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T M Smith

Publications and source records attributed to T M Smith.

At least 73 records · Page 4Linked to original sources
PubMed1989

Adrenergic receptors mediate changes in c-fos mRNA levels in brain.

Recent evidence supports a role for transient c-fos expression as one step in signalling pathways by which membrane receptor-ligand interactions are transduced into appropriate intracellular responses. The activity of adrenergic receptors is mediated by second messenger systems which include ion fluxes, changes in cAMP concentration and enhanced phosphoinositide turnover. In order to determine if C-fos induction was also a step in adrenergic signal transduction in the brain, we performed in vivo studies with drugs specific for different adrenergic receptor types. Unexpectedly, we found that the stress associated with a single intraperitoneal (i.p.) injection of drug vehicle produced a transient increase (averaging 4.0-fold) in c-fos mRNA levels in rat brain. Injection of the alpha 2-adrenoreceptor antagonist, yohimbine, produced a transient increase which was larger in magnitude (averaging 9.6-fold) and longer in duration than that produced by injection of the drug vehicle alone. In experiments designed to ask whether either of these inductions was mediated by specific types of adrenergic receptors, we found that the alpha 2- and beta-adrenoreceptors were involved in both responses, while the alpha 1-receptor played a role in mediating the yohimbine induction, but no detectable role in the solvent induction. One hypothesis consistent with our results is that the norepinephrine (NE) released due to the stress associated with an i.p. injection interacts with postsynaptic beta-adrenergic receptors, resulting in the observed c-fos mRNA induction. When the negative feedback effect of NE, mediated by presynaptic alpha 2-receptors, is blocked by yohimbine, the postsynaptic response is enhanced and prolonged.

Adrenergic alpha-Antagonists↗
PubMed1989

AY-31,906, a novel high ceiling diuretic: characterization of its relative potassium-sparing actions in rats and dogs.

AY-31,906, exo-2-amino-4-[(bicyclo[2.2.1]hept-2-yl)amino-N-[[1- methylethyl)amino]carbonyl]-5-pyrimidinesulfonamide, exhibited potent diuretic and natriuretic activity in rats and dogs. After p.o. administration, AY-31,906 was 1.5- and 12.3-times more potent as a natriuretic than furosemide in rats and dogs, respectively, whereas it was 0.5- and 6.1-times as potent after i.v. administration. The maximum natriuretic effect of AY-31,906 in both species was similar to that observed with furosemide. At equiactive natriuretic p.o. doses in both species, AY-31,906 produced a greater increase in the urinary ratio of Na/K than furosemide, indicating a relative potassium-sparing effect. AY-31,906 produced significant increases in the fractional excretion of sodium and chloride in dogs at a dose that produced no statistically significant changes in the fractional excretion of potassium, glomerular filtration rate or renal plasma flow. After p.o. administration, the onset of activity of AY-31,906 occurred within the 1st hr in both rats and dogs and preliminary data demonstrated that the activity lasted for approximately 2 hr in rats and 4 hr in dogs. Clearance studies in conscious dogs suggest that AY-31,906 inhibited electrolyte reabsorption in the ascending limb of the loop of Henle and, unlike furosemide, AY-31,906 had no activity at the proximal tubule. These results indicate that AY-31,906 is a potent, high ceiling diuretic with relative potassium-sparing properties. The compound is well absorbed after p.o. administration with diuretic activity occurring in the 1st hr.

Animals↗
PubMed1988

Differential expression of Ustilago maydis DNA sequences during induction of nitrate reductase enzyme activity.

A differential hybridisation screen of an Ustilago maydis genomic DNA library was used to identify DNA sequences transcribed at higher levels under growth conditions which induce nitrate reductase activity. After two rounds of screening, four different sequences showed a strongly enhanced hybridisation signal with an induced cDNA probe relative to a repressed cDNA probe. The sequence in plasmid pMH3007 hybridised to a U. maydis RNA transcript of a 4.2 kb. This is identical in size to a transcript, also nitrate inducible, which hybridised to cloned Aspergillus nidulans nitrate reductase gene sequences at a reduced stringency.

