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PubMed1998

The relationship between intracellular UDP-N-acetyl hexosamine nucleotide pool and monoclonal antibody production in a mouse hybridoma.

The effect of intracellular UDP-N-acetyl hexosamine accumulation in a murine hybridoma was investigated using tunicamycin and ammonium chloride. The treatment of cells with tunicamycin resulted in the inhibition of glycosylation of the secreted monoclonal antibody (IgGl) and cell growth arrest. Tunicamycin concentrations of 0.01-0.1 microgram ml-1 resulted in the formation of both glycosylated and non-glycosylated heavy chains of the immunoglobulin, whereas complete inhibition of protein glycosylation was observed at higher concentrations of tunicamycin. Tunicamycin treatment also resulted in a dose dependent accumulation of UDP-N-acetyl hexosamine. It was concluded that the specific monoclonal antibody production rate (qMab) was not dependent on the extent of glycosylation. Treatment of cells with NH4Cl also resulted in dose dependent accumulation of UDP-N-acetyl hexosamine. Supplementation of cultures with 10 mM NH4Cl resulted in a 40% reduction in cell growth rate and a 36% increase in the qMab. The data suggest that the reduction in growth rate and not UDP-N-acetyl hexosamine accumulation was the cause of increased qMab in the ammonium supplemented cultures. Ammonium chloride did not affect the extent of protein glycosylation. We conclude that UDP-N-acetyl hexosamine does not act as a mediator of enhanced rates of monoclonal antibody synthesis in the hybridoma cell culture system.

Ammonium Chloride↗

PubMed1997

Impaired bone growth after ileal augmentation cystoplasty.

PURPOSE: We evaluated how ileal augmentation cystoplasty predisposes growing animals to hyperchloremic acidosis and abnormal skeletal development. MATERIALS AND METHODS: Weanling female Wistar rats weighing 35 to 50 gm. underwent ileal augmentation cystoplasty or sham operation consisting of a similar ileal resection and closure (ileoileostomy). Both groups were stressed with 1% ammonium chloride loading. Serial bone densitometry measurements, weight and blood gas studies were performed in an 8-week growth period. Femur bone ashing and mineral analysis, arterial blood gas studies and serum bone mineral determinations (calcium, magnesium and phosphorus) were obtained at study conclusion. RESULTS: Augmented and control animals had similar serum calcium, phosphorus and magnesium concentrations. In augmented animals metabolic acidosis developed with respiratory compensation and decreased mean serum bicarbonate plus or minus standard deviation compared to controls (18.34 +/- 3.23 versus 21.76 +/- 2.46 mEq./l., p <0.003). Growth curves of both groups were similar, although augmented animals had shorter femur lengths than controls (p <0.04). Bone density results were mixed. Whole body bone density was decreased (p <0.05), while bone ash and mineral content (except phosphorus) were not. When rats with augmentation cystoplasty given 1% ammonium chloride were fed an equal molar diet of sodium bicarbonate, metabolic acidosis and bone mineral density normalized to control values. CONCLUSIONS: Acid challenged weanling rats that underwent ileal augmentation cystoplasty demonstrated decreased bone mineral density and growth compared to controls. These changes were prevented by bicarbonate replacement.

Acidosis↗

PubMed2001

The mechanism of propagation of intracellular calcium waves in cultured human uterine myocytes.

