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Biomedical subjects

M Salter

Publications and source records attributed to M Salter.

At least 19 recordsLinked to original sources
PubMed1995

The effects of a novel and selective inhibitor of tryptophan 2,3-dioxygenase on tryptophan and serotonin metabolism in the rat.

The effects of a novel inhibitor 680C91 ((E)-6-fluoro-3-[2-(3- pyridyl)vinyl]-1H-indole) of the key enzyme of tryptophan catabolism tryptophan 2,3-dioxygenase (TDO) (EC 1.13.11.11), were examined on tryptophan catabolism in vitro and in vivo and on brain levels of tryptophan, serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA). 680C91 was a potent (Ki = 51 nM) and selective TDO inhibitor with no inhibitory activity against indoleamine 2,3-dioxygenase (EC 1.13.11.17), monoamine oxidase A and B, 5-HT uptake and 5-HT1A,1D,2A and 2C receptors at a concentration of 10 microM. 680C91 had no effect on the binding of tryptophan to serum albumin in plasma and inhibited TDO competitively with respect to its substrate tryptophan. 680C91 inhibited the catabolism of tryptophan by rat liver cells and rat liver perfused in situ. The catabolism of L-[ring-2-14C]-tryptophan and a load dose of tryptophan (100 mg/kg) in vivo were inhibited by prior administration of 680C91. Administration of 680C91 alone produced marked increases in brain tryptophan, 5-HT and 5-HIAA. A load dose of tryptophan (100 mg/kg), producing increases in brain tryptophan 4-fold greater than that seen with 680C91, did not increase brain 5-HT and 5-HIAA to levels greater than those seen with 680C91 and produced a shorter-lasting increase in these parameters. These data therefore demonstrate the importance of TDO as a regulator of whole-body tryptophan catabolism and brain levels of tryptophan and 5-HT and suggest that a greater antidepressant efficacy might be achieved with inhibitors of TDO than tryptophan administration alone.

Animals↗
PubMed1995

The effects of an inhibitor of tryptophan 2,3-dioxygenase and a combined inhibitor of tryptophan 2,3-dioxygenase and 5-HT reuptake in the rat.

The effects of a novel inhibitor 680C91 ((E)-6-fluoro-3-[2-(3-pyridyl)vinyl]-1H-indole) of the key enzyme of tryptophan catabolism tryptophan 2,3-dioxygenase (TDO), and a novel inhibitor 709W92 ((E)-6-fluoro-3-[2-(4-pyridyl)vinyl]-1H-indole), of both TDO and 5-hydroxytryptamine (5-HT) reuptake, were examined on tryptophan catabolism, cerebrospinal fluid (CSF) concentrations of tryptophan and 5-HT and serotonergic-mediated physiology and behaviour in the rat. The catabolism of L-[ring-2-14C]tryptophan in vivo was completely inhibited by prior administration of 709W92. 709W92, but not 680C91, potentiated head-twitch produced by 5-hydroxytryptophan, prevented head-twitch and whole brain 5-HT depletion produced by p-chloroamphetamine and rapidly decreased dorsal raphe firing. Both 709W92 and 680C91 elevated CSF tryptophan by up to 260% of basal concentration. A maximally effective dose of 680C91 elevated a global measure of brain extracellular 5-HT (CSF 5-HT) to concentrations similar to those seen maximally after exogenous tryptophan administration (approx 170% of basal). Maximally effective doses of 709W92 increased CSF 5-HT to concentrations comparable to those seen after tryptophan and 5-HT reuptake inhibitor coadministration (approx 900% of basal) and to concentrations greater than those achieved maximally with serotonergically active antidepressant monotherapy (approx 500% of basal). 709W92 did not elevate CSF 5-HT to concentrations associated with the serotonin syndrome (approx 3000% of basal). The combined TDO inhibitor/5-HT reuptake inhibitor, 709W92, showed anxiolytic activity in the rat-pup vocalization model of anxiety. These results show that 709W92 (a novel inhibitor of both TDO and 5-HT reuptake), can produce an elevation of CSF 5-HT similar to that achieved with a serotonin reuptake inhibitor/tryptophan combination therapy but with a more sustained timecourse; such compounds may therefore have superior antidepressant efficacy in the clinic.

Animals↗
PubMed1995

Determination of brain nitric oxide synthase inhibition in vivo: ex vivo assays of nitric oxide synthase can give incorrect results.