Basidiomycota↗
PubMed1987

Correlation of type A behaviour with adrenergic receptor density: implications for coronary artery disease pathogenesis.

In 17 healthy young men who had a parent with documented early coronary disease, ratings of type A behaviour correlated with upregulated lymphocyte beta 2 receptor density and inversely with the ratio of platelet alpha 2 to lymphocyte beta 2 receptor density ratio. This indicates a correlation of type A behaviour with receptor-based determinations of increased peripheral alpha-adrenergic balance, consistent with increased coronary arterial vasoconstriction, perhaps leading to coronary artery disease.

Adult↗
PubMed1987

Glutathione S-transferases in human prostate.

A number of human prostatic tissue biopsies have been analyzed for glutathione S-transferase activity, using 1-chloro-2,4-dinitrobenzene (CDNB) as a substrate. Samples from nine patients (age range 61-90) with benign prostatic hypertrophy who had received no prior chemotherapy had a mean glutathione S-transferase activity of 137 +/- 44 nmol/min per mg with a range of 97-237. A qualitative comparison of the glutathione S-transferase of normal prostate and benign prostatic hypertrophy samples was carried out. Approximately 260-fold purification was achieved using glutathione-Sepharose affinity chromatography, with glutathione S-transferase accounting for approximately 0.19-0.33% of the total protein. Substrate specificity determinations suggested similar, but not identical, glutathione S-transferase subunits in normal prostate and benign prostatic hypertrophy. One- and two-dimensional electrophoresis (isoelectric focusing and 12.5% SDS-polyacrylamide gel electrophoresis) identified at least seven stained polypeptides in the purified glutathione S-transferase preparations. These ranged in Mr from approximately 24,000 to 28,500 and in pI from near neutral to basic. Western blot analysis using polyclonal antibodies raised against rat liver glutathione S-transferase suggested crossreactivity with five of the human isoenzymes in both normal prostate and benign prostatic hypertrophy. One of the glutathione S-transferases, present in both normal prostate and benign prostatic hypertrophy, had an Mr of approx. 24,000 and a near-neutral pI and crossreacted immunologically with a polyclonal antibody raised against human placental glutathione S-transferase (Yf, subunit 7 or pi). These data suggest that four glutathione S-transferases are expressed in human prostate, with subunits from each of the major classes alpha, mu and pi. These are characterized as Ya, Yb, Yb' and Yf (analogous alternative nomenclature subunits 1, 3, 4 and 7).

Aged↗
PubMed1986

Characterization of rat schwannoma-Schwann cell hybrids.

Sciatic nerve Schwann cells from strain LEC rats, homozygous for the c form of 6-phosphogluconate dehydrogenase (6-PGD), and RN22 rat Schwannoma cells, a subclone of RN2 deficient in hypoxanthine phosphoribosyltransferase and expressing the s form of 6-PGD, were fused to produce 'RNS' hybrid clones which proliferate rapidly in a medium containing hypoxanthine, aminopterin and thymidine (HAT) and express c, s and c/s heterodimeric forms of 6-PGD. RNS cells, like both parents, maintain a high baseline activity of 2', 3'-cyclic nucleotide 3'-phosphohydrolase and, as in RN22, activity of this enzyme is further inducible by 1 mM N6, O2'-dibutyryl 3', 5'-cyclic AMP. The RNS clones resemble normal Schwann cells in the capacity to bind radioiodinated axolemmal fragments to their plasma membranes.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1986

Brain regional [3H]flunitrazepam binding in rats chronically treated with bupropion or B.W.306U.

After 21 days of twice daily i.p. injections of bupropion (10 mg/kg), B.W.306U (10 mg/kg) or saline, 5 rat brain regions were removed for [3H]flunitrazepam binding assay. Scatchard analysis of the binding data revealed no change in the Bmax in any brain regions in drug-treated rats compared to controls. There was, however, a significant change in the Kd value in the limbic forebrain of B.W.306U-treated rats.

Animals↗
PubMed1986

Effect of plasma from patients containing bupropion and its metabolites on the uptake of norepinephrine.

