Decrease In Tissue Concentration Research Articles

Paradigm shift in understanding hyaluronic acid filler effects

Hyaluronic acid (hyaluron; HA) is an important constituent of the extracellular matrix and has an age-dependent decrease in tissue concentration. While natural HA is rapidly degraded, filler cross-linked HA achieve ahalf-life of 6-12months. Such fillers enjoy increasing popularity in esthetic medicine and are versatile tools. Although HA fillers can activate fibroblasts it is of minor importance for long-term results. Fillers are injected into subcutaneous adipose tissue. Their interaction with somatic stem cells and mature adipocytes has gained increasing interest. Cross-linked HA can indeed support proliferation of pre-adipocytes, stimulate their differentiation into mature adipocytes and protect the mature cells from senescence, apoptosis and lipolysis. This view offers anew perspective on the development of future fillers for esthetic medicine.

The Effect of Aerobic Training and Tribulus terrestris Extract on Some Oxidative Stress Indices in the Heart Tissue of Male Wistar Rats Poisoned with Hydrogen Peroxide

Background: Oxidative stress plays a key role in cardiovascular diseases. Hydrogen peroxide poisoning also increases oxidative stress. In contrast, aerobic exercise and the use of Tribulus terrestris (Tt) extract can individually play an antioxidant defense balance. Objectives: The aim of this study was to investigate the simultaneous effect of aerobic training (AT), and alcoholic extract of Tt on some oxidative stress indices in the heart tissue of hydrogen peroxide poisoned male Wistar rats. Methods: Forty-two male Wistar rats were randomly divided into seven groups, including (1) healthy-control, (2) H2O2, (3) H2O2 + AT, (4) H2O2 + Tt 1 (5 mg/kg), (5) H2O2 + Tt 2 (10 mg/kg), (6) H2O2 + AT + Tt 1, and (7) H2O2 + AT + Tt 2. The AT protocol consisted of eight weeks (5 sessions per week) of treadmill running at 20 m/min for 60 minutes per session. Tissue samples were collected to measure oxidative stress indices. Two-way analysis of variance was used for statistical analysis. Results: A significant decrease in tissue concentration of cytochrome C (ng/mL), MDA (Pmol/mL), PAB index (HK), while an increase in tissue concentration of ATP (µM) was observed in the H2O2 + AT + Tt 2 group compared to other groups (P ≤ 0.05). Conclusions: Combining AT and Tt can be a good strategy to reduce the complications of hydrogen peroxide poisoning. Because the observed changes were far from complete improvement compared to the healthy control group, it is likely that longer treatment periods and higher drug doses should be used. Future studies should use Tribulus terrestris (Tt) supplementation in addition to Tribulus terrestris (Tt) intake prior to training sessions.

Silicon Influences Soil Availability and Accumulation of Mineral Nutrients in Various Plant Species.

Silicon (Si) effects on mineral nutrient status in plants are not well investigated. It is known that Si has a beneficial effect on plants under stressed conditions. The aim was to make a state of the art investigation of the Si influence: (1) on nutrient availability in four different soil types, namely clayish, sandy, alum shale and submerged soil; and (2) on accumulation of various nutrients in maize, lettuce, pea, carrot and wheat growing in hydroponics. Soil was treated with K2SiO3 corresponding to 80 and 1000 kg Si ha−1 and the nutrient medium with 100, 500, 1000 and 5000 μM Si. In general, Si effects were similar in all analyzed plant species and in all soil types tested. Results showed that, in soil, Si increased the availability of Ca, P, S, Mn, Zn, Cu and Mo and that of Cl and Fe tended to increase. The availability of K and Mg was not much affected by Si. Uptake from solution of S, Mg, Ca, B, Fe, and Mn increased; N, Cu, Zn and K decreased; P decreased/increased; and Cl and Mo was not influenced. Translocation to shoot of Mg, Ca, S, Mn, and Mo increased; Fe, Cu and Zn decreased; and K, P, N, Cl and B was not affected. It was concluded that, if plants had been cultivated in soil, Si-maintained increased availability of nutrients in the soil solution would probably compensate for the decrease in tissue concentration of those nutrient elements. The study shows that Si also influences the nutrient uptake in non-stressed plants.