The in vivo potencies of N omega-nitro-L-arginine (L-NA), N omega-monomethyl-L-arginine (L-NMMA) and N omega-iminoethyl-L-ornithine (L-NIO) against brain nitric oxide synthase (NOS) were determined by assessing their ability to inhibit harmaline-induced increases in rat cerebellar cGMP. L-NA, L-NIO and L-NMMA were all able to completely prevent the harmaline-induced increase in cGMP with ID50s of 0.5, 30 and 55 mg/kg, respectively, and with the same order of potency as that seen for inhibition of cerebellar NOS in vitro. The inhibitory effects of low doses of L-NA on cerebellar cGMP were maintained for at least 8 hr. The ID50 of L-NA for inhibition of cerebellar cGMP in vivo was similar to its ID50 for inhibition of cerebellar NOS ex vivo but only when NOS activity was assayed as an initial rate. However, doses of L-NMMA and L-NIO that inhibited harmaline-induced increases in cerebellar cGMP in vivo by 50% failed to inhibit NOS ex vivo. The methyl ester of L-NA, L-NAME, produced substantial inhibition of cerebellar NOS ex vivo when given either orally, intraperitoneally or intravenously but with a slower onset of action than L-NA. These results demonstrate that measurement of NOS activity ex vivo can accurately reflect the degree of inhibition of NOS in vivo with inhibitors that dissociate slowly from the enzyme such as L-NA, but only when the initial rate of NOS activity is measured.

Amino Acid Oxidoreductases↗
PubMed1995

Substantial regional and hemispheric differences in brain nitric oxide synthase (NOS) inhibition following intracerebroventricular administration of N omega-nitro-L-arginine (L-NA) and its methyl ester (L-NAME).

Nitric oxide synthase (NOS) enzyme activity was determined in a comprehensive selection of regions of the rat brain. The effects of lateral ventricular administration of N omega-nitro-L-arginine (L-NA, 30 micrograms) and its methyl ester (L-NAME, 3-100 micrograms) on NOS activity were examined in the ipsilateral and contralateral areas of 4 of these brain regions and in the cerebellum. NOS activity was determined using a new and rapid ex vivo assay method which ensures minimal dissociation of the enzyme-inhibitor complex. Following infusion of L-NAME, NOS activity was rapidly and dose-dependently inhibited in all brain regions studied (cerebral cortex, striatum, hippocampus, cerebellum and thalamus). However, NOS activity of brain regions within the contralateral hemisphere was inhibited significantly less than in ipsilateral regions, with the exception of the thalamus. The degree of NOS inhibition varied markedly between brain regions within each hemisphere and correlated with their ventricular proximity to the site of NOS inhibitor administration. Therefore, NOS in the thalamus was inhibited most effectively and NOS in the cerebral cortex the least. Within the cerebral cortex further regional differences could be observed, with NOS in the frontal/parietal areas inhibited more effectively than NOS in the temporal/occipital areas. Maximal inhibition of NOS was sustained for approx 6 hr after administration of 30 and 100 micrograms L-NAME. No inhibition of NOS was observed 24 hr after administration. Lateral ventricular administration of the metabolite and active moiety of L-NAME, L-NA, resulted in a similar degree of inhibition and time of inhibitory onset. In contrast, when L-NAME was administered i.p., a significant delay in the onset of NOS inhibition was observed in the above brain regions compared to L-NA. However, no regional or hemispheric differences in NOS inhibition were detected following peripheral administration of these inhibitors. These results indicate that central administration of NOS inhibitors yields a complex pattern of NOS inhibition and that data obtained on brain physiology following the i.c.v. administration of NOS inhibitors, or for that matter any other CNS effector, should therefore be interpreted with extreme caution.

Animals↗
PubMed1994

Potent and selective inhibition of human nitric oxide synthases. Selective inhibition of neuronal nitric oxide synthase by S-methyl-L-thiocitrulline and S-ethyl-L-thiocitrulline.

