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Q R Smith

Publications and source records attributed to Q R Smith.

At least 37 records · Page 2Linked to original sources
PubMed1991

Chloride efflux from isolated choroid plexus.

Chloride efflux was analyzed in adult rat lateral ventricle choroid plexus (LVCP) incubated in artificial CSF (aCSF) at 37 degrees C. Following steady-state loading of 36Cl in LVCP, the tracer release from plexus to aCSF was quantified by the efflux coefficient (k, s-1), equal to ln 2/t/2. Cl efflux could be described by a 2-component model, with a t/2 for the 'fast' component matching well that for [3H]sucrose (extracellular marker) and a slower, drug-inhibitable component of 36Cl release thought to reflect cellular washout. The cellular Cl efflux was more than twice as fast as 37 degrees C than at 15 degrees C. There was progressively more rapid efflux (k) of 36Cl from cells as the aCSF was altered over a range of several pH values from 6.7 (k = 0.026 s-1) to 8.2 (0.070 s-1). CSF medium anion replacement (isethionate and HEPES for Cl and HCO3, respectively) reduced the k for 36Cl by 57%. Acetazolamide (0.1 mM) and other Cl transport inhibitors (disulfonic stilbenes and loop diuretic) reduced Cl efflux by 35-55%. Acetazolamide inhibited Cl release from LVCP into aCSF whether the latter contained Cl and HCO3, or not. Overall, the findings suggest that Cl extrusion from choroid plexus is by way of an anion exchanger and via channels.

Acetazolamide↗
PubMed1991

Calcium deficiency enhances cadmium accumulation in the central nervous system.

Weanling male rats were administered 1 of 4 diets for 40 days: control (CONT), low Ca (LOCA), control plus Cd (CONT + Cd) or low Ca plus Cd (LOCA + Cd). After 40 days, Cd was analyzed in 7 brain regions, spinal cord, serum, liver, kidney, muscle and femur by atomic absorption spectrophotometry with Zeeman background correction. No significant difference in Cd between CONT and LOCA was found except in femur, where it was increased. In CONT + Cd rats, peripheral tissues showed an increase in Cd of 30-71 fold above CONT rats. Brain regions exhibited a more modest 7-10 fold change, and serum Cd was 8.5 times above control. LOCA + Cd rats showed a 25-fold increase of Cd above LOCA in serum, 25-100 fold in peripheral tissues, and a 14-20 times in brain. These findings show that brain Cd is increased during Ca deficiency, but that central nervous system Cd changes less than peripheral tissue Cd. This increase in brain Cd could alter brain function.

Animals↗
PubMed1991

2-amino-3-(methylamino)-propanoic acid (BMAA) pharmacokinetics and blood-brain barrier permeability in the rat.

2-Amino-3-(methylamino)-propanoic acid (BMAA) is a neurotoxic, excitatory amino acid which has been linked through cycad use and consumption with the onset of a variant of amyotrophic lateral sclerosis occurring with high incidence in the western Pacific region. We have studied BMAA pharmacokinetics, oral bioavailability and blood-brain barrier permeability in the rat in an attempt to better define the possible role for BMAA in this disease. To evaluate its kinetics and uptake, BMAA (25-400 mg/kg) was administered to rats, either acutely or chronically, and then plasma and brain concentrations were determined at various times thereafter by combined gas chromatography mass spectrometry. After single dose i.v. injection, BMAA was cleared from plasma in a rapid distribution phase (Vd approximately 16 liters/kg) followed by a slower elimination phase (t1/2 approximately 1 day). Brain uptake was limited by a low blood-brain barrier permeability-surface area product of 2 to 5 x 10(-5) ml/sed/g. Brain BMAA levels peaked within 8 hr after injection, and then declined with a t1/2 similar to that of plasma. After two weeks of continuous infusion (100 mg/kg/day), steady-state brain concentrations equalled 10 to 30 micrograms/g, and only moderately exceeded those in plasma. The results suggest that BMAA may reach potentially toxic levels in brain (i.e., greater than 250 microM) after large doses (greater than 100 mg/kg). However, such doses are orders of magnitude greater than those available from dietary or medicinal use of cycads.

Administration, Oral↗
PubMed1991

Saturable transport of Ca into CSF in chronic hypo- and hypercalcemia.