Imaging Changes in Synaptic Acetylcholine Availability in Living Human Subjects

In vivo estimation of β(2)-nicotinic acetylcholine receptor availability with molecular neuroimaging is complicated by competition between the endogenous neurotransmitter acetylcholine and the radioligand (123)I-3-[2(S)-2-azetidinylmethoxy]pyridine ((123)I-5-IA). We examined whether binding of (123)I-5-IA is sensitive to increases in extracellular levels of acetylcholine in humans, as suggested in nonhuman primates. Six healthy subjects (31 ± 4 y) participated in a (123)I-5-IA SPECT study. After baseline scans, physostigmine (1-1.5 mg) was administered intravenously over 60 min, and 9 additional scans were obtained. We observed a significant reduction in the total volume of distribution after physostigmine administration (29% ± 17% in the cortex, 19% ± 15% in the thalamus, 19% ± 15% in the striatum, and 36% ± 30% in the cerebellum; P < 0.05). This reduction reflected a combination of a region-specific 7%-16% decrease in tissue concentration of tracer and a 9% increase in plasma parent concentration. These data suggest that increases in acetylcholine compete with (123)I-5-IA for binding to β(2)-nicotinic acetylcholine receptor. Additional validation of this paradigm is warranted, but it may be used to interrogate changes in extracellular acetylcholine.

Herb-Drug Interaction ofPaullinia cupana(Guarana) Seed Extract on the Pharmacokinetics of Amiodarone in Rats

Paullinia cupana is used in weight-loss programs as a constituent of medicinal/dietary supplements. This study aimed to assess a potential herb-drug interaction among a standardized (certified) Paullinia cupana extract and amiodarone (narrow therapeutic index drug) in rats. In a first pharmacokinetic study rats were simultaneously coadministered with a single dose of Paullinia cupana (821 mg/kg, p.o.) and amiodarone (50 mg/kg, p.o.), and in a second study rats were pretreated during 14 days with Paullinia cupana (821 mg/kg/day, p.o.) receiving amiodarone (50 mg/kg, p.o.) on the 15th day. Rats of the control groups received the corresponding volume of vehicle. Blood samples were collected at several time points after amiodarone dosing, and several tissues were harvested at the end of the experiments (24 h after dose). Plasma and tissue concentrations of amiodarone and its major metabolite (mono-N-desethylamiodarone) were measured and analysed. A significant reduction in the peak plasma concentration (73.2%) and in the extent of systemic exposure (57.8%) to amiodarone was found in rats simultaneously treated with Paullinia cupana and amiodarone; a decrease in tissue concentrations was also observed. This paper reports for the first time an herb-drug interaction between Paullinia cupana extract and amiodarone, which determined a great decrease on amiodarone bioavailability in rats.

A Randomized, Double-Blind, Placebo-Controlled Phase 3 Skin Cancer Prevention Study of α-Difluoromethylornithine in Subjects with Previous History of Skin Cancer

AbstractPreclinical studies have shown that the inhibition of ornithine decarboxylase (ODC) by α-difluoromethylornithine (DFMO) and resultant decreases in tissue concentrations of polyamines (putrescine and spermidine) prevents neoplastic developments in many tissue types. Clinical studies of oral DFMO at 500 mg/m2/day revealed it to be safe and tolerable and resulted in significant inhibition of phorbol ester–induced skin ODC activity. Two hundred and ninety-one participants (mean age, 61 years; 60% male) with a history of prior nonmelanoma skin cancer (NMSC; mean, 4.5 skin cancers) were randomized to oral DFMO (500 mg/m2/day) or placebo for 4 to 5 years. There was a trend toward a history of more prior skin cancers in subjects randomized to placebo, but all other characteristics including sunscreen and nonsteroidal anti-inflammatory drug use were evenly distributed. Evaluation of 1,200 person-years of follow-up revealed a new NMSC rate of 0.5 events/person/year. The primary end point, new NMSCs, was not significantly different between subjects taking DFMO and placebo (260 versus 363 cancers, P = 0.069, two-sample t test). Evaluation of basal cell (BCC) and squamous cell cancers separately revealed very little difference in squamous cell cancer between treatment groups but a significant difference in new BCC (DFMO, 163 cancers; placebo, 243 cancers; expressed as event rate of 0.28 BCC/person/year versus 0.40 BCC/person/year, P = 0.03). Compliance with DFMO was &amp;gt;90% and it seemed to be well tolerated with evidence of mild ototoxicity as measured by serial audiometric examination when compared with placebo subjects. The analysis of normal skin biopsies revealed a significant (P &amp;lt; 0.05) decrease in 12-0-tetradecanoylphorbol-13-acetate–induced ODC activity (month 24, 36, and 48) and putrescine concentration (month 24 and 36 only) in DFMO subjects. Subjects with a history of skin cancer taking daily DFMO had an insignificant reduction (P = 0.069) in new NMSC that was predominantly due to a marked reduction in new BCC. Based on these data, the potential of DFMO, alone or in combination, to prevent skin cancers should be explored further. Cancer Prev Res; 3(1); 35–47

