Theory and methods for measuring the unidirectional clearance constant for the blood-brain barrier transport of alpha-aminoisobutyric acid.
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Aminoisobutyric Acids↗
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In vitro effect of insulin on the uptake of glucose and alpha-aminoisobutyric acid in the thyroid gland of the turtle (Chrysemys dorbigni).
The presence of specific insulin binding sites in the thyroid gland of the turtle Chrysemys dorbigni has been previously reported. The purpose of the present work was to investigate the probable action of insulin on the uptake of [14C]deoxy-D-glucose ([14C]DG) and [14C]alpha-aminoisobutyric acid ([14C]AIB) in turtle (C. dorbigni) thyroid glands in vitro. Thyroid fragments (+/- 40 mg) were incubated at 25 degrees in Krebs-Ringer-bicarbonate buffer containing 0.2 microCi of [14C]DG or [14C]AIB without or with bovine insulin at different periods of time. The uptake of [14C]DG and [14C]AIB increased with incubation time. The presence of insulin (7 x 10(-6) M) in the incubation medium during 240 min did not modify the [14C]DG uptake. However if the thyroid fragments were previously incubated with insulin (60 min) and then incubated (240 min) with the same concentration of the hormone, the [14C]DG uptake was markedly increased. This stimulatory effect of insulin was dose-dependent. In similar experimental conditions, insulin also produced a significant increase in the uptake of [14C]AIB. Therefore, these findings strongly support the hypothesis that insulin might exert a direct action on the thyroid function.
Aminoisobutyric Acids↗
Establishment of gradients of riboflavin, L-lysine and alpha-aminoisobutyric acid across the perfused human placenta.
The mechanism for establishing transplacental gradients was studied in the dually perfused human placental lobule by recirculating either the maternal or fetal perfusate and leaving the other circuit open. Antipyrine, used as a reference molecule, rapidly reached equivalent concentrations in both perfusates regardless of which was recirculated. In contrast, riboflavin, L-lysine and alpha-aminoisobutyric acid showed distinctive kinetics at each surface of the placenta. Recirculation of the maternal perfusate quickly depressed the concentrations of these compounds and maintained them at levels of 50-70% of the fetal concentration. Recirculation of the fetal perfusate was followed by a gradual increase in concentrations, establishing gradients 1.2-1.7 times the maternal. It appears that uptake at the maternal surface greatly exceeds release, whereas the two rates are more nearly balanced at the fetal surface. The net effect is extraction of substrate from the maternal circulation and transfer to the fetal, where it accumulates to form a gradient.
Aminoisobutyric Acids↗
Temporal effects of dexamethasone on blood-to-brain and blood-to-tumor transport of 14C-alpha-aminoisobutyric acid in rat C6 glioma.
We used quantitative autoradiography (QAR) to evaluate the effect of systemically administered dexamethasone on capillary permeability in brain tumors and surrounding brain. Rats bearing unilateral right hemispheric C6 gliomas were studied at one and twelve hours after 10 mg/kg of intraperitoneal dexamethasone. Capillary permeability was determined by measuring unidirectional blood-to-brain and blood-to-tumor transport of 14C-alpha aminoisobutyric acid (14C-AIB) over fifteen minutes. 14C-AIB entry into tumor, brain adjacent-to-tumor (BAT), and ipsilateral and contralateral cortices was determined and expressed as a unidirectional transfer constant, K. Nontreated tumor K was more than two-fold greater than K for BAT and ten-fold greater than ipsilateral cortical K, confirming substantial barrier disruption in tumor. In addition, the K for BAT was also significantly greater than K for cortex, indicating that the barrier in the peritumoral region was also disrupted. One hour after dexamethasone treatment, tumor K fell to 63% of its pretreatment value (p less than 0.025). By twelve hours post-treatment, tumor K fell to 25% of the untreated value (p less than 0.001) and to 47% of the one-hour value (p less than 0.005). BAT K fell to 29% of its untreated value (p less than 0.02) and to 46% of its one-hour value (p less than 0.02). By 12 hours, ipsilateral cortical K fell to 67% of the untreated cortical value (p less than 0.05). Compared to untreated values, there was no significant difference between contralateral cortical K at either one or twelve hours.(ABSTRACT TRUNCATED AT 250 WORDS)
Aminoisobutyric Acids↗
Endothelial cell damage after gamma-irradiation in vitro: impaired uptake of alpha-aminoisobutyric acid.