To further characterize possible saturable transport of Ca into CSF during chronic plasma [Ca] changes, weanling rats were fed diets differing in Ca for 10 weeks. Transfer coefficients for unidirectional uptake of 45Ca and 36Cl into CSF (Kcsf) were determined 3 or 10 min after intravenous tracer injection in unanesthetized animals. In rats fed low Ca diet, Kcsfs for 45Ca and 36Cl were elevated above control, but the 45Ca/36Cl ratio for Kcsf, a more specific measure of Ca transport, was also increased. In animals fed high Ca diet, Kcsfs of both radiotracers were not statistically different from control, but the 45Ca/36Cl ratio was decreased. Injection of CaCl2 into hypocalcemic rats elevated plasma [Ca], depressed 45Ca Kcsf, and returned the 45Ca/36Cl ratio to the control value. The inverse relationship between plasma ionized [Ca] and 45Ca Kcsf was fitted to saturation kinetics with Km less than or equal to 0.53 mumol/ml, maximal Ca influx for the saturable component between 27 and 67 x 10(-5) mumol.g-1.s-1, and the passive component of Kcsf less than or equal to 15 x 10(-5) ml.g-1.s-1. We conclude that Ca transport into CSF is saturable and this transport is important in the regulation of CSF [Ca].

Animals↗
PubMed1991

Affinity of antineoplastic amino acid drugs for the large neutral amino acid transporter of the blood-brain barrier.

The relative affinity of six anticancer amino acid drugs for the neutral amino acid carrier of the blood-brain barrier was examined in rats using an in situ brain perfusion technique. Affinity was evaluated from the concentration-dependent inhibition of L-[14C]-leucine uptake into rat brain during perfusion at tracer leucine concentrations and in the absence of competing amino acids. Of the six drugs tested, five, including melphalan, azaserine, acivicin, 6-diazo-5-oxo-L-norleucine, and buthionine sulfoximine, exhibited only low affinity for the carrier, displaying transport inhibition constants (Ki, concentrations producing 50% inhibition) ranging from 0.09 to 4.7 mM. However, one agent - D,L-2-amino-7-bis[(2-chloroethyl)amino]- 1,2,3,4-tetrahydro-2-naphthoic acid (D,L-NAM) - demonstrated remarkably high affinity for the carrier, showing a Ki value of approximately 0.2 microM. The relative affinity (1/Ki) of D,L-NAM was greater than 100-fold that of the other drugs and greater than 10-fold that of any compound previously tested. As the blood-brain barrier penetrability of most endogenous neutral amino acids is related to their carrier affinity, the results suggest that D,L-NAM may be a promising agent which may show enhanced uptake and distribution to brain tumors.

2-Naphthylamine↗
PubMed1991

Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism.

To evaluate the potential contribution of circulating kynurenines to brain kynurenine pools, the rates of cerebral uptake and mechanisms of blood-brain barrier transport were determined for several kynurenine metabolites of tryptophan, including L-kynurenine (L-KYN), 3-hydroxykynurenine (3-HKYN), 3-hydroxyanthranilic acid (3-HANA), anthranilic acid (ANA), kynurenic acid (KYNA), and quinolinic acid (QUIN), in pentobarbital-anesthetized rats using an in situ brain perfusion technique. L-KYN was found to be taken up into brain at a significant rate [permeability-surface area product (PA) = 2-3 x 10(-3) ml/s/g] by the large neutral amino acid carrier (L-system) of the blood-brain barrier. Best-fit estimates of the Vmax and Km of saturable L-KYN transfer equalled 4.5 x 10(-4) mumol/s/g and 0.16 mumol/ml, respectively. The same carrier may also mediate the brain uptake of 3-HKYN as D,L-3-HKYN competitively inhibited the brain transfer of the large neutral amino acid L-leucine. For the other metabolites, uptake appeared mediated by passive diffusion. This occurred at a significant rate for ANA (PA, 0.7-1.6 x 10(-3) ml/s/g), and at far lower rates (PA, 2-7 x 10(-5) ml/s/g) for 3-HANA, KYNA, and QUIN. Transfer for KYNA, 3-HANA, and ANA also appeared to be limited by plasma protein binding. The results demonstrate the saturable transfer of L-KYN across the blood-brain barrier and suggest that circulating L-KYN, 3-HKYN, and ANA may each contribute significantly to respective cerebral pools. In contrast, QUIN, KYNA, and 3-HANA cross the blood-brain barrier poorly, and therefore are not expected to contribute significantly to brain pools under normal conditions.

Animals↗
PubMed1991

Saturable transport of manganese(II) across the rat blood-brain barrier.