OBJECTIVE: The primary goal of this work was to determine the relative importance of sarcoplasmic reticulum inositol 1,4,5-triphosphate receptors and ryanodine receptors in the mechanism of intracellular calcium wave propagation in human uterine myocytes. A secondary goal was to identify the rate-determining step of calcium wave propagation. STUDY DESIGN: Pregnant human myometrium was obtained at the time of cesarean delivery, enzymatically dispersed, and cultured through several passages. Intracellular calcium wave velocities were measured with video fluorescence microscopy and the calcium-dependent fluorescent dye calcium green 1. Experimental conditions were modified by exposure of the cells to ruthenium red (blocked ryanodine receptor), ryanodine (locked open ryanodine receptor), oxytocin (increased inositol-1,4,5-triphosphate), sodium butyrate (intracellular acidification), ammonium chloride (intracellular alkalinization), and elevation of temperature (from 19 degrees C to 30 degrees C). RESULTS: Wave velocities were found to be the same for spontaneously occurring (9.6 +/- 2.6 microm/s) and oxytocin-stimulated (10.3 +/- 3.4 microm/s) waves. Advance treatment of the cells with ryanodine or ruthenium red failed to change oxytocin-stimulated wave velocities from control values. The temperature dependence of calcium wave velocities was studied across the range 19 degrees C to 30 degrees C. Plots of wave velocities versus the inverse of the temperature yielded apparent activation energies that were the same for spontaneous (13.2 +/- 0.3 kcal/mol) and oxytocin-induced (14.3 +/- 1.6 kcal/mol) waves. After intracellular acidification by treatment with butyrate (20 mmol/L) wave velocities increased by 44%. Wave velocities decreased by 35% after treatment with ammonium chloride (20 mmol/L). CONCLUSION: Propagation of intracellular calcium waves in cultured human uterine myocytes exhibited mechanisms of sarcoplasmic reticulum calcium release that could use either inositol 1,4,5-triphosphate receptors alone or ryanodine receptors alone, or both together. The rate-determining step for calcium wave propagation was diffusion of calcium though a highly buffered cytoplasm.

Ammonium Chloride↗

PubMed1997

Contribution of lysosomal trapping to the total tissue uptake of psychotropic drugs.

The present study was aimed at assessing individual contributions of the phospholipid binding and lysosomal trapping to the total tissue uptake of psychotropic drugs with different chemical structures, such as promazine, imipramine, amitriptyline, fluoxetine, sertraline (basic lipophilic drugs) and carbamazepine (lipophilic, but not basic). We also tried to find out whether lysosomal trapping may be involved in the pharmacokinetic interactions in clinical combinations of psychotropics. Uptake experiments were carried out on slices of various rat tissues as a system with intact lysosomes. Initial concentration of each drug was 5 microM. The results were compared with those obtained in the presence of the "lysosomal inhibitors", ammonium chloride or monensin. The basic lipophilic psychotropics showed high uptake in tissues known for the abundance of lysosomes, mainly the lungs. The highest drug accumulation was found for promazine and amitriptyline. "Lysosomal inhibitors" significantly decreased the uptake of the basic lipophilic drugs, particularly in the lungs and liver. The most potent effect was observed for amitriptyline, imipramine and promazine. The brain showed moderate accumulation of basic lipophilic psychotropics and the effect of the "lysosomal inhibitors" was significant only in the case of amitriptyline, imipramine and sertraline. The only exception to the above regularity were imipramine and sertraline which were taken up more extensively by the adipose tissue than by lysosome-rich tissues such as the lungs or liver. Carbamazepine did not show lysosomotropism. Amitriptyline and promazine mutually decreased their uptake by lung slices when the drugs were incubated jointly. In the presence of ammonium chloride the interaction did not occur. In conclusion, the obtained results show that (1) the lysosomal trapping is an important factor determining the distribution of the basic lipophilic psychotropics; however (2) their tissue uptake depends more on the phospholipid binding than on the lysosomal trapping; (3) the lysosomal trapping may be involved in the pharmacokinetic interactions between psychotropics.

1-Naphthylamine↗

PubMed1999

The role of lysosomes in the cellular distribution of thioridazine and potential drug interactions.