The effects of gamma-irradiation with a cesium-137 source were assessed on endothelial cells isolated from bovine pulmonary arteries and maintained in culture. The radiobiologic parameters that characterize the dose-response survival curve for these cells, expressed as mean +/- SD were found to be n = 1.6 +/- 0.2, Dq = 71 +/- 13 rads, and Do = 161 +/- 35 rads, indicating a relatively low capacity of these cells to accumulate or repair radiation damage. Increasing doses of radiation led to decreasing uptake by endothelial cells of [14C]2-aminoisobutyric acid (AIB), a Na+-dependent and nonmetabolizable amino acid. A dose of 500 rads, which caused marked inhibition of cell survival, resulted in a 45% decrease in AIB uptake at 6 h and a 69% decrease in uptake at 24 h after irradiation. No morphologic abnormality was noted in these cells by light microscopy at 24 h after this dose of radiation. Bovine pulmonary artery fibroblasts, on the other hand, showed no significant impairment in uptake of AIB 24 h after exposure to doses of radiation as high as 5,000 rads. The uptake by endothelial cells of [14C]1-aminocyclopentane-1-carboxylic acid, an amino acid transported by a Na+-independent process, was not influenced by 5,000 rads of radiation. Our studies show that endothelial cells are sensitive to radiation and that impaired Na+-dependent uptake of AIB represents an early event in radiation damage to the endothelial cell.
Aminoisobutyric Acids↗
Insulin stimulation of aminoisobutyric acid transport in human skin fibroblasts is mediated through both insulin and type I insulin-like growth factor receptors.
A monoclonal antibody to the human type I insulin-like growth factor (IGF-I) receptor (alpha IR-3) was used to distinguish actions of insulin and IGF-I that are mediated through insulin as opposed to IGF-I receptors on human skin fibroblasts. Both insulin and IGF-I stimulate uptake of the nonmetabolized alanine analog alpha-aminoisobutyric acid (AIB) in these cells. alpha IR-3 inhibited AIB uptake stimulated by both of these hormones in a dose-dependent manner. However, the pattern of hormone action in the presence of alpha IR-3 differed for the two hormones. In the case of IGF-I, alpha IR-3 potently inhibited AIB uptake at low hormone concentrations, but this inhibition was overcome by high hormone concentrations, consistent with impairment of IGF-I action through the IGF-I receptor. In the case of insulin, the action of low concentrations (i.e. 10 ng/ml) was not inhibited, but that of higher insulin concentrations was, suggesting a dual receptor mechanism of cell stimulation by insulin. alpha IR-3 will be an important tool in further studies of the biology of the IGF-I receptor in normal and abnormal human cells.
Aminoisobutyric Acids↗
Application of alpha-aminoisobutyric acid, L-methionine, thymidine and 2-fluoro-2-deoxy-D-glucose to monitor effects of chemotherapy in a human colon carcinoma cell line.
Up to 4 h after treatment of human SW 707 colon carcinoma cells with the antineoplastic drug 4-amino-N-(2'-aminophenyl)-benzamide (GOE 1734, dinaline), the effects of tumour cell metabolism and proliferation were examined in vitro. Four tracers which can be labelled with isotopes suitable for positron emission tomography (PET) were used for this purpose: alpha-aminoisobutyric acid (AIB) and methionine to study changes in amino acid transport and protein synthesis, thymidine to observe changes in tumour proliferation and 2-fluoro-2-deoxy-D-glucose (FDG) to estimate glucose metabolism. Dinaline showed an inhibition of the sodium-dependent and -independent uptake of AIB. The methionine uptake was found to increase shortly after therapy. Thymidine incorporation into DNA was impaired and the FDG uptake showed a maximally 2.2-fold enhancement. Inhibition of AIB uptake suggests changes in amino acid transport, whereas increased uptake of methionine and FDG points to an enhancement of protein synthesis and glycolysis caused by repair mechanisms. The cytostatic and antiproliferative effect of dinaline, observed in cell growth curves, could be demonstrated by the impaired thymidine incorporation into DNA. This study demonstrates that in vitro screening with radiotracers suitable for PET can help to clarify effects of new antineoplastic substances on tumour cell metabolism. These data may be applied to choose the appropriate time schedule for monitoring therapeutic effects on tumour tissue.
Aminoisobutyric Acids↗
Muscle alpha-aminoisobutyric acid transport after exercise: enhanced stimulation by insulin.