Potent and selective inhibition of neuronal nitric oxide synthase (nNOS) compared to endothelial NOS (eNOS) and inducible NOS (iNOS) may be useful to treat cerebral ischemia (stroke) and other neurodegenerative diseases. S-Methyl-L-thiocitrulline (Me-TC) and S-ethyl-L-thiocitrulline (Et-TC) inhibited the oxidation of L-arginine and the L-arginine-independent oxidation of NADPH by nNOS from human brain. Me-TC and Et-TC were slow, tight binding inhibitors of nNOS with second-order association rate constants (kon) of 2.6 x 10(5) M-1 s-1 and 1.3 x 10(5) M-1 s-1, respectively. The respective dissociation rate constants (koff) were 3 x 10(-4) s-1 and 0.7 x 10(-4) s-1. Thus, the Kd values calculated from koff/kon were 1.2 and 0.5 nM, respectively. L-Arginine was a competitive inhibitor of Me-TC and Et-TC binding with competition constant (Ks) values of 2.2 and 2.7 microM, respectively. The Km of nNOS for L-arginine was 1.6 microM. The active site concentration of nNOS was estimated by titration with Et-TC. Based on this active site concentration, a kcat of 0.4 s-1 for the oxidation of L-arginine, was calculated. Me-TC and Et-TC were less potent inhibitors of human iNOS (Ki values of 34 and 17 nM, respectively) and human eNOS (Ki values of 11 and 24 nM). Thus, Me-TC and Et-TC were 10- and 50-fold, respectively, more potent inhibitors of nNOS than eNOS. Furthermore, Me-TC was also 17-fold selective for rat nNOS in neuronal tissue compared to rat eNOS in vascular endothelium, suggesting that Me-TC may be selective for nNOS in vivo and therefore, may be therapeutically useful to treat neurodegenerative diseases.

Amino Acid Oxidoreductases↗
PubMed1993

A quantitative analysis of the control of glutamine catabolism in rat liver cells. Use of selective inhibitors.

1. At a physiological concentration of glutamine (0.5 mM), 87% of the total transport across the plasma membrane of liver cells isolated from fed rats involved the Na(+)-dependent system N; this was substantially inhibited by L-histidine. The residual Na(+)-independent component was attributed to system L on the basis of inhibition by 2-amino-2-norbornanecarboxylate and L-tryptophan. 2. Catabolism of glutamine by intact liver cells or by isolated mitochondria was inhibited by glutamate gamma-hydrazide with IC50 values of 13.7 +/- 3.5 microM and 22.6 +/- 3.8 microM respectively and a maximal inhibition of approx. 75%. The site of inhibition was identified as glutaminase; glutamate gamma-hydrazide inhibited this enzyme in cell-free extracts (IC50 37.8 +/- 7.7 microM) but had no activity against glutamate dehydrogenase or transport of glutamine, whether across mitochondrial or plasma membranes. 3. The major control site in cells from fed animals incubated with 0.5 mM L-glutamine was glutaminase (flux control coefficient 0.96). Appreciable control also resided in both plasma membrane transport systems, with coefficients of 0.51 for system N and -0.46 for system L, such that both interacted to provide a fine control of the intracellular concentration of the amino acid. Similar values were obtained by computer simulation based on theoretical determination of elasticities. 4. Previous controversy about the locus of regulation of hepatic glutamine metabolism is resolved by this distribution of control.

Animals↗
PubMed1991

Widespread tissue distribution, species distribution and changes in activity of Ca(2+)-dependent and Ca(2+)-independent nitric oxide synthases.

The distribution of Ca(2+)-dependent and Ca(2+)-independent nitric oxide synthase (NOS) was studied in rabbits and in control and endotoxin-treated rats and guinea-pigs. There was a widespread localization of NOS which differed for the two forms of the enzyme and which showed marked differences between species. Endotoxin induced the activity of the Ca(2+)-independent NOS in many tissues and also increased the activity of Ca(2+)-dependent NOS in the rat ileum and caecum. These results demonstrate the differential distribution of NOSs in control and endotoxin-treated animals and emphasize the widespread biological role of nitric oxide (NO).

Amino Acid Oxidoreductases↗
PubMed1991

A possible novel pathway of regulation by murine T helper type-2 (Th2) cells of a Th1 cell activity via the modulation of the induction of nitric oxide synthase on macrophages.