The purpose of the present study was to investigate the contribution of lysosomal trapping to the total tissue uptake of thioridazine and to potential drug distribution interactions between thioridazine and tricyclic antidepressants (imipramine, amitriptyline) or selective serotonin reuptake inhibitors (SSRIs; fluoxetine, sertraline). The experiment was carried out on slices of various rat tissues as a system with intact lysosomes. Thioridazine and antidepressants (5 microM) were incubated separately or jointly with the tissue slices in the absence or presence of "lysosomal inhibitors," i.e., ammonium chloride or monensin. The results show that the contribution of lysosomal trapping to the total tissue uptake of thioridazine is as important as phospholipid binding. A high degree of dependence of thioridazine tissue uptake on the lysosomal trapping is the cause of substantial distributive interactions between thioridazine and the investigated antidepressants at the level of cellular distribution. Thioridazine and the antidepressants, both tricyclic and SSRIs, mutually decreased their tissue uptake. The potency of antidepressants to decrease thioridazine uptake was similar to that of lysosomal inhibitors. In general, the observed interactions between thioridazine and antidepressants occurred only in those tissues in which thioridazine showed lysosomotropism (the lungs, liver, kidneys, brain, and muscles) but were not observed in the presence of ammonium chloride. The above finding provides evidence that the interactions proceeded at the level of lysosomal trapping. In the adipose tissue and heart no lysosomal trapping of thioridazine was detected and those tissues were not the site of such an interaction. Since the organs and tissues involved in the distributive interactions constitute a major part of the organism and take up most of the total drug in the body, the interactions occurring in them may cause a substantial shift of the drugs to organs and tissues poor in lysosomes, e.g. the heart and muscles. An in vivo study into the thioridazine-imipramine interaction showed that joint administration of the drugs under study (10 mg/kg ip) increased drug concentration ratios of lysosome-poor tissue/plasma and lysosome-poor/lysosome-rich tissue. Considering serious side effects of thioridazine and tricyclic antidepressants (cardiotoxicity, anticholinergic activity), the thioridazine-antidepressant combinations studied should be approached with respect to the appropriate dose adjustment.

Amitriptyline↗

PubMed1981

Tibial dyschondroplasia in broilers: comparison to dietary additives and strains.

The effects of broiler strain and various additives to practical corn-soy diets on the incidence of tibial dyschondroplasia (TD) were studied using broiler chicks maintained in battery brooders. At the termination of each experiment, birds were killed and examined for TD by cutting longitudinally along the tibia. No significant difference in the incidence of TD was found among the nine broiler strains compared. While the incidence of twisted legs was higher than TD among the nine strains there was no apparent correlation between the two leg disorders. Studies conducted using the following additives did not significantly increase the incidence of TD in broilers when compared to controls: monensin, sodium chloride, copper sulfate, magnesium sulfate, potassium sulfate, roxarsone, gentian violet, erythromycin, vitamin K, or vitamin D3. However, dietary ammonium chloride (1.5 or 30%) did increase the incidence of TD, whereas adding various fermentation products at levels of 10 and 20% either in the absence or presence of ammonium chloride failed to reduce the incidence of the disease. The incidences of TD among broiler chicks fed high dietary fluoride were nonsignificant; no evidence of the disease was found in Leghorn chicks fed the same diets. Chicks maintained in battery brooders in these studies, generally had a lower incidence of TD than that reported for commercial flocks in the field. Furthermore, manipulation of feed additives or ingredients in practical rations for broiler chickens did not increase the incidence of the disease.

Animal Feed↗

PubMed1969

Renal metabolic response to acid base changes. I. Enzymatic control of ammoniagenesis in the rat.