Unanesthetized adult male rats were infused intravenously with solutions containing 54Mn (II) and one of six concentrations of stable Mn(II). The infusion was timed to produce a near constant [Mn] in plasma for up to 20 min. Plasma was collected serially and on termination of the experiment, samples of CSF, eight brain regions, and choroid plexus (CP) were obtained. Influx of Mn (JMn) was calculated from uptake of 54Mn into tissues and CSF at two different times. Plasma [Mn] was varied 1,000-fold (0.076-78 nmol/ml). Over this plasma concentration range, JMn increased 123 times into CP, 18-120 times into brain, and 706 times into CSF. CP and brain JMn values fit saturation kinetics with Km (nmol/ml) equal to 15 for CP and 0.7-2.1 for brain, and Vmax (10(-2) nmol.g-1.s-1) of 27 for CP and 0.025-0.054 for brain. Brain JMn except at cerebral cortex had a nonsaturable component. CSF JMn varied linearly with plasma [Mn]. These findings suggest that Mn transport into brain and CP is saturable, but transport into CSF is nonsaturable.

Animals↗
PubMed1991

Regional blood-brain barrier transport of cationized bovine serum albumin in awake rats.

Regional blood-brain barrier permeability-surface area products (PAs) of cationized bovine serum albumin (cBSA) with isoelectric point (pI) approximately 8 or greater than or equal to 11 and of native bovine serum albumin (nBSA;pI approximately 4) were determined in awake male Sprague-Dawley rats after bolus intravenous injection. The albumins were labeled with 125I. Brain uptakes were assessed by autoradiography and by direct assay of radioactivity in brain regions. nBSA uptake into brain was statistically insignificant over 3 h, whereas cBSA uptake was significantly even at 6 min. Mean PA values of cBSA with pI approximately 11 (1.69-2.65 x 10(-5) ml.s-1.g-1) in most brain regions were twofold higher than PAs of cBSA with pI approximately 8 (0.98-1.37 x 10(-5) ml.s-1.g-1), whereas mean PA for nBSA did not differ significantly from zero. Autoradiographs of brain slices and net distributions in brain compartments at 6 and 30 min after injection suggested that cBSA entered the brain parenchyma via blood vessels and cerebrospinal fluid but that the former was the main route. The results quantitate for the first time regional brain PA values for cationized proteins and suggest specific mechanisms at cerebral blood vessels that distinguish transport of cationized from noncationized macromolecules.

Animals↗
PubMed1991

Elevation of brain manganese in calcium-deficient rats.

Rats, 3 weeks of age, consumed diets low or normal in calcium (Ca) with or without supplemental manganese (Mn) as Mn (II) acetate in drinking water. After 6 weeks, the animals were killed and [Mn] was determined in 8 brain regions, spinal cord, liver, serum, kidney, femur, and skeletal muscle. Serum [Mn] increased 1.5-, 4-, and 40-fold respectively, in normal Ca-supplemented Mn rats, low Ca rats, and low Ca-supplemented Mn rats. Elevation of tissue [Mn] occurred in all experimental groups with the greatest changes in the low Ca-extra Mn group: 6 - 12 fold in brain and spinal cord, and 2.5 - 140 fold in muscle, liver, kidney, and femur. Ratios of serum [Mn]/tissue [Mn] decreased as serum [Mn] increased suggesting saturable distribution. The findings suggest that Ca deficiency may cause Mn neurotoxicity by increasing dietary Mn absorption and brain [Mn].

Animals↗
PubMed1991

L-methionine uptake by human cerebral cortex: maturation from infancy to old age.

Age-associated changes in amino acid transport from blood to normal frontal cortex were studied using positron emission tomography (PET). Seventeen patients, 1.8-71 yr, were injected intravenously with tracer doses of [11C] L-methionine and a baseline PET scan was obtained. To assess competitive inhibition of [11C]L-methionine uptake, patients received either oral L-phenylalanine or an i.v. infusion of amino acids 1 hr before a second PET study. Uptake of [11C]L-methionine by frontal cortex decreased seven-fold between 1.8 and 71 yr (r = -0.71; p less than 0.05). Blood-to-brain transfer of [11C]L-methionine, at 4.5 yr, exceeded mean adult values by more than five-fold. Competitive inhibition reduced L-methionine uptake in all patients older than 4.6 yr. These developmental changes parallel findings in animals. The neutral amino acid transport system may modulate human brain amino acid levels to meet changing developmental metabolic needs.