The uptake of norepinephrine into cortical punches from the brain of the rat was studied in the presence of buffer and plasma from patients containing bupropion and its metabolites. Even though bupropion and its metabolite (compound II) were equipotent in inhibiting the uptake of NE in buffer, compound II was twice as active as bupropion in the presence of human plasma. When the inhibition of uptake of NE in the presence of plasma, obtained from patients on bupropion on steady-state, was correlated with levels of bupropion and its metabolites (II, III, IV) a highly significant correlation was seen in the presence of compound II. Since this compound accumulated in plasma from patients 20-100 times that of the parent compound, the mode of action of bupropion may in part be due to the effect of this compound on the uptake of NE.

Animals↗
PubMed1986

Down regulation of beta-receptors by bupropion and its major metabolite in mouse brain.

Mice were treated with bupropion Compound II (major metabolite of bupropion) or desmethylimpramine (DMI) twice a day intraperitoneally for either 1 or 3 weeks. The binding of dihydroalprenolol and spiroperidol in the frontal cortex and limbic forebrain areas were analyzed. There was a significant reduction in beta-receptors in the frontal cortex induced by DMI at both times examined. Bupropion showed a significant reduction of beta-receptor in the frontal cortex by 3 weeks. Though propiophenone did not have any significant effect on beta-receptors in the frontal cortex, it down-regulated beta-receptors in the limbic forebrain area significantly by 1 and 3 weeks. There was no significant effect of buropion or propiophenone on the binding of spiroperidol either in the cortex (S2 receptor) or in the limbic forebrain (dopaminergic). These results show that bupropion may exert part of its clinical effect through its metabolite propiophenone.

Animals↗
PubMed1986

Insulin-like growth factor I/somatomedin C: a potent inducer of oligodendrocyte development.

Cell cultures established from cerebrum of 1-day-old rats were used to investigate hormonal regulation of the development of oligodendrocytes, which synthesize myelin in the central nervous system. The number of oligodendrocytes that developed was preferentially increased by insulin, or by insulin-like growth factor I (IGF-I), also known as somatomedin C. High concentrations (5 micrograms/ml) of insulin were required for substantial induction of oligodendrocyte development, whereas only 3.3 ng of IGF-I per ml was needed for a 2-fold increase in oligodendrocyte numbers. At an IGF-I concentration of 100 ng/ml, oligodendrocyte numbers were increased 6-fold in cultures grown in the presence of 10% fetal bovine serum, or up to 60-fold in cultures maintained in serum-free medium. IGF-I produced less than a 2-fold increase in the number of nonoligodendroglial cells in the same cultures. Type I IGF receptors were identified on oligodendrocytes and on a putative oligodendrocyte precursor cell population identified by using mouse monoclonal antibody A2B5. These results indicate that IGF-I is a potent inducer of oligodendrocyte development and suggest a possible mechanism based on IGF deficiency for the hypomyelination that results from early postnatal malnutrition.

Animals↗
PubMed1985

Trazodone and m-chlorophenylpiperazine. Concentration in brain and receptor activity in regions in the brain associated with anxiety.

Trazodone, its active metabolite 1-(m-chlorophenyl)piperazine (mCPP) and two isomers of mCPP were tested for affinity to the binding sites for [3H]flunitrazepam ([3H]FLU) and [3H]p-aminoclonidine ([3H]pAC) in the frontal cortex, amygdala and hippocampus of the rat. When tested at the binding site for [3H]flunitrazepam, trazodone showed an average IC50 of 1.7 mM in all three regions of the brain while mCPP yielded an average IC50 of 0.36 mM. These same two compounds, when tested at the binding site for [3H]p-aminoclonidine, resulted in an average IC50 of 4.5 microM for trazodone and 0.6 microM for mCPP. When plasma values of trazodone and mCPP in the rat were similar to those obtained in patients given therapeutic doses, the concentrations of trazodone were found to be between 6 and 7 microM and between 2 and 3 microM for mCPP in the same brain regions of the brain used in the binding assays. Thus, a sufficient concentration of trazodone and mCPP can accumulate in brain tissue to displace approx. 50% of the [3H]p-aminoclonidine from its binding site but very little [3H]flunitrazepam from its binding site. These results, combined with the reported anxiolytic effects of the alpha-2 agonist, clonidine and the noradrenergic hyperactivity theory of anxiety, indicate that the mechanism of the anxiolytic activity of trazodone, may be a direct action on the central alpha-2 binding site.