Experiments were done on rats to investigate the nature of the renal response to metabolic acidosis and the changes in enzyme activity associated with increased ammoniagenesis. When metabolic acidosis was induced with oral feeding of ammonium chloride for 48 hr, there was an increase of activity of the enzyme phosphoenolpyruvate carboxykinase (PEPCK) in whole kidneys as well as in the kidney cortex. There was no change in PEPCK in liver, and glucose-6-phosphatase showed no change in kidney or liver in response to metabolic acidosis. The increase in PEPCK activity in kidney cortex varied with the degree of acidosis and there was a close correlation between cortical PEPCK activity and urinary ammonia. Kidney cortex mitochondrial PEPCK did not change in response to metabolic acidosis. An increase in PEPCK occurred as early as 6 hr after NH(4)Cl feeding, before there was any increase in kidney glutaminase I activity. Rats fed sodium phosphate, or given triamcinolone intramuscularly, developed a metabolic alkalosis, but there was increased urinary ammonia and an increase in activity of renal cortical PEPCK. Triamcinolone plus ammonium chloride induced a greater increase of PEPCK activity than triamcinolone by itself; on the contrary, the rise of glucose-6-phosphatase induced by triamcinolone was not enhanced by acidosis. Glucose-6-phosphatase from control and acidotic rats had identical kinetic characteristics. The results indicate that increased PEPCK activity is constantly related to increases of urinary ammonia. It is proposed that the increase of PEPCK activity is the key event in the ammoniagenesis and gluconeogenesis which follow on metabolic acidosis.

Acid-Base Equilibrium↗

PubMed1994

Specific mannose-6-phosphate receptor-independent sorting of pro-cathepsin D in breast cancer cells.

The secretion of pro-cathepsin D (pro-cath-D) in some human metastatic breast cancer cells (MCF7, MDA/MB231), contrary to normal mammary cells, is not increased by ammonium chloride treatment, indicating a mannose-6-phosphate-independent sorting to lysosomes. By studying a variety of cell lines and lysosomal enzymes, we show that secretion of newly synthesized pro-cath-D was not mediated by the 46-kDa mannose-6-phosphate receptor (MPR) and that its resistance to NH4Cl for secretion was specific to cath-D and not to other lysosomal enzymes. This resistance appeared to be correlated with the basal hypersecretion of pro-cath-D, but not with its overexpression. By contrast, pro-cath-D secretion was increased by NH4Cl in fibroblasts and nontumoral epithelial mammary cells, suggesting a specificity for cancer cells. Immunofluorescence staining showed that pro-cath-D, but neither cathepsin B nor beta-hexosaminidase, accumulated in intracytoplasmic vesicles of cells treated with ammonium chloride. In pulse--chase experiments and by subcellular fractionation on Percoll gradient, cath-D was found to be sorted into dense lysosomes whether cells were treated or not by NH4Cl. Treatment of cells with NH4Cl, however, inhibited processing and maturation of pro-cath-D, which was also observed in light vesicles in the absence of NH4Cl. Part of pro-cath-D, but not processed enzyme, was also found to be membrane associated in saponin-permeabilized cells. We conclude that in breast cancer cells, the MPR-independent pathway of pro-cath-D to lysosome is predominant compared to normal cells and other lysosomal enzymes. This alternative pathway should therefore be considered, in addition to MPR, to explain pro-cath-D sorting and activation in breast cancer cells.

Ammonium Chloride↗

PubMed1982

Mannose-specific endocytosis receptor of alveolar macrophages: demonstration of two functionally distinct intracellular pools of receptor and their roles in receptor recycling.

Receptor-mediated endocytosis of rat preputial beta-glucuronidase and the glycoconjugate mannose-BSA by rat alveolar macrophages is inhibited by chloroquine and ammonium chloride. We have previously reported that these drugs cause a loss of cell surface binding activity and that they do not inhibit internalization of receptor ligand complexes when incubated with cells at 37 degrees C. In this report we more clearly delineate the intracellular site of weak base inhibition of receptor recycling and the mechanism of that inhibition. From our analysis of the kinetics of ligand transport we conclude that there are two functionally distinct intracellular pools of receptor. One of these, the cycling pool, is not sensitive to the presence of weak bases, and receptor-ligand complexes return from this pool to the cell surface intact. The second pool is responsible for the time-dependent intracellular delivery of ligand to acid vesicles, which is inhibited by weak bases. Chloroquine and ammonium chloride appear to inhibit the dissociation of receptor-ligand complexed in this second pool and thereby the production of free receptors for the continuation of receptor-mediated endocytosis. We examine the internalization and binding of ligand in normal and paraformaldehyde-treated cells and find that these are strongly affected by pH. In particular, the dissociation rate of receptor ligand complexes is enhanced greater than 7.5 fold by lowering the medium pH from 7 to 6. From these results we propose that weak bases raise the pH of acid intracellular compartments, slowing the rate of receptor-ligand dissociation and thereby reducing the cellular pool of free receptors available for further uptake of ligand. In addition, we demonstrate that receptor-ligand complexes cannot return to the cell surface from the amine-sensitive (acid) intracellular pool that led us to call this the nonreleasable pool. This final observation indicates that receptor movements through these two pools are functionally distinct processes.

