL-1 beta), interleukin-2 (IL-2), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) on the permeability of the blood-brain barrier (BBB) in the rat. A regional blood-to-brain transfer constant (Ki) for [14C] alpha-aminoisobutyric acid ([14C]AIB) and the cerebral residual blood volume were calculated 10 min following administration of cytokines (CKs; 1000 U/rat). The injection of IL-2 and IL-6 (but not of IL-1 beta) induced a significant enhancement of Ki values for [14C]AIB within several brain areas; conversely, when the rats were given TNF-alpha, a striking decrease in BBB permeability was observed. The cerebral regional blood volumes appeared significantly lower in the rats injected with IL-6 than in the control animals, but markedly increased following TNF-alpha administration. Our findings confirm the ability of some CKs to affect the permeability of the BBB and/or to act, probably indirectly, as vasomodulator agents of the cerebral microvessel endothelium.

Aminoisobutyric Acids↗
PubMed1999

Effects of cyclic GMP on microvascular permeability of the cerebral cortex.

This study was performed to test the hypothesis that a direct application of cyclic guanosine monophosphate (cGMP) to the cortex would increase blood-brain barrier (BBB) permeability. Rats were anesthetized with 1.4% isoflurane and were mechanically ventilated. Two cranial windows (3 mm in diameter) were made on each side of the rat's skull (a total of four windows on each rat) to expose the cerebral cortex. A patch of normal saline, 10(-5) M, 10(-4) M, or 10(-3) M 8-bromo-cGMP was applied to each cranial window. The patches were changed every 5 min. Ten minutes after applying the patches, BBB permeability was determined by measuring the transfer coefficient (Ki) of [alpha-14C]aminoisobutyric acid. Vital signs were not changed after applying 8-bromo-cGMP. Blood gases were within normal limits. In the cortex, 10(-5) M 8-bromo-cGMP did not significantly affect the Ki; 10(-4) M 8-bromo-cGMP increased the Ki by 115%; 10(-3) M 8-bromo-cGMP increased the Ki by 124%. However, there was no statistical difference in the Ki between the doses of 10(-4) M and 10(-3) M 8-bromo-cGMP. In the pons where no patch was applied, the Ki was similar to that of the cortical area where a normal saline patch was applied. Our data demonstrated that a direct application of cGMP to the cerebral cortex significantly increased the permeability of the BBB.

Aminoisobutyric Acids↗
PubMed1996

Protective effects of tirilazad mesylate in a cellular model of peroxynitrite toxicity.

Following CNS trauma or ischemia, peroxynitrite may be a toxic intermediate which forms in vivo when nitric oxide condenses with superoxide. Alone, peroxynitrite appears to directly react with aromatic and sulfhydryl nucleophiles. However, at physiological pH, peroxynitrite is protonated and, in that form, will rapidly (within seconds) decompose to species with hydroxyl radical and nitrogen dioxide characteristics. These reactive species are shown to initiate lipid peroxidation, hydroxylate aromatic residues, and nitrate aromatic residues. This reactivity may contribute to differential toxicity in vivo and in vitro. Tirilazad mesylate (TZ) is a lipid-soluble antioxidant shown to inhibit iron-dependent lipid peroxidation. It is an effective therapy in a variety of CNS injury and ischemia models and is currently undergoing human clinical evaluation in stroke, head injury, and spinal injury. This study was designed to investigate the cytoprotective properties of TZ in a cerebellar granule cell model of peroxynitrite toxicity. Cytoprotective efficacy of TZ was based on viability measurements, blockade of lipid hydroperoxide generation, and blockade of nitrotyrosine formation. Cell viability was determined by [3H]-aminoisobutyric acid (3H-AIB) uptake, and lipid hydroperoxide and nitrotyrosine content were determined by HPLC assays. Tirilazad mesylate was found to have similar cytoprotective effects (approximately 50% protection at 100 microM) when applied before or after exposure of cells to peroxynitrite. In contrast, post-treatment with superoxide dismutase (50 units/ml) or allopurinol (100 microM) failed to produce any cytoprotection. Furthermore, we discovered that TZ inhibited the peroxynitrite-induced increase of phosphatidylethanolamine hydroperoxide (PEOOH), but did not affect the peroxynitrite-induced formation of nitrotyrosine formation. This suggests that the ability of TZ to afford cytoprotection in this peroxynitrite toxicity model is due to the inhibition of membrane-localized lipid peroxidation, and not to the inhibition of nitration of tyrosine residues.