Adult↗
PubMed1990

Brain uptake and anticancer activities of vincristine and vinblastine are restricted by their low cerebrovascular permeability and binding to plasma constituents in rat.

Unidirectional blood-brain barrier transfer of the lipophilic anticancer agents vincristine and vinblastine was studied in anesthetized rats, using an isolated, in situ brain perfusion technique. Drug binding to plasma constituents was also measured. Despite the high lipophilicity of these agents (the log octanol/physiological saline partition coefficient equalled 2.14 and 1.68, respectively), the cerebrovascular permeability-surface area product, PA, of vincristine in plasma was only 0.49 x 10(-4) ml s-1 g-1 for parietal cerebral cortex, whereas that of vinblastine was too low for determination. These values are similar to those of water-soluble, poorly diffusible nonelectrolytes. The PAs were significantly higher in the absence of plasma protein, being 1.24 x 10(-4) and 5.36 x 10(-4) ml s-1 g-1, respectively. Even these values, determined by brain perfusion of protein-free buffer, were lower than would be expected from the lipophilicity of the agents. The results suggest that additional factors, such as steric hindrance and molecular charge distribution, related to the chemical and geometric structure and the large size of vincristine and vinblastine (molecular weight, 825 and 814 daltons, respectively) restrict their passage across the blood-brain barrier. As a consequence of their paradoxically low permeability at the blood-brain barrier and restrictive binding to plasma and blood constituents, doses of both agents that cause significant inhibition of extracerebral Walker 256 carcinosarcoma tumor implants in rat have no effect on tumor located in the brain.

Animals↗
PubMed1990

Facilitated transport of L-phenylalanine across blood-nerve barrier of rat peripheral nerve.

L-Phenylalanine transport across the blood-nerve barrier was studied by perfusing Ringer solution containing trace amounts of L-[14C]phenylalanine and [3H]dextran (a vascular marker) through the hindlimb of an anesthetized rat. At the end of perfusion, a segment of sciatic nerve was removed, frozen, desheathed, and processed for radioactivity counting. The permeability-surface area product of the blood-nerve barrier (PABNB) to L-[14C]phenylalanine decreased from 58 +/- 9 X 10(-5) to 1.7 +/- 0.3 X 10(-5) (SE) ml.s-1.g wet wt-1, as the perfusate concentration of unlabeled L-phenylalanine was increased to 10 mM. D-Phenylalanine had less of an inhibitory effect on L-[14C]phenylalanine uptake than did L-phenylalanine. PABNB did not change in the presence of 50 mM alpha-(methylamino)isobutyric acid (MeAIB) in the perfusion medium, nor by replacing NaCl by Tris.HCl. However, addition of 50 mM 2-aminobicyclo(2,2,1)heptane-2-carboxylic acid (BCH) reduced PABNB to 2.1 +/- 0.3 X 10(-5) ml.s-1.g wet wt-1 (n = 4). PA at epiperineurial barrier (PAper) of L-[14C]phenylalanine at the epiperineurial barrier, determined from in situ incubation, was 1.4 +/- 0.2 X 10(-5) ml.s-1.g wet wt-1 (n = 6) and was unaffected by 10 mM L-phenylalanine concentration in the incubation medium. The results demonstrate for the first time carrier-mediated transport system for L-phenylalanine at the blood-nerve barrier of the rat peripheral nerve.

Amino Acids↗
PubMed1989

Uptake and concentrations of calcium in rat choroid plexus during chronic hypo- and hypercalcemia.

The choroid plexus has been implicated in the regulation of cerebrospinal fluid (CSF) [Ca], but little information is available concerning Ca transport by this epithelium. We determined the transfer coefficients for 45Ca uptake into choroid plexus from blood, as well as tissue [Ca], in weanling Fischer-344 rats fed low, normal, or high Ca diets for 8 weeks. Plasma [Ca] decreased by 45% with low Ca diet and increased by 25% with high Ca diet. Choroid plexus 45Ca uptake varied inversely with plasma [Ca]. This relation was due largely to changes in extracellular Ca binding rather than to entry from blood, as the transfer coefficient was independent of plasma [Ca]. The extracellular Ca distribution in choroid plexus, the intercept of a plot of tissue 45Ca distribution against time, was reciprocally related to plasma [Ca]. Changes in total cell [Ca] during hypercalcemia were equivalent to those in plasma, and in hypocalcemia were 70% of those in plasma. These findings indicate that regulation of CSF [Ca] does not involve saturable transport of Ca into the choroid epithelium from blood, and that the apical membrane of the choroid epithelium is involved in homeostasis of CSF [Ca].