Ammonium Chloride↗

PubMed1991

Differentiation of acid-pH-dependent and -nondependent entry pathways for mouse hepatitis virus.

Early events of infection of MHV were studied in comparison with those of VSV, which is known to enter cells by an endocytic pathway. Treatment of mouse L-2 fibroblasts with ammonium chloride, chloroquine, or dansylcadaverine inhibited infection of MHV to a much lesser degree than that of VSV, suggesting a relatively minor role for the endocytic pathway and functional endosomes in MHV infection. Endocytosis of MHV and VSV into L-2 cells was assayed by the recovery of infectious (i.e., not uncoated) viruses from homogenates of cells harvested within the first few minutes of infection (and treated with protease to remove surface-bound virus). The results thus suggest that while a small proportion of the MHV inoculum is internalized by endocytosis, productive infection does not depend on functional endocytosis as utilized by VSV. Studies on direct virion-mediated cell fusion showed that MHV can induce fusion at pH 7.4, whereas VSV causes fusion at pH 5.0. Taken together, the above results suggest that MHV enters L-2 cells predominantly by membrane fusion with a non-acidified compartment such as the plasma membrane, endocytic vesicles, or endosomes (prior to their acidification). Results obtained from cell lines which differed in permissiveness to MHV infection suggested that the ability to support MHV infection does not correlate with endocytosis. Rather, nonpermissive cells, such as rat astrocytoma (C-6) and Vero cells, showed higher levels of recoverable internalized MHV than did fully permissive L-2 cells. Cells which are normally nonpermissive to MHV, could be rendered MHV-susceptible by PEG-induced fusion of cell surface-bound virus. Such PEG-mediated susceptibility to MHV infection was insensitive to inhibition by ammonium chloride, supporting the idea that host cell restriction of MHV infection in C-6 and Vero cells may be due to a block in nonendosomal membrane fusion. Thus endocytic internalization of MHV, which clearly occurs in a variety of cells, does not guarantee productive infection.

Acids↗

PubMed1999

Incomplete renal tubular acidosis in 'primary' osteoporosis.