Aminoisobutyric Acids↗
PubMed1995

Effects of growth factors and gut regulatory peptides on nutrient uptake in ovine muscle cell cultures.

Effects of gut regulatory peptides and growth factors on the uptake of 2-aminoisobutyric acid (AIB) and 2-deoxy-D-glucose (2-DOG) were examined in differentiated ovine satellite cell cultures. Insulin and insulin-like growth factor I (IGF-I) gave maximal increases of 160-180% of controls for AIB and over 190% for 2-DOG. IGF-I showed half-maximal effects at 0.1-1 nM, and insulin at 1-10 nM. Bovine growth hormone (0.01-100 nM) had no effect. Gastrin, gastric inhibitory polypeptide (GIP), bombesin and somatostatin had no action in either the absence or presence of insulin. In primary cultures epidermal growth factor (EGF) increased the uptake of AIB (133-137%) and 2-DOG (171-176%). In clonal lines, EGF had little effect on nutrient uptake but still simulated protein synthesis.

Aminoisobutyric Acids↗
PubMed1998

Effects of isoproterenol on blood-brain barrier permeability in rats.

This study was performed to examine whether the direct topical application of isoproterenol to the cerebral cortex could modify the blood-brain barrier (BBB) permeability and whether this effect could be blocked by Timolol, a beta-adrenergic receptor antagonist without a membrane stabilizing effect. After a craniotomy in each animal, a low-dose (10(-4) M, n = 6) or a high-dose (10(-3) M, n = 6) isoproterenol patch was placed on one cortex (Ipsilateral Cortex: IC) and a normal saline patch was placed on the other cortex (Control Cortex: CC). Another 6 animals were pretreated with Timolol 1.5 mg kg(-1) i.v. before the placement of high dose isoproterenol patches. The BBB transfer coefficient (Ki) was determined using 14C-alpha-aminoisobutyric acid. Mean arterial blood pressure decreased after low- and high-dose isoproterenol patches. The low- and high-dose of isoproterenol increased Ki by 58% (IC: 5.94+/-2.02, CC: 3.77+/-1.75 microl g min(-1)) and 66% (IC: 6.97+/-3.66, CC: 4.19+/-2.48 microl g min(-1)) respectively when compared to that of the corresponding CC. Pretreatment with Timolol prevented the increase of the Ki by a high-dose of isoproterenol (IC: 5.33+/-1.88, CC: 5.66+/-1.72 microl g min(-1)). Our data demonstrate that a direct application of a beta-adrenergic receptor agonist to the brain parenchyma increased the permeability of the BBB, and that this effect could be prevented with a beta-adrenoceptor antagonist.

Adrenergic beta-Agonists↗
PubMed1981

Loss of differentiative potential of the mammary gland in ovariectomized mice: identification of a biochemical lesion.

The differentiative functions, lactose synthetase activity and casein synthesis, can be induced in mammary gland explants from intact mice when insulin, cortisol, and PRL are present in the medium. By contrast, the tissue from mice castrated for 1--2 months does not differentiate in vitro. Explants from these ovariectomized animals retain their sensitivity toward insulin, as evidenced by the ability of this hormone to stimulate DNA synthesis, alpha-aminoisobutyric acid accumulation, and glucose-6-phosphate/gluconate-6-phosphate dehydrogenase activities. This tissue also remains sensitive to cortisol, as evidenced by the ability of this steroid to stimulate NADH-cytochrome c reductase activity. However, the tissue from ovariectomized mice has lost biological responsiveness to PRL. Such insensitivity may be due to a deficiency of PRL receptors, which are reduced in the glands from castrated mice to 20--25% of control values. However, a second defect between the receptor and the genome is also likely, since PRL unresponsiveness is still present in the tissue of ovariectomized animals whose mammary PRL-binding has been partially maintained by elevating serum PRL levels with a pituitary transplant. Therefore, this system may be useful for the study of cellular processes related to PRL action beyond the receptor level.

Aminoisobutyric Acids↗
PubMed1986

Parallel packing of alpha-helices in crystals of the zervamicin IIA analog Boc-Trp-Ile-Ala-Aib-Ile-Val-Aib-Leu-Aib-Pro-OMe.2H2O.