Aberrant Insulin Receptor Signaling and Amino Acid Homeostasis as a Major Cause of Oxidative Stress in Aging

The mechanisms leading to the increase in free radical-derived oxidative stress in "normal aging" remains obscure. Here we present our perspective on studies from different fields that reveal a previously unnoticed vicious cycle of oxidative stress. The plasma cysteine concentrations during starvation in the night and early morning hours (the postabsorptive state) decreases with age. This decrease is associated with a decrease in tissue concentrations of the cysteine derivative and quantitatively important antioxidant glutathione. The decrease in cysteine reflects changes in the autophagic protein catabolism that normally ensures free amino acid homeostasis during starvation. Autophagy is negatively regulated by the insulin receptor signaling cascade that is enhanced by oxidative stress in the absence of insulin. This synopsis of seemingly unrelated processes reveals a novel mechanism of progressive oxidative stress in which decreasing antioxidant concentrations and increasing basal (postabsorptive) insulin receptor signaling activity compromise not only the autophagic protein catabolism but also the activity of FOXO transcription factors (i.e., two functions that were found to have an impact on lifespan in several animal models of aging). In addition, the aging-related decrease in glutathione levels is likely to facilitate certain "secondary" disease-related mechanisms of oxidative stress. Studies on cysteine supplementation show therapeutic promise.

Zinc mediated normalization of histoarchitecture and antioxidant status offers protection against initiation of experimental carcinogenesis

The present study evaluated the inhibitory effects of zinc on colonic antioxidant defense system and histoarchitecture during 1,2 dimethylhydrazine (DMH) induced colon carcinogenesis in male Spraque Dawley rats. The rats were segregated into four groups viz., normal control, DMH treated, zinc treated, DMH + zinc treated. Colon carcinogenesis was induced through weekly subcutaneous injections of DMH (30 mg/kg body weight) for 8 weeks. Zinc (in the form of zinc sulphate) was supplemented to rats at a dose level of 227 mg/l in drinking water, ad libitum for the entire duration of the study. Increased lipid peroxidation was accompanied by a decrease in reduced glutathione (GSH), glutathione reductase (GR), glutathione-s-transferase (GST), superoxide dismutase (SOD), and catalase. Administration of zinc to DMH treated rats significantly decreased the lipid peroxidation levels with simultaneous enhancement of GSH, GR, GST, SOD, and Catalase. Histopathological studies from DMH treated rats revealed disorganization of colonic histoarchitecture. However, zinc treatment to DMH treated rats greatly restored normalcy in the colonic histoarchitecture, with no apparent signs of abnormality. Energy Dispersive X-Ray Fluorescence (EDXRF) studies revealed a significant decrease in tissue concentrations of zinc in the colon following DMH treatment, which upon zinc supplementation were recovered to near normal levels. In conclusion, the results of this study suggest that zinc has a beneficial effect during the initiation of key events leading to the development of experimentally induced carcinogenesis.