Animals↗
PubMed1989

Structural specificity of sugar transport at the blood-nerve barrier.

The major component of D-glucose transfer across the membranous sites of the blood-nerve barrier (BNB) occurs via a facilitative mechanism at a rate greater than twice the rate of D-glucose metabolism by nerve. To characterize further properties of monosaccharide transport at the BNB, unidirectional transfer constant (K) values were determined in vivo in tibial nerve of anesthetized rats for radiolabeled mannitol, L-glucose, and a series of D-glucose analogs. K values(X 10(-4) mls-1 g-1) equaled 4.8 for 2-deoxy-D-glucose, 3.7 for D-glucose, 2.3 for 3-O-methyl-D-glucose, 1.4 for D-mannose, 0.6 for D-galactose, 0.2 for mannitol, and 0.19 for L-glucose. The rank order of ratios between K values of a D-hexose and D-glucose, which reflects the rank order of affinity of the system for individual sugars, was 2-deoxy-D-glucose greater than D-glucose greater than 3-O-methyl-D-glucose greater than D-mannose greater than D-galactose. The results demonstrate that the order of substrate affinity of the monosaccharide carrier at the BNB is similar to that at cerebral capillaries and at erythrocytes. At normal concentrations of plasma D-glucose, the contribution of simple passive diffusion to unidirectional D-glucose influx across the BNB equals 5%, which is greater than that at cerebral capillaries and reflects the greater permeability to hydrophilic nonelectrolytes of the endoneurial vasculature.

Animals↗
PubMed1989

Prevention of nerve edema and increased blood-nerve barrier permeability-surface area product in galactosemic rats by aldose reductase or thromboxane synthetase inhibitors.

Nerve water content and the permeability-surface area product (PA) to [3H]-or [14C]sucrose at the blood-nerve barrier were determined in unanesthetized control rats fed a normal diet and in rats fed galactose with or without an aldose reductase inhibitor (Statil or AL 1576) or a thromboxane synthetase inhibitor (CGS 12970). Nerve water content was determined by taking the difference between dry and wet weights of whole tibial nerves. PA was determined by an intravenous bolus injection of radiotracer with multiple-time-point graphic and quantitative autoradiographic methods. The mean nerve water content in galactosemic rats was 15% higher than in control rats after 7-11 mo on the diet. Statil and AL 1576 prevented nerve edema, but CGS 12970 was only partially effective in preventing an increase in nerve water content in galactose-fed rats. In galactosemic rats, the mean PA to sucrose at the blood-nerve barrier, calculated from nerve dry weight, was twofold higher than in control rats. Treatment with Statil, AL 1576, or CGS 12970 prevented increased PA. Our results suggest that nerve edema and increased blood-nerve barrier PA are secondary to polyol production and can be prevented by inhibiting aldose reductase.

Aldehyde Reductase↗
PubMed1988

Kinetics and distribution volumes for tracers of different sizes in the brain plasma space.

Regional brain and plasma concentrations were determined for a series of radiotracers that differ in molecular weight and size in pentobarbital-anesthetized rats at 1, 5 and 30 min after i.v. injection. The tracers, [3H]inulin (mol. wt. 5000 Da, radius 1.5 nm), 5 [3H]dextrans (10,000-200,000 Da, 2.3-9.5 nm) and [51Cr]transferrin (79,000 Da, 3.8 nm), are not taken up into erythrocytes and do not measurably cross the blood-brain barrier in 30 min. Results were expressed as a brain distribution volume, defined as (dpm/g brain)/(dpm/ml plasma). Within 1 min after injection, all tracers attained an initial distribution volume which varied regionally from 0.4 to 1.6 X 10(-2) ml/g. The volumes remained constant between 1 and 30 min for tracers with radii greater than or equal to 3.8 nm, whereas the volumes increased up to 90% for tracers with radii less than or equal to 3.1 nm. Rates of equilibration for tracers with radii less than or equal to 3.1 nm were size dependent with smaller tracers equilibrating before larger tracers. These results indicate that the brain distribution volume for plasma tracers consists of two compartments: one which is quickly filled (less than or equal to 1 min) by all tracers and comprises approximately 60% of the total volume, and one which allows only tracers with radii less than or equal to 3.1 nm and comprises 40% of the total volume. The inverse relation between the rate of equilibration in the second compartment and molecular size may indicate a diffusion limitation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