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C Lemieux

Publications and source records attributed to C Lemieux.

104 records · Page 6Linked to original sources
PubMed1985

Renal tubular biochemistry during acute and chronic metabolic alkalosis in the dog.

Acute metabolic alkalosis was induced in dogs by the infusion of sodium bicarbonate, 0.3 M. Chronic alkalosis was induced by chloride restriction and the administration of sodium bicarbonate and furosemide. In a third group of dogs, potassium was added to the regimen to prevent frank potassium depletion. Plasma bicarbonate ranged from 29.0 to 32.9 mM. In all three dog groups, renal ammoniagenesis fell by over 30%, which was consistent with a decrease in the renal uptake of glutamine. Glutamate was released in the renal vein and alanine production was decreased. Total production of ammonia was lowest in the animals given a potassium supplement where muscle potassium decreased much less than in the other chronic animals. Urinary ammonia excretion was very low in all three animal groups; this was related to an alkaline urine. However, this relationship was not entirely consistent and the low excretion of ammonia could also be related to decreased ammonia production by the renal tubular cell. In the renal cortical tissue (freeze-clamped), the concentration of glutamate did not change and that of alpha-ketoglutarate rose only in the animals supplemented with potassium. Malate rose in all groups. In all animals, renal tissue concentration of lactate and citrate rose while citrate excretion increased. We feel that glycolysis could play an important role in renal metabolism during acute and chronic metabolic alkalosis. We have proposed a unified theory to explain the metabolic changes that occur in lactate and citrate metabolism during metabolic alkalosis with a depressing effect on ammoniagenesis. Although citrate could be generated in the mitochondria from pyruvate, its oxidation is probably inhibited with exit and accumulation in the cytosol.

Acute Disease↗
PubMed1985

The metabolic response of the kidney to acute sodium lactate alkalosis.

In vivo studies were performed in the dog to verify if sodium lactate had an important effect on the metabolism of glutamine by the kidney. The animals were infused with 0.6 M sodium lactate to induce acute metabolic alkalosis with plasma bicarbonate of 29.7 mM. During these experiments, it was demonstrated that the renal uptake of glutamine increased by 46%, while the renal production of ammonia was unchanged. The renal production of alanine rose from 6.0 to 16.8 mumol/min. Plasma concentration of lactate increased from 1.3 to 19.2 mM, while that of pyruvate increased from 0.075 to 0.454 mM. In the renal tissue, alpha-ketoglutarate, malate, oxaloacetate, lactate, pyruvate, citrate, and alanine increased significantly. Similar changes were found in the liver and skeletal muscle. The observed changes are best described by transamination of pyruvate and glutamate under the influence of alanine aminotransferase (GPT). It can be calculated that this reaction was responsible for 76% of the production of ammonia from glutamine, the latter being necessary to provide glutamate for the synthesis of alanine. Dogs infused with 0.3 M sodium bicarbonate instead of sodium lactate with the same degree of acute metabolic alkalosis, showed a depression of 40% in the renal uptake of glutamine with a 38% decrease in renal ammoniagenesis and a 20% fall in the production of alanine. The present studies demonstrate that the production of ammonia from glutamine is not necessarily related to changes in acid-base balance, but may be associated with biochemical alterations related to the synthesis of alanine by the kidney.

Alanine↗
PubMed1984

Evidence of a peptide backbone contribution toward selective receptor recognition for leucine enkephalin thioamide analogs.

The in vitro opioid activities of a series of leucine enkephalin analogs containing a thioamide linkage in place of the peptide bond at various positions of the backbone were determined in mu- and delta-receptor-selective bio- and binding-assays. Thioamide substitution in the 1-2 position resulted in an inactive compound, whereas the same modification in the 2-3 and 4-5 position produced potency enhancement. Most interestingly, the 2-3 modified analog showed a 3 to 5 times higher preference for delta- over mu-receptors than natural leucine enkephalin. These results suggest that subtle backbone modifications can have a profound effect on receptor affinity and selectivity of biologically active peptides.

Amides↗
PubMed1984

Chloroplast DNA recombination in interspecific hybrids of Chlamydomonas: Linkage between a nonmendelian locus for streptomycin resistance and restriction fragments coding for 16S rRNA.

Differences in the distribution of Ava I and BstEII restriction sites in the chloroplast DNA (cpDNA) of Chlamydomonas eugametos and C. moewusii have been used to detect extensive cpDNA recombination in the hybrid progeny of these interfertile algae. In the present study, the inheritance of these restriction-site differences was tested for recombination with nonmendelian genetic markers for resistance to streptomycin and erythromycin in interspecific crosses and in hybrid backcrosses to C. moewusii. Most of the restriction-pattern markers appear linked to the antibiotic-resistance markers, thus supporting the chloroplast localization of the resistance markers. The streptomycin marker, in particular, shows perfect coordinate inheritance with an Ava I band containing one cpDNA fragment and a BstEII band containing two comigrating cpDNA fragments. Molecular hybridization experiments using DNA from the Ava I band as a probe show sequence homology between this DNA, the two comigrating BstEII fragments, and cpDNA fragments from C. reinhardtii containing the genes for 16S rRNA. The results show the feasibility of using C. eugametos-C. moewusii hybrids to identify cpDNA sequences that either contain or are closely linked to nonmendelian genetic markers.

Journal Article↗
PubMed1984

Renal enzymes during experimental diabetes mellitus in the rat. Role of insulin, carbohydrate metabolism, and ketoacidosis.

The activities of various ammoniagenic, gluconeogenic, and glycolytic enzymes were measured in the renal cortex and also in the liver of rats made diabetic with streptozotocin. Five groups of animals were studied: normal, normoglycemic diabetic (insulin therapy), hyperglycemic, ketoacidotic, and ammonium chloride treated rats. Glutaminase I, glutamate dehydrogenase, glutamine synthetase, phosphoenolpyruvate carboxykinase (PEPCK), hexokinase, phosphofructokinase, fructose-1,6-diphosphatase, malate dehydrogenase, malic enzyme, and lactate dehydrogenase were measured. Renal glutaminase I activity rose during ketoacidosis and ammonium chloride acidosis. Glutamate dehydrogenase in the kidney rose only in ammonium chloride treated animals. Glutamine synthetase showed no particular variation. PEPCK rose in diabetic hyperglycemic animals and more so during ketoacidosis and ammonium chloride acidosis. It also rose in the liver of the diabetic animals. Hexokinase activity in the kidney rose in diabetic insulin-treated normoglycemic rats and also during ketoacidosis. The same pattern was observed in the liver of these diabetic rats. Renal and hepatic phosphofructokinase activities were elevated in all groups of experimental animals. Fructose-1,6-diphosphatase and malate dehydrogenase did not vary significantly in the kidney and the liver. Malic enzyme was lower in the kidney and liver of the hyperglycemic diabetic animals and also in the liver of the ketoacidotic rats. Lactate dehydrogenase fell slightly in the liver of diabetic hyperglycemic and NH4Cl acidotic animals. The present study indicates that glutaminase I is associated with the first step of increased renal ammoniagenesis during ketoacidosis. PEPCK activity is influenced both by hyperglycemia and ketoacidosis, acidosis playing an additional role. Insulin appears to prevent renal gluconeogenesis and to favour glycolysis. The latter would seem to remain operative in hyperglycemic