Chemopreventive potential of zinc in experimentally induced colon carcinogenesis

The present study was performed to evaluate the efficacy of zinc treatment on colonic antioxidant defense system and histoarchitecture in 1,2-dimethylhydrazine- (DMH) induced colon carcinogenesis in male Sprague–Dawley rats. The rats were segregated into four groups viz., normal control, DMH treated, zinc treated, DMH + zinc treated. Colon carcinogenesis was induced through weekly subcutaneous injections of DMH (30 mg/kg body weight) for 16 weeks. Zinc (in the form of zinc sulphate) was supplemented to rats at a dose level of 227 mg/L in drinking water, ad libitum for the entire duration of the study. Increased tumor incidence, tumor size and number of aberrant crypt foci (ACF) were accompanied by a decrease in lipid peroxidation, glutathione- S-transferase, superoxide dismutase (SOD) and catalase. On the contrary, significantly increased levels of reduced glutathione (GSH) and glutathione reductase (GR) were observed in DMH treated rats. Administration of zinc to DMH treated rats significantly decreased the tumor incidence, tumor size and aberrant crypt foci number with simultaneous enhancement of lipid peroxidation, SOD, catalase and glutathione- S-transferase. Further, the levels of GSH and GR were also decreased following zinc supplementation to DMH treated rats. Well-differentiated signs of dysplasia were evident in colonic tissue sections by DMH administration alone. However, zinc treatment to DMH treated rats greatly restored normalcy in the colonic histoarchitecture, with no apparent signs of neoplasia. EDXRF studies revealed a significant decrease in tissue concentrations of zinc in the colon following DMH treatment, which upon zinc supplementation were recovered to near normal levels. In conclusion, the results of this study suggest that zinc has a positive beneficial effect against chemically induced colonic preneoplastic progression in rats induced by DMH.

Two fatal cases of selenium toxicity

Two patients, a 36-year-old female and a 36-year-old male, separately experienced new onset nausea, vomiting, diarrhea, abdominal pain, muscle weakness and pallor. Over a period of 14–16 h these symptoms continue and progress to include hypotension refractory to therapy, pulmonary edema and cardiovascular collapse. Autopsies show hemorrhagic pulmonary edema, splenomegaly and lack of anatomical cause for sudden death. Postmortem analysis, in one case post-embalming and exhumation, revealed elevated selenium concentrations and a determination of the cause of death. These two cases present several important features associated with selenium toxicity, two of which are previously unreported: (1) selenium as a potential homicidal agent, (2) the toxidrome and time frame of selenium toxicity, (3) selenium determination in exhumed, embalmed tissues, (4) postmortem urinary selenium concentration, and (5) decrease in tissue concentrations over time.

Fertilizer Concentration Affects Growth and Foliar Elemental Concentration of Strobilanthes dyerianus

Grown as an annual in most of the United States, Strobilanthes dyerianus Mast. has become increasingly popular in summer landscapes partially due to its superior performance in hot and humid conditions. At present, there is no published research on the nutritional requirements of S. dyerianus. Our study examined growth and foliar elemental response to different levels of fertilizer. Rooted cuttings were transplanted and grown with 0, 100, 200, 300, and 400 mg·L–1 N from 5N–2.2 P–12.4 K fertilizer as constant liquid feed. Plants were irrigated whenever the volumetric water content of the substrate was &lt;20% as determined with a Theta Probe moisture meter. Weekly pH and electrical conductivity (EC) were monitored using the pour through method. Eight weeks after initiation of treatment, dry weight and leaf area was measured. Recently mature leaf tissue was analyzed for total N, P, K, Ca, Mg, S, Fe, Mn, B, Cu, Zn, and Mo. There were no significant differences in plant quality under the 100, 200, 300, or 400 mg·L–1 N treatments. The largest plants, based on leaf area and shoot dry weight, were produced with 200 mg·L–1 N. Compared to recommended EC levels for bedding plants, the treatments receiving 300 and 400 mg·L–1 N had excessively high levels of substrate soluble salts though overall plant quality was not reduced. The increase in fertilizer concentration yielded a linear increase in tissue concentration of N, P, and K and a linear decrease in tissue concentration of Ca and Mg.