After exercise the ability of insulin to stimulate glucose transport and glycogen synthesis in rat skeletal muscle is markedly enhanced (25). The present study was designed to determine whether prior exercise augments the stimulation of other processes by insulin and, if so, whether this can be attributed to an increase in insulin binding to its receptor. Toward this end rats were run on a treadmill for 45 min at moderate intensity and the uptake of alpha-aminoisobutyric acid (AIB) by muscle was then assessed using the isolated perfused hindquarter preparation. Approximately 30 min after the cessation of exercise, both the sensitivity and responsiveness of insulin-stimulated AIB uptake were significantly enhanced in the soleus and the red portion of the gastrocnemius. As previously shown for glucose transport and glycogen synthesis, only small effects were observed in the white portion of the gastrocnemius, which unlike the other muscles was not depleted of glycogen during the run. Insulin-stimulated glucose utilization was also enhanced in the incubated soleus muscle of exercised rats; however, insulin binding to the soleus was not altered. These studies indicate that the ability of insulin to stimulate processes other than glucose transport and glycogen synthesis is enhanced in skeletal muscle after exercise and that this is not due to an alteration in insulin binding. The changes in insulin-stimulated AIB uptake and glucose metabolism after exercise are the reverse of those found in denervated and immobilized muscle and in both situations insulin binding is not altered. This suggests that a common factor(s) modulates the increase in insulin effect after exercise and the insulin resistance of disuse.
Aminoisobutyric Acids↗
Effect of growth at low Na+ concentrations on the capacity of a marine bacterium to establish ion gradients and transport alpha-aminoisobutyric acid.
Cells of a histidine-auxotrophic, streptomycin-resistant mutant of marine bacterium Alteromonas haloplanktis 214 were grown at or near the lowest concentration of Na+ permitting growth (30-33 mM Na+). When suspended in solutions containing 10 mMKCl and either 30, 100, or 300 mM NaCl, the intracellular to extracellular K+ ratios were similar to those obtained with cells of the parent organism grown at more nearly optimum Na+ concentrations, whereas the Na+ ratios were somewhat larger. Cells of the parent organism grown at 32 mM Na+ transported alpha-aminoisobutyric acid (AIB) at only one-third the rate and to less than one-quarter of the extent of cells grown at 130 mM Na+ even when the NaCl concentration during transport was raised to optimum levels. The Km for uptake of AIB by cells grown at 32 and 130 mM Na+ was the same but the Vmax was higher for cells grown at 130 mM. The Vmax for cells grown at both concentrations of Na+ increased as the Na+ concentration in the uptake medium increased. It was concluded that none of the observations made could account for the fact that both parent and mutant of A. haloplanktis grow at 30-32 mM Na+ only after a very long lag period, and then grow at near normal rates once logarithmic growth begins despite the fact that the osmotic pressure of the medium is very low.
Aminoisobutyric Acids↗
Effects of fentanyl on alpha-aminoisobutyric acid transfer across the blood-brain barrier.
The effect of fentanyl on the transfer of small hydrophilic molecules across the blood-brain barrier was studied in rats by measuring the blood-brain transfer coefficient (Ki) and the regional cerebral blood flow (rCBF) and by calculating the capillary permeability-surface area product. In the control group (n = 14), after a femoral artery and vein were catheterized under isoflurane anesthesia, the rats were allowed to remain awake for 1.5 h before measuring Ki (n = 8) using intravenous 14C-alpha-aminoisobutyric acid or rCBF (n = 6) using 14C-iodoantipyrine. In the fentanyl groups, rats were injected with 25 micrograms/kg (low (n = 6) or 100 micrograms/kg (high dose) of fentanyl (n = 14), followed by a continuous infusion at a rate of 50 or 200 micrograms.kg-1.h-1, respectively. Their lungs were mechanically ventilated. The Ki (low dose, n = 6; high dose, n = 8) and rCBF (high dose, n = 6) were measured 1 h after fentanyl infusion. The Ki was lower in 9 of 13 brain regions in the low-dose fentanyl group and in 7 of 13 brain regions in the high-dose fentanyl group than in the control animals. The average value of Ki in all the brain regions was 8.6 +/- 4.6 microL.g-1.min-1 in the control group, 5.2 +/- 2.9 microL.g-1.min-1 in the low-dose fentanyl group, and 5.7 +/- 2.9 microL.g-1.min-1 in the high-dose fentanyl group. High-dose fentanyl did not significantly affect rCBF in any brain region studied. The value of the regional permeability-surface area product was similar to the corresponding regional Ki in the groups studied. In conclusion, fentanyl decreased the transfer of small hydrophilic molecules across the blood-brain barrier, as demonstrated by a decreased Ki and permeability-surface area product, without significant changes in rCBF.