Animals↗
PubMed1985

[3H]-Flunitrazepam binding in the presence of beta-phenylethylamine and its metabolites.

It has recently been reported that the concentration of beta-phenylethylamine (PEA) was elevated in the plasma of an individual experiencing convulsions because of an overdose of tranylcypromine. Also, high concentrations of PEA, injected into mice, were reported to induce convulsions. This convulsive effect was prevented by pretreatment with the benzodiazepines diazepam and chlordiazepoxide. In this study, PEA in concentrations from 0.5 to 100 microM failed to alter the binding of [3H]-flunitrazepam ([3H]-FLU) in membrane preparations from mouse rostral forebrain. The metabolites of PEA: phenylacetic acid, phenylethanolamine, octopamine and tyramine, also failed to affect [3H]-FLU binding. This suggests that although there are substances that act as convulsants by interacting with the benzodiazepine receptor sites, the convulsant effect of PEA and its metabolites is mediated elsewhere.

Animals↗
PubMed1985

Absorption of calcium from milk and yogurt.

An increased prevalence of osteoporosis has been observed in lactase-deficient subjects. This association has been attributed to an avoidance of calcium-containing dairy products by lactase-deficient subjects and/or an adverse affect of lactose malabsorption on calcium absorption. Because the lactose in yogurt can be digested and absorbed by hypolactasic subjects, we tested the ability of lactase-deficient subjects and controls to absorb calcium from milk and yogurt. Subjects ingested 270 mg of Ca plus 45Ca in 250 g of milk or 147 g of commercial, unflavored yogurt, and blood radioactivity was assessed at intervals over 24 h. Based on the areas under the blood radioactivity curves, lactase-deficient subjects and controls absorbed calcium equally well from yogurt and milk. Lactase-deficient subjects absorbed 45Ca from both sources at least as well as did the controls. While we found no evidence to indicate that calcium in yogurt is better absorbed than calcium in milk, yogurt remains an excellent source of calcium because this fermented product is well tolerated by lactase-deficient subjects.

Adult↗
PubMed1985

Induction of myelin components: cyclic AMP increases the synthesis rate of 2',3'-cyclic nucleotide 3'-phosphohydrolase in C6 glioma cells.

In an effort to determine the factors that stimulate myelin synthesis, we investigated the mechanism by which dibutyryl cyclic AMP induces the activity of the myelin enzyme, 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP; EC 3.1.4.37), in C6 glioma cells. Immunotitration experiments and measurements of the accumulation of [35S]methionine-labeled CNP showed that dibutyryl cyclic AMP increased the amount of CNP in the cells but not the catalytic activity per molecule of the enzyme. Moreover, inhibition of protein synthesis with cycloheximide abolished induction of enzyme activity. Dibutyryl cyclic AMP doubled the rate of CNP synthesis but had no effect on the half-life of the enzyme (approximately 33 h). The induction was partially blocked by the inhibitors of mRNA synthesis, cordycepin or alpha-amanitin. Thus, cyclic AMP induces the synthesis of CNP.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
PubMed1983

Differential inhibition of brain specific [3H]flunitrazepam binding by several types of dyes.

Several dyes, representing different structural classes, inhibit [3H]flunitrazepam binding to brain specific receptors in the rat with 50% inhibition in the 1 to 100 microM range. Crystal Violet and Methyl Violet 2B inhibited more potently in the forebrain than in the cerebellum. Congo Red yielded a Hill number near 2.3, probably reflecting positive cooperativity between interacting binding sites in benzodiazepine receptor complexes. Toluidine Blue 0 was the most potent of the dyes tested (IC50 = 1 microM in cerebellum) and inhibited more potently in cerebellum than in forebrain.

Animals↗