Effect of Cu Toxicity on Growth of Cowpea (Vigna unguiculata)

Accurate determination of the rhizotoxicity of Cu in dilute nutrient solutions is hindered by the difficulty of maintaining constant, pre-determined concentrations of Cu (micromolar) in solution. The critical Cu2+ activity associated with a reduction in the growth of solution-grown cowpea (Vigna unguiculata (L.) Walp. cv Caloona) was determined in a system in which Cu was maintained constant through the use of a cation exchange resin. The growth of roots and shoots was found to be reduced at solution Cu2+ activities ≥ 1.7 µM (corresponding to 90 % maximum growth). Although root growth was most likely reduced due to a direct Cu2+ toxicity, it is considered that the shoot growth reduction is attributable to a decrease in tissue concentrations of K, Ca, Mg, and Fe and the formation of interveinal chlorosis. At high Cu2+ activities, roots were brown in color, short and thick, had bent root tips with cracking of the epidermis and outer cortex, and had local swellings behind the roots tips due to a reduction in cell elongation. Root hair growth was reduced at concentrations lower than that which caused a significant reduction in overall root fresh weight.

From the Laboratory to the Bedside

From the Laboratory to the Bedside

Accentuation of ANP secretion to endothelin-1 in hypertrophied atria

To investigate modulation of ANP secretion by atrial hypertrophy, the secretion of ANP in response to stretch and endothelin-1 was studied using isolated perfused quiescent atria from rats treated with monocrotaline (MCT). Male Sprague-Dawley rats were given a single subcutaneous injection of 50 mg/kg MCT or saline and were sacrificed at 6 weeks. Rats with right heart hypertrophy showed an increase in ANP mRNA and decrease in tissue concentration of ANP in hypertrophied atria and a marked increase in plasma concentration of ANP. In isolated perfused hypertrophied right atria from MCT rats, changes in atrial volume induced by increased atrial pressure caused proportional increases in mechanically stimulated extracellular fluid (ECF) translocation and stretch-activated ANP secretion. Changes in atrial volume and mechanically stimulated ECF translocation in hypertrophied right atria were not different from those in control right atria. The stretch-activated ANP secretion was suppressed without significant difference in basal ANP secretion, as compared to control right atria. Therefore, the stretch-activated ANP secretion from hypertrophied right atria into the atrial lumen in relation to the ECF translocation (ANP concentration in the interstitium) was lower than that from control atria. A positive correlation between the stretch-activated ANP secretion in relation to the ECF translocation and tissue ANP content was found in control atria but not in hypertrophied atria. Endothelin-1 caused increases in stretch-activated ANP secretion in a dose-dependent manner, which were accentuated in hypertrophied right atria. Therefore, we suggest that atrial hypertrophy causes an attenuated response to stretch and accentuated response to endothelin-1 of ANP secretion.

Cardiac troponin I and T alterations in dog hearts with myocardial infarction: correlation with infarct size.

We studied the distribution of cardiac troponins I (cTnI) and T (cTnT) in ischemic left ventricular (LV) tissue in 7 infarct zones, 7 remote nonischemic LV areas, and 7 nonischemic areas each from the right ventricle and circumflex in an acute coronary artery occlusion dog model to correlate myocardial loss of troponins with infarct size 3 weeks after the infarction and to determine whether the decrease of troponins in ischemic myocardium can be used to assess the infarct size in dogs after coronary occlusion. The serum profiles for time vs mean cTnI and cTnT concentrations in 6 dogs after occlusion showed peak concentrations at 1 day and 5 days, respectively. The concentrations of troponins were similar in all nonischemic zones. However, cTnI and cTnT decreased significantly in the LV ischemic tissues. Loss of cTnT, but not cTnI, in ischemic LV tissues correlated significantly with infarct size 3 weeks after the infarction. Biochemical alterations suggest that the increases in serum troponins after the infarction parallel the decreases in tissue concentrations of troponins.

Effect of L-Dopa and the catechol-O-methyltransferase inhibitor Ro 41-0960 on sulfur amino acid metabolites in rats.