An apolar synthetic analog of the first 10 residues at the NH2-terminal end of zervamicin IIA crystallizes in the triclinic space group P1 with cell dimensions a = 10.206 +/- 0.002 A, b = 12.244 +/- 0.002 A, c = 15.049 +/- 0.002 A, alpha = 93.94 +/- 0.01 degrees, beta = 95.10 +/- 0.01 degrees, gamma = 104.56 +/- 0.01 degrees, Z = 1, C60H97N11O13 X 2H2O. Despite the relatively few alpha-aminoisobutyric acid residues, the peptide maintains a helical form. The first intrahelical hydrogen bond is of the 3(10) type between N(3) and O(0), followed by five alpha-helix-type hydrogen bonds. Solution 1H NMR studies in chloroform also favor a helical conformation, with seven solvent-shielded NH groups. Continuous columns are formed by head-to-tail hydrogen bonds between the helical molecules along the helix axis. The absence of polar side chains precludes any lateral hydrogen bonds. Since the peptide crystallizes with one molecule in a triclinic space group, aggregation of the helical columns must necessarily be parallel rather than antiparallel. The packing of the columns is rather inefficient, as indicated by very few good van der Waals' contacts and the occurrence of voids between the molecules.

Aminoisobutyric Acids↗
PubMed1985

Binding, degradation, and biological activity of insulin in vascular smooth muscle cells.

The interaction of insulin with the vascular smooth muscle was studied using cultures derived from the bovine aortic arch. The cultured cells exhibited specific binding of 125I-insulin that was reversible and dependent on pH. Both insulin and insulinlike growth factor (IGF) I competed for 125I-insulin binding; IGF I, however, was less effective than insulin by at least an order of magnitude. Insulin binding was accompanied by internalization and degradation of the hormone in a temperature- and time-dependent manner. Chloroquine and other lysosomotropic agents elevated the internalized insulin and reduced its degradation. Pre-exposure of cell cultures to insulin resulted in downregulation of cell surface receptors. Insulin stimulated alpha-aminoisobutyric acid transport in confluent smooth muscle cells. The maximal response was observed at 100 ng/ml insulin with a half-maximal effect at 10 ng/ml. Sparse, serum-starved smooth muscle cells responded to insulin with a dose-dependent increase in [3H]-thymidine incorporation into DNA. Although the effect was already apparent at 1 ng/ml insulin, it reached near maximal level only at 10,000 ng/ml. IGF I also stimulated DNA synthesis in smooth muscle cells; however, at low concentrations insulin was more efficient in this respect. Human growth hormone was inactive. The data indicate the presence of specific receptors for insulin in bovine aortic smooth muscle cells. These receptors appear to mediate the metabolic activity as well as part of the mitogenic effect of insulin in these cells.

Aminoisobutyric Acids↗
PubMed1986

Effects of insulin and prior exercise on prostaglandin release from perfused rat muscle. Evidence that prostaglandins do not mediate changes in glucose uptake.

Prostaglandin generation and its inter-relation to the metabolic effects of insulin and prior exercise were examined in perfused muscle of fed rats. During a 60 min perfusion of the rat hindquarter, a substantial release of the prostaglandins PGF2 alpha, PGE2 and 6-oxoPGF1 alpha was observed. Blood cells present in the perfusate released these substances in negligible amounts indicating the prostaglandins were produced by the hindquarter. Addition of insulin to the perfusate increased both glucose uptake and the generation of PGE2 and 6-oxoPGF1 alpha. At 30 min after intense treadmill exercise, glucose and alpha-aminoisobutyric acid (AIB) uptake by the hindquarter were increased in the absence of added insulin, but prostaglandin release was not increased. Insulin further increased glucose and AIB uptake; however, in contrast with its effects in non-exercised rats, insulin no longer stimulated prostaglandin generation. Indomethacin (10 microM) added to the perfusate inhibited the release of PGF2 alpha and PGE2 by 90% and the release of 6-oxoPGF1 alpha by 54%. It had no effect on the stimulation of glucose uptake by either insulin or prior exercise. The data indicate that insulin increases prostaglandin synthesis by perfused rat muscle, and that prior exercise blocks this effect. They suggest that under the conditions studied prostaglandins do not mediate the effects of insulin or prior exercise on glucose uptake.

Aminoisobutyric Acids↗
PubMed1984

Mechanisms of insulin resistance in cultured fibroblasts from a patient with leprechaunism: impaired post-binding actions of insulin and multiplication-stimulating activity.