Chronic metabolic acidosis may increase alkali mobilization from bone and thus promote the development of osteoporosis. While it is undisputed that overt metabolic acidosis is associated with metabolic bone disease, renal acidification in patients with idiopathic osteoporosis has not been studied systematically. The purpose of this study was to investigate the prevalence of renal acidification defects in patients with 'primary' osteoporosis. Thirty-two women (including 10 premenopausal women) and 16 men who were referred to our department for investigation of osteoporosis were enrolled in this study. Patients with obvious or possible secondary osteoporosis were excluded. None of the patients had overt metabolic acidosis. In random urine samples 12 of the 48 patients had pH levels below 5.5 and were therefore considered to have normal renal acidification. The remaining 36 patients underwent further testing by a short-course oral ammonium chloride load. In this test nine of these 36 patients (7 men and 2 premenopausal women) failed to lower urinary pH below 5.5 despite the induction of systemic metabolic acidosis. In these patients, therefore, the diagnosis of incomplete distal renal tubular acidosis was made (RTA I). Patients with incomplete RTA I had significantly lower spontaneous plasma pH (7.38 +/- 0.0081 vs 7.41 +/- 0.004, mean +/- SEM, p = 0.002), a lower serum bicarbonate concentration (21.9 +/- 0.49 mmol/l vs 23.1 +/- 0.24 mmol/l, p = 0.034), a lower base excess (-2.33 +/- 0.42 mmol/l vs -0.55 +/- 0.21 mmol/l, p = 0.001) and lower Z-scores in bone densitometry (-2.18 +/- 0.27 vs -1.40 +/- 0.15, p = 0.028) than patients with normal renal acidification. In conclusion, a high prevalence of incomplete RTA I (in 44% of the male patients, 20% of the premenopausal female patients and 6% of all female patients) was found in patients with osteoporosis who, without testing, would have been diagnosed as having 'primary' osteoporosis. The mild metabolic acidosis observed in these patients may have contributed to loss of bone mass by a compensatory mobilization of alkali and calcium from bone. Because of possible therapeutic consequences (e.g., administration of alkali salts and high doses of vitamin D) we propose that measurements of urinary pH and, if necessary, ammonium chloride testing should be included in the diagnostic investigation especially of male and of premenopausal female patients with osteoporosis. Since referral bias, although unlikely, cannot be excluded in our study, the prevalence of RTA I in unselected patients with osteoporosis needs to be determined at primary screening institutions.

Absorptiometry, Photon↗

PubMed2001

Synthesis and Characterization of Optically Active Surfactants Derived from Phenylalanine and Leucine.

Two optically active cationic surfactants, (2S)-N-hexadecyl-N, N-dimethyl-(1-hydroxy-3-phenylpropyl)-2-ammonium chloride 1 and (2S)-N-hexadecyl-N,N-dimethyl-(1-hydroxy-4-methylpentyl)-2-ammonium chloride 2, have been selected and synthesized for use as enantioselective micellar catalysts in aqueous media. Their surface and aggregation behavior has been investigated at 298 K using surface tension and light scattering studies, which revealed that both molecules associate at low concentrations to produce micellar aggregates. Interestingly, although the area per molecule occupied by the surfactants at the air-water interface (43.6 Å(2) for 1 and 54.6 Å(2) for 2) is similar to that of related cationic surfactants, their aggregation number (23 for 1 and 19 for 2) is much smaller, perhaps reflecting the influence of the size or homochiral nature of the head group in the packing of the micelle. Copyright 2001 Academic Press.

Journal Article↗

PubMed1999

Host cell receptor binding by baculovirus GP64 and kinetics of virion entry.

GP64 is the major envelope glycoprotein from budded virions of the baculoviruses Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) and Orgyia pseudotsugata multicapsid nucleopolyhedrovirus (OpMNPV). To examine the potential role of GP64 as a viral attachment protein in host cell receptor binding, we generated, overexpressed, and characterized a soluble form of the OpMNPV GP64 protein, GP64solOp. Assays for trimerization, sensitivity to proteinase K, and reduction by dithiothreitol suggested that GP64solOp was indistinguishable from the ectodomain of the wild-type OpMNPV GP64 protein. Virion binding to host cells was analyzed by incubating virions with cells at 4 degrees C in the presence or absence of competitors, using a single-cell infectivity assay to measure virion binding. Purified soluble GP64 (GP64solOp) competed with a recombinant AcMNPV marker virus for binding to host cells, similar to control competition with psoralen-inactivated wild-type AcMNPV and OpMNPV virions. A nonspecific competitor protein did not similarly inhibit virion binding. Thus specific competition by GP64solOp for virion binding suggests that the GP64 protein is a host cell receptor-binding protein. We also examined the kinetics of virion internalization into endosomes and virion release from endosomes by acid-triggered membrane fusion. Using a protease sensitivity assay to measure internalization of bound virions, we found that virions entered Spodoptera frugiperda Sf9 cells between 10 and 20 min after binding, with a half-time of approximately 12.5 min. We used the lysosomotropic reagent ammonium chloride to examine the kinetics of membrane fusion and nucleocapsid release from endosomes after membrane fusion. Ammonium chloride inhibition assays indicated that AcMNPV nucleocapsids were released from endosomes between 15 and 30 min after binding, with a half-time of approximately 25 min.