L-Dopa is the most effective drug known for the treatment of Parkinson's disease. However, the large doses required to treat this neurodegenerative disorder can significantly affect tissue concentrations of sulfur amino acid metabolites due to peripheral and central O-methylation. These effects include decreases in tissue concentrations of the biochemical methyl donor S-adenosylmethionine (SAM), increases in tissue concentrations of the methylation inhibitor S-adenosylhomocysteine (SAH), and increases in plasma concentrations of homocysteine, recently identified as an independent risk factor for vascular disease. In the present study, the ability of the catechol-O-methyltransferase inhibitor Ro 41-0960 to prevent L-Dopa-induced changes in SAM, SAH, and homocysteine concentrations was determined in rats. Rats were injected intraperitoneally with Ro 41-0960 or vehicle 30 min prior to an intraperitoneal injection of L-Dopa or vehicle. One hour after the second injection, the rats were killed and their brains, livers, spleens, kidneys, and plasma collected. SAM and SAH concentrations were then determined in discrete brain regions and peripheral tissues, and total homocysteine concentrations were determined in plasma. In the rats treated with only L-Dopa, decreased SAM concentrations and increased SAH concentrations were found in all brain regions and peripheral tissues measured, and increased homocysteine concentrations were found in plasma, consistent with previous reports. In rats pretreated with Ro 41-0960, however, these L-Dopa-induced effects on sulfur amino acid metabolite concentrations were attenuated or prevented entirely. It remains to be determined if this sparing effect of Ro 41-0960 on sulfur amino acid metabolites has clinical significance.

Nitric oxide inhibits the release of norepinephrine and dopamine from the medial basal hypothalamus of the rat.

Previous research indicates that norepinephrine and dopamine stimulate release of luteinizing hormone (LH)-releasing hormone (LHRH), which then reaches the adenohypophysis via the hypophyseal portal vessels to release LH. Norepinephrine exerts its effect via alpha 1-adrenergic receptors, which stimulate the release of nitric oxide (NO) from nitricoxidergic (NOergic) neurons in the medial basal hypothalamus (MBH). The NO activates guanylate cyclase and cyclooxygenase, thereby inducing release of LHRH into the hypophyseal portal vessels. We tested the hypothesis that these two catecholamines modulate NO release by local feedback. MBH explants were incubated in the presence of sodium nitroprusside (NP), a releaser of NO, and the effect on release of catecholamines was determined. NP inhibited release of norepinephrine. Basal release was increased by incubation of the tissue with the NO scavenger hemoglobin (20 micrograms/ml). Hemoglobin also blocked the inhibitory effect of NP. In the presence of high-potassium (40 mM) medium to depolarize cell membranes, norepinephrine release was increased by a factor of 3, and this was significantly inhibited by NP. Hemoglobin again produced a further increase in norepinephrine release and also blocked the action of NP. When constitutive NO synthase was inhibited by the competitive inhibitor NG-monomethyl-L-arginine (NMMA) at 300 microM, basal release of norepinephrine was increased, as was potassium-evoked release, and this was associated in the latter instance with a decrease in tissue concentration, presumably because synthesis did not keep up with the increased release in the presence of NMMA. The results were very similar with dopamine, except that reduction of potassium-evoked dopamine release by NP was not significant. However, the increase following incubation with hemoglobin was significant, and hemoglobin, when incubated with NP, caused a significant elevation in dopamine release above that with NP alone. In this case, NP increased tissue concentration of dopamine along with inhibiting release, suggesting that synthesis continued, thereby raising the tissue concentration in the face of diminished release. When the tissue was incubated with NP plus hemoglobin, which caused an increase in release above that obtained with NP alone, the tissue concentration decreased significantly compared with that in the absence of hemoglobin, indicating that, with increased release, release exceeded synthesis, causing a fall in tissue concentration. When NO synthase was blocked by NMMA, the release of dopamine, under either basal or potassium-evoked conditions, was increased. Again, in the latter instance the tissue concentration declined significantly, presumably because synthesis did not match release. Therefore, the results were very similar with both catecholamines and indicate that NO acts to suppress release of both amines. Since both catecholamines activate the release of LHRH, the inhibition of their release by NO serves as an ultra-short-loop negative feedback by which NO inhibits the release of the catecholamines, thereby reducing the activation of the NOergic neurons and decreasing the release of LHRH. This may be an important means for terminating the pulses of release of LHRH, which generate the pulsatile release of LH that stimulates gonadal function in both male and female mammals.

Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on levels of glutamate and aspartate in the mouse brain

Perturbations of energy metabolism and activation of N-methyl- d-aspartate (NMDA) receptors have been suggested to play a role in the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In the present study, the concentrations of the excitatory amino acids, l-glutamate and l-aspartate, were evaluated in the mouse brain after administration of MPTP and correlated with MPTP-induced energy impairment. Levels of glutamate and aspartate were determined in the brain of C57BL/6 mice exposed to a single dose of MPTP (40 mg/kg, s.c.). MPTP significantly decreased glutamate and aspartate concentrations in the striatum and ventral mesencephalon but not in the cerebellar cortex 4 h after MPTP administration. This effect was only temporary, however, since glutamate and aspartate concentrations returned to control levels 24 h after MPTP exposure. Pretreatment with the monoamine oxidase B inhibitor deprenyl (10 mg/kg, i.p.) or the catecholamine uptake blocker mazindol (20 mg/kg, s.c.) 30 min before MPTP administration prevented MPTP-induced decrease in glutamate and aspartate. Moreover, injection of 2-deoxyglucose, a competitive inhibitor of cellular glucose transport and utilization, significantly potentiated MPTP-induced decrease in striatal levels of glutamate and aspartate. The present results indicate that systemic administration of MPTP causes a decrease in tissue concentrations of glutamate and aspartate in the striatum and ventral mesencephalon. These effects may result from the perturbation of energy metabolism induced by MPTP in the nigrostriatal dopamine system.

Diethylmaleate produces diaphragmatic impairment after resistive breathing.

Formation of oxygen-derived free radicals and activation of the glutathione (GSH) redox cycle has been associated with impaired rat diaphragm performance. Diethylmaleate (DEM) given intraperitoneally irreversibly conjugates with GSH, resulting in marked decreases in tissue concentrations of GSH. We have investigated the effects of acute GSH depletion by DEM on diaphragmatic function during resistive breathing (RB) in the rat. The experimental groups were 1) control, 2) DEM alone, 3) RB, and 4) DEM with RB (DEM + RB). RB was obtained by inspiratory RB until the rats were unable to sustain 70% of maximum airway opening pressure. A portion of the diaphragm was frozen for biochemical assays, and the rest of the diaphragm was prepared for measurement of in vitro contractile properties, including maximum tetanic tension, twitch tension, force-frequency curves, and contraction times. DEM treatment produced a profound depletion of GSH in the DEM and DEM + RB groups. Neither DEM nor RB alone significantly altered diaphragm contractile properties. In DEM + RB rats, however, there was a significant decrease in maximum tetanic tension, twitch tension, and tetanic tension. These data reveal that DEM produced an acute depletion of GSH in the diaphragm without impairment of the muscle in nonstressed rats. In the presence of DEM-induced GSH depletion, RB did result in marked diaphragm impairment. The depletion of GSH and the subsequent impairment in diaphragm contractility after RB suggest that GSH may play an important role in protecting the diaphragm against oxidative stress associated with RB.

Enteroendocrine peptides in a canine model of orthotopic jejunoileal autotransplantation.

The enteroendocrine cells of the small bowel provide a rich source of regulatory peptides involved in the modulation of gastrointestinal function. Recent work from our laboratory showed that in situ neural isolation (autotransplantation) of the jejunoileum produced marked changes in tissue expression of several neuropeptides. In the present study, we examined the influence of extrinsic innervation on the tissue expression of endocrine peptides localized to various regions of the gastrointestinal tract. Concentrations of immunoreactive gastric inhibitory polypeptide (GIP), neurotensin (NT) and peptide tyrosine tyrosine (PYY) in fasting plasma and regional tissue biopsies were determined before and at varying time points (2, 6, 12 weeks) after a model of canine orthotopic jejunoileal autotransplantation. GIP was not altered in plasma or tissue at any time point. Plasma concentrations of NT and PYY increased after autotransplantation. Following a decrease in tissue concentrations two weeks after autotransplantation, NT increased progressively from 2 to 6 to 12 weeks, reaching a maximal increase of 895% over baseline in proximal ileum. Tissue concentrations of PYY followed much the same pattern as NT, but these trends never achieved statistical significance. Chromatographic characterization of tissue biopsy extracts revealed molecular heterogeneity of NT-like immunoreactivity, while GIP and PYY immunoreactivity coeluted as single species with authentic standards. Taken together with our earlier observations, it appears that disruption of extrinsic and intrinsic neural continuity to the jejunoileum (autotransplantation) does not affect gut endocrine peptides such as GIP and PYY to the same extent as enteric neuropeptides. NT has been localized to neural as well as endocrine cells and is involved in the temporal adaptive response to autotransplantation.