The binding and action of insulin and of the insulin-like growth factor, multiplication-stimulating activity (MSA), were studied in cultured skin fibroblasts from an infant with leprechaunism and associated insulin resistance. Three actions of insulin were reduced in the leprechaun cells: activation of glycogen synthase was 30% as great as in control fibroblasts, the increase in 2-deoxyglucose transport was 33% of the control value, and the uptake of alpha-aminoisobutyric acid was sevenfold less sensitive to enhancement. On a molar basis, MSA was at least as effective as insulin in activating glycogen synthase in control fibroblasts; in the patient's cells there was a reduction in activation that paralleled the changes observed with insulin. To localize the site of insulin resistance, the binding of both [125I]-insulin and [125I]-MSA to fibroblasts was measured and found to be reduced in the leprechaun cells. However, the impairment of the actions of insulin and MSA in the patient's cells was not explained solely by the diminished binding of the two polypeptides. Since the hexose transport system and the terminal enzymes studied thus far are intact, the defect is postulated to involve the post-binding coupling mechanism and mediator formation.

Adult↗
PubMed1981

Role of insulin in the intermediary metabolism of the activated thymic-derived lymphocyte.

The hypothesis that a role for insulin in the metabolism of T cells would be evident after cell activation when receptors appear was tested to validate the T cell model and to analyze the mechanism by which insulin may function in immunoregulation. Measuring the flux rates of 3-O-[methyl-3H]-D-glucose and aminoisobutyric acid, alpha-[1-14C], lactate production and oxidation, and glucose oxidation from carbon 1- and carbon 6-labeled substrates, it was determined that (a) mitogens such as phytohemagglutinin enhance basal T lymphocyte intermediary metabolism, (b) physiologic concentrations of insulin have no impact on the metabolism of unstimulated, cultured, receptor-negative lymphocytes, and (c) insulin provided to receptor bearing lymphocytes augments intermediary metabolism above mitogen stimulated levels. The importance of the pentose phosphate shunt pathway for energy metabolism in the stimulated lymphocyte was confirmed. These studies demonstrate that insulin has a classical physiologic role to play in the activated lymphocyte further validating the use of this cell to examine potential receptor defects in disorders of carbohydrate metabolism. By enhancing energy metabolism of stimulated lymphocytes, insulin serves biologic economy and thus may perform its immunoregulatory role.

3-O-Methylglucose↗
PubMed1983

Reciprocal modulation of growth and differentiated functions of mature rat hepatocytes in primary culture by cell--cell contact and cell membranes.

In primary monolayer cultures of rat mature hepatocytes, many metabolic functions as well as cell growth are regulated by cell density. There are two types of regulatory response of these functions to change of cell density. Growth-related functions, such as DNA synthesis, induction of glucose-6-phosphate dehydrogenase, 2-aminoisobutyric acid transport, synthesis of cellular protein, and cholesterogenesis, are stimulated by low cell density. In contrast, functions related to hepatocyte-specific characters, such as the inductions of tyrosine aminotransferase, serine dehydratase, and malic enzyme and synthesis of triglycerides, are stimulated by high cell density. The reciprocal responses of these cellular activities to cell density were mimicked by addition of plasma membranes purified from adult rat liver to hepatocytes cultured at low cell density. The modulator activity was heat labile and trypsin sensitive. The activity was also found in plasma membranes from kidney, brain, and erythrocytes, although the specific activities of these preparations seemed to be different. These results suggest that the reciprocal regulations of cell growth and hepatocyte-specific functions are mediated by some surface components via cell-cell contact.

Acetates↗
PubMed1993

Hormonal influence on the permeability of the blood-brain barrier: effect of an analog of adrenocorticotropic hormone, beta 1-24 corticotrophin.

Regional unidirectional transport of alpha-aminoisobutyric acid (AIB) (mol. wt.: 104) and sucrose (mol wt.: 342) which have a low permeability across the intact endothelium was investigated in brain of rats either treated with synacthène: an analog of ACTH, tetracosactide retard (beta-1-24 corticotrophin) or in brain of placebo-treated controls. Three days treatment with synacthène, reduced the rate of influx of AIB and sucrose in most of the brain regions studied especially in thalamus, hypothalamus, cortex, and caudate nucleus without affecting the vascular compartment. The brainstem, cerebellum and white matter were less affected. These experimental findings may suggest that ACTH exhibits significant influence on hormonal regulation of blood-brain barrier permeability. Thereby such a regulation may involve the entry of polar compounds into the CNS and may influence the central effects of diffusion-limited drugs.

Aminoisobutyric Acids↗