Animals↗

PubMed2001

Selective amination of secoiridoid glycosides to give monomeric pyridine, dimeric pyridine, and naphthyridine alkaloids.

Treatment of the secoiridoids oleuropein (4), ligstroside (5) and methyloleoside (6) by beta-D-glucosidase in the presence of ammonium chloride led exclusively to monomeric pyridine alkaloids 7, 1, and 8. Dimeric 3,4,5-trisubstituted pyridines were obtained from methyloleoside (6) when ammonium chloride was generated in the reaction mixture by successive additions of ammonia and hydrochloric acid. The use of ammonium acetate permitted conversion of secoiridoids 4 and 5 into the naphthyridine alkaloid jasminine (3).

Alkaloids↗

PubMed1993

Metabolic acidosis inhibits growth hormone secretion in rats: mechanism of growth retardation.

To test the hypothesis that growth retardation in nonanion gap acidosis may be associated with impairment of growth hormone (GH) secretory patterns, we examined GH secretion in rats made acidotic with ammonium chloride ingestion. Considerable growth retardation was demonstrated in pair-fed and acidotic rats after 1 wk of ammonium chloride ingestion compared with control. With stable metabolic acidosis sustained on the 8th day of experiment, pulsatile secretion of GH was evaluated by blood samples drawn every 10 min for 6 h. Using deconvolution analysis to quantitate in vivo GH secretory rates, we found significant inhibition of pulsatile GH secretion in acidotic rats. Changes in amplitude of GH pulses and mean mass of GH pulses correlated with changes in body weight. These studies showed that chronic metabolic acidosis causes growth impairment, reduced food efficiency, and amplitude-specific inhibition of pulsatile secretion of GH. We propose that this GH axis suppression, whether mediated by decreased nutrients or not, contributes significantly to growth failure in children with renal tubular acidosis. Because a similar degree of inhibition of GH secretion was seen in pair-fed rats, we infer that insufficient calorie intake in metabolic acidosis may contribute to disruption of normal GH secretion patterns. These changes in GH secretion were specific, because acidotic rats were different from pair-fed controls in that they showed no change in either half-life of GH in circulation or in pulse frequency. Such observations offer a rationale for more detailed clinical investigations into the impact of metabolic acidosis on physiological regulation of pulsatile GH secretion in humans.

Acid-Base Equilibrium↗

PubMed1991

Aspartate aminotransferase, malate dehydrogenase, and pyruvate carboxylase activities in rat cerebral synaptic and nonsynaptic mitochondria: effects of in vitro treatment with ammonia, hyperammonemia and hepatic encephalopathy.

The effects of in vitro treatment with ammonium chloride, hepatic encephalopathy (HE) due to thioacetamide (TAA) induced liver failure and chronic hyperammonemia produced by i.p. administration of ammonium acetate on the activity of the two malate-aspartate shuttle enzymes: aspartate aminotransferase (AAT), malate dehydrogenase (MDH), and on the pyruvate carboxylase (PC) activity were examined in synaptic and nonsynaptic mitochondria from rat brain. With regard to the shuttle enzymes the response to ammonium ions in vitro (3mM NH4Cl) was observed in nonsynaptic mitochondria only, and was manifested by a 27% decrease of AAT activity and a 16% decrease in MDH activity. By contrast, both in vivo conditions primarily affected the synaptic mitochondrial enzymes: TAA-induced HE produced a 26% decrease of synaptic mitochondrial AAT and a 50% decrease of synaptic mitochondrial MDH. Hyperammonemia inhibited synaptic mitochondrial AAT by 30% and synaptic mitochondrial MDH by 45%. HE produced no effect at all in nonsynaptic mitochondria while hyperammonemia produced a 30% increase in the AAT activity, but no changes in MDH. All the experimental conditions affected the nonsynaptic mitochondria PC: ammonium chloride in vitro produced a 20% decrease, TAA-induced HE--a 30% decrease, whereas hyperammonemia inhibited the enzyme by 53%. The PC activity in synaptic mitochondria was very low (about 2% of that measured in nonsynaptic mitochondria), which is consistent with the primarily astrocytic localization of the enzyme.