Murine peritoneal macrophages activated with interferon (IFN)-gamma and lipopolysaccharide (LPS) produce high levels of nitric oxide (NO) and are efficient in killing the intracellular protozoan parasites Leishmania major in vitro. Earlier studies have shown that NO, whose synthesis in murine macrophages is catalyzed by an inducible enzyme NO synthase, plays a major effector role in the host resistance against microbial infection. We now shown that both the NO synthesis and the leishmanicidal activity can be inhibited by prior treatment of the cells with recombinant interleukin 4 (IL4). IL4 treatment had no effect on the binding of IFN-gamma to macrophages but prevented the induction of NO synthase in these cells activated with IFN-gamma and LPS. Since IFN-gamma is produced by murine T helper type-1 (Th1) cells, whereas IL4 is secreted by Th2 cells, these results suggest a novel pathway by which Th2 cells regulate an activity of Th1 cells, namely by inhibiting the induction of NO synthase. These results may also account for the mechanism by which the disease-promoting Th2 cells counteract the host-protective effect of Th1 cells in leishmaniasis and other intracellular parasitic diseases.

Amino Acid Oxidoreductases↗
PubMed1991

Parents' worries about children compared to actual risks.

To investigate the concerns of parents, questionnaires were given to the "first 100" parents waiting for their child's pediatric appointment in four different medical settings. They were asked to rate whether they worry "frequently," "occasionally," or "not at all" about 17 physical health issues, 16 psychosocial problems, 7 possible injuries, 4 instances of victimization, and 4 questions about parents' ability to provide discipline, affection, values and financial support. The response rate was 94%; 89% were completed adequately for analysis. Parental concerns were compared to data from the National Center for Health Statistics about the statistical likelihood of the risks occurring. Ear infections (65%) were the most common health concern, followed by reaction to immunization (57%), common colds (51%), and cancer (50%). The greatest psychosocial concern was about children watching too much television (53%), followed by concerns about the quality of day care (50%). Three-quarters of parents worry about car accidents and 72% worry about abduction of their children. Parents worry significantly about their own contribution to their child's welfare: appropriate discipline (73%), affection (56%), values and being a role model (55%), and financial support (66%). Parents who had not completed high school worried more than parents who had more than a high school education (P less than 0.03).

Adolescent↗
PubMed1990

Anti-inflammatory glucocorticoids inhibit the induction by endotoxin of nitric oxide synthase in the lung, liver and aorta of the rat.

The induction by endotoxin of Ca2(+)-independent nitric oxide (NO) synthase in the lung and liver of the rat was prevented by the glucocorticoids dexamethasone and cortisol but not by progesterone. The activity of the constitutive Ca2(+)-dependent NO synthase in the brain and the aorta was not affected by treatment with either endotoxin or glucocorticoids. In the aorta a Ca2(+)-independent NO synthase was also found following endotoxin treatment of rats, and this induction was likewise prevented by dexamethasone. The Ca2(+)-dependent NO synthase in the aorta was located in the vascular endothelium, whereas the Ca2(+)-independent enzyme was predominantly located in the vascular smooth muscle layer. Inhibition of induction of the Ca2(+)-independent NO synthase in vivo may underlie some of the physiological and pharmacological effects of the anti-inflammatory glucocorticoids.

Amino Acid Oxidoreductases↗
PubMed1990

Differential induction of brain, lung and liver nitric oxide synthase by endotoxin in the rat.

Nitric oxide (NO) synthase in rat brain was found to be constitutive and Ca2(+)-dependent. The enzyme in rat lung or liver (predominantly in parenchymal cells) was not constitutive, but was induced by endotoxin treatment and was Ca2(+)-independent. The NO synthases in rat brain and liver or lung are therefore distinct both in their properties and in their regulation.

Amino Acid Oxidoreductases↗
PubMed1989

How does displacement of albumin-bound tryptophan cause sustained increases in the free tryptophan concentration in plasma and 5-hydroxytryptamine synthesis in brain?

Models of tryptophan catabolism and binding to serum albumin are presented to explain the observed effect of displacement of tryptophan from albumin on the concentrations of free and bound tryptophan and on the rate of 5-hydroxytryptamine (5-HT) synthesis from tryptophan in the brain. A rapid rate of dissociation of tryptophan from albumin (compared to the transit time of tryptophan through the liver) and a large fractional extraction of the free pool of tryptophan during passage through the liver are shown to be necessary factors in determining the effects observed. Because of the low fractional extraction of free tryptophan in the brain, the synthesis of 5-HT will be dependent only upon the free pool of tryptophan. Dissociation of tryptophan from albumin only causes a sustained increase in 5-HT synthesis in the brain because of the effect that this dissociation has on hepatic tryptophan catabolism and thereby on the free pool of tryptophan.

Animals↗