Aminoisobutyric Acids↗
Measurement of solute transport across the blood-brain barrier in the perfused guinea pig brain: method and application to N-methyl-alpha-aminoisobutyric acid.
A technique for the vascular perfusion of the guinea pig head in vivo, suitable for measurements of blood-to-brain transport under controlled conditions of arterial inflow, has been developed. With a perfusion pressure ranging between 13 and 18 kPa and PCO2 in the arterial inflow of 5 and 5.5 kPa, cerebral blood flow, measured with [14C]butanol, was about 1 ml min-1 g-1 in the cerebral cortex, hippocampus, and caudate-putamen of the ipsilateral hemisphere; in the cerebellum and pontine white matter it was considerably less, and much higher perfusion pressures were required to establish equal blood flow throughout the whole brain. Regional water content, Na+/K+ ratio, ATP, energy charge potential, and lactate content of the ipsilateral side of perfused and nonperfused brain were not significantly different after 10 min perfusion. The D-[3H]mannitol space did not exceed 1% after 30 min of perfusion, indicating the integrity of the barrier. Over this period, EEG, ECG, and respiratory waveform remained normal. When [14C]N-methyl-alpha-aminoisobutyric acid (MeAIB), and D-[3H]mannitol were perfused together over periods extending to 30 min progressive uptakes of both solutes by the parietal cortex could be measured, and the unidirectional transfer constants estimated from multiple time-uptake data. The Kin for MeAIB (0.75 X 10(-3) ml min-1 g-1) was some three times that for mannitol. It is concluded that the technique provides a stable, well-controlled environment in the cerebral microvasculature of the ipsilateral perfused brain hemisphere suitable for examining the transport of slowly penetrating solutes into the brain.
Aminoisobutyric Acids↗
ISOLATION OF GAMMA-L-GLUTAMYL-L-BETA-AMINOISOBUTYRIC ACID FROM BOVINE BRAIN.
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Amino Acids↗
Immunocytoma effect upon circadian variation in murine urinary excretion of beta-aminoisobutyric acid, beta-alanine, phenylalanine and tyrosine.
Under the conditions of disynchronization by the manipulation of both the alternation of light and darkness and the availability and unavailability of food, circadian rhythms characterize the excretion of several amino acids by inbred LOU rats bearing an immunocytoma. Large amplitude rhythms can be demonstrated for urinary beta-aminoisobutyric acid, beta-alanine, phenylalanine and tyrosine. Under the same conditions of disynchronization, control animals excrete the same compounds also with a marked circadian variation but at an invariably lower average rate. These excretory rhythms, along with those demonstrated earlier for polyamines and light-chains, are of interest as potential markers for the chronotherapy of cancer.
Amino Acids↗
[Differences in allele frequency at the BAIB locus, determining the level of expression of beta-aminoisobutyric acid, in healthy donors and coronary artery atherosclerosis patients from Buryat and Lithuanian populations].
Phenotype and allele frequencies of the genetically dimorphic system determining urinary excretion of beta-aminoisobutyric acid (BAIB) were studied in population samples of Buryats from the Aginskii Buryat Autonomous District and Lithuanians from Vilnius and in patients with coronary atherosclerosis (CA) from both populations. Frequency of allele BAIB*b, which determines high BAIB excretion, proved to be more than twice higher in Buryats compared with the population sample of Lithuanians (0.620 versus 0.289, respectively). The proportion of individuals with high BAIB excretion in CA patients of either ethnic sample was twice higher than in the corresponding control sample. Frequency of allele BAIB*b in CA patients and healthy individuals was 0.348 and 0.242, respectively, in the Lithuanian population and 0.775 and 0.557, respectively, in the Buryat population. Thus, assessment of urinary excretion of BAIB proved to be prognostically valuable. The method used to detect a variation in BAIB excretion is relatively inexpensive, simple, and suitable for mass screening of patients and healthy individuals (population control). After additional testing with representative samples, the method can be used as an accessory diagnostic test in patients with cardiovascular disorders.
Alleles↗
Rat testis and epididymis can transport [3H] 3-O-methyl-D-glucose, [3H] inositol and [3H] alpha-aminoisobutyric acid across its epithelia in vivo.