Ammonia↗

PubMed1993

The two catalytic components of the 2-oxoglutarate dehydrogenase complex in rat cerebral synaptic and nonsynaptic mitochondria: comparison of the response to in vitro treatment with ammonia, hyperammonemia, and hepatic encephalopathy.

The effects of in vitro treatment with ammonium chloride, hepatic encephalopathy (HE) due to thioacetamide (TAA) induced liver failure and chronic hyperammonemia produced by i.p. administration of ammonium acetate on the two components of the multienzyme 2-oxoglutarate dehydrogenase complex (OGDH): 2-oxoglutarate decarboxylase (E1) and lipoamide dehydrogenase (E3), were examined in synaptic and nonsynaptic mitochondria from rat brain. With regard to E1 the response to ammonium ions in vitro (3 mM NH4Cl) was observed in nonsynaptic mitochondria only and was manifested by a 21% decrease of Vmax and a 35% decrease of Km for 2-oxoglutarate (2-OG). By contrast, both in vivo conditions primarily affected the synaptic mitochondrial E1: TAA-induced HE produced an 84% increase of Vmax and a 38% increase of Km for 2-OG. Hyperammonemia elevated Vmax of E1 by 110% and Km for 2-OG by 30%. HE produced no effect at all in nonsynaptic mitochondria while hyperammonemia produced a 35% increase of Vmax and a 30% increase of Km for 2-OG of E1. Both in vivo conditions produced a 20% increase of E3 activity in synaptic mitochondria, but no effect at all in nonsynaptic mitochondria. The preferential sensitivity of E1 to ammonium chloride in vitro in nonsynaptic mitochondria and hyperammonemic conditions in vivo in synaptic mitochondria may play a crucial role in the compartmentation of OGDH responses under analogous conditions. These results confirm the intrinsic differences between the OGDH properties in the synaptic and nonsynaptic brain compartments.

Acetates↗

PubMed2005

A brainstem substrate for analgesia elicited by intraoral sucrose.

Previous studies demonstrated that nursing or intraoral infusion of certain components of mother's milk (e.g. sugars and fats) produces calming and opiate receptor-dependent analgesia in newborn rats and humans. However, the neural circuitry underlying such analgesia is unknown. The aim of the present study was to specify the central pathways by which taste stimuli engage neural antinociceptive mechanisms. For this purpose, midcollicular transactions were used to investigate the role of the forebrain in analgesia elicited by intraoral infusion of 0.2 M sucrose in neonatal rats. Sucrose-induced analgesia persisted, and was enhanced, following midcollicular transection, indicating that it did not require neural circuits confined to the forebrain. Fos immunohistochemistry was used to identify brainstem neurons activated by a brief (90 s) intraoral infusion of a small volume (90 microl, 0.2M) of sucrose or a salt solution (0.1 M ammonium chloride) in 10-day-old rat pups. Compared with control groups (intact, cannula, distilled water), both sucrose and ammonium chloride induced Fos expression in the rostral nucleus tractus solitarius, the first relay in the ascending gustatory pathway. Sucrose also elicited Fos expression in several brainstem areas associated with centrally mediated analgesia, including the periaqueductal gray and the nucleus raphe magnus. Taken together, these findings demonstrate that analgesia elicited by intraoral sucrose does not require involvement of the forebrain. Intraoral sucrose activates neurons in the periaqueductal gray and nucleus raphe magnus, two key brainstem sites critically involved in descending pain modulation.

Administration, Oral↗