The in vivo movement of [3H] 3-0-methyl-D-glucose ([3H] 30MG), [3H] L-glucose, [3H] inositol and [3H] alpha-aminoisobutyric acid ([3H] alpha AIB) into and across the rat testicular and epididymal epithelium was investigated. After systemic infusion of [3H] 30MG, both epididymal and testicular tissue concentrations of the isotope were approximately 50% lower than blood plasma levels, even 24 h after infusion. Similar results were observed for caput and seminiferous tubule fluid. There was a significant reduction of [3H] 30MG caput lumen to blood ratio when the blood glucose concentration was increased to 2-5 times that of normal. A similar reduction of [3H] 30MG caput lumen to blood ratio was observed when 1000 mumol of 2-methylaminoisobutyric acid (meAIB) was infused with the isotope. Caput luminal [3H] L-glucose concentration never exceeded 10% of blood levels. The data suggest that glucose is transported across the testicular and epididymal epithelium via a facilitated diffusion mechanism (carrier mediated) and that the carrier is situated on the basolateral membrane. This study did not demonstrate either a glucose countertransport system or a glucose-inositol exchange system across the epithelium of the caput epididymidis. Epididymal tissue (except cauda) and caput luminal fluid concentrations of [3H] inositol exceeded that of blood plasma within 1 h after infusion of isotope. The proximal regions of the epididymis demonstrated significantly higher transporting activity than either cauda or testis. Systemic infusion of 100 mumol myo-inositol significantly reduced the transport of [3H] inositol into caput luminal fluid and epididymal and testicular tissue. It is suggested that there is a carrier situated on the basolateral membrane which is able to transport inositol against a concentration gradient (probably active transport). Epididymal tissue (except cauda), testicular tissue and caput luminal fluid concentrations of [3H] alpha AIB also exceeded that of blood plasma but only 24 h after infusion of isotope. The initial segment and corpus regions of the epididymis had a significantly higher transporting activity compared to the remainder of the epididymis and the testis. A dose of 500 mumol meAIB reduced epididymal uptake of [3H] alpha AIB. These results suggest that there is a carrier situated in the basolateral membrane which can transport the amino acid against a concentration gradient (probably active transport). The differences in transport activities of the compounds investigated along the reproductive tract probably indicate differences in the affinity or quantity of the carriers. These epididymal transporting systems regulate the movement of material across its epithelium and may help to protect the epididymis from fluctuations in the blood concentration of each compound.
3-O-Methylglucose↗
Nerve growth factor-induced stimulation of alpha-aminoisobutyric acid uptake in PC 12 cells: evaluation of its biological significance.
In the clonal PC12 pheochromocytoma cell line, the observed effects of nerve growth factor (NGF) on the uptake rates of alpha-aminoisobutyric acid (AIB) depend upon the assay conditions employed. In orthodox uptake assays calling for serum removal prior to the addition of AIB, 50 ng/ml NGF causes a stimulation of uptake of 62% after 40 minutes and 46% after 24-hours exposure. However, serum stimulates AIB uptake to a similar extent and the effects of serum and NGF are not additive. An uptake assay which directly measures the AIB uptake experienced by PC12 cells undergoing NGF-induced morphological differentiation was therefore employed. When compared with control cells growing in serum-containing medium, NGF-induced differentiating PC12 calls experience (1) only a transient and modest increase in AIB uptake, and (2) a significant long-term decrease in AIB uptake under conditions optimal for differentiation. It is concluded that NGF-directed neurite outgrowth is not mediated by NGF effects on amino acid uptake via the A-system.
Absorption↗
Interaction and orientation of an alpha-aminoisobutyric acid- and tryptophan-containing short helical peptide pore-former in phospholipid vesicles, as revealed by fluorescence spectroscopy.
The interaction and orientation of a membrane protein ion channel model, an alpha-aminoisobutyric acid analogue of gramicidin B (GBA), in egg yolk phosphatidylcholine vesicles was studied by means of fluorescence spectroscopic techniques. GBA helices form stable ion-conducting pores in membranes [Jelokhani-Niaraki et al. (1995) J. Chem. Soc. Perkin Trans. 2, 801-808]. In an alpha-helical model for the peptide, all Trp residues (intrinsic fluorophores) are distributed near the C-terminus. Fluorescence quenching experiments revealed the exposure of the helical peptides' C-termini to aqueous environments. Dansyl-labeled vesicles were used to investigate the GBA dynamism of the interaction with membranes. It was shown that considerable amounts of peptide reside on and in the vicinity of the outer surface of lipid bilayers. The transmembrane transfer to the inner layer is slow due to the high affinity of Trp residues for bilayer interfaces which anchor the peptide to the outer surface. A structural-functional interpretation of the GBA interaction with membranes is presented.
Gramicidin↗
Inhibition of amyloid fibril formation by peptide analogues modified with alpha-aminoisobutyric acid.
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Aminoisobutyric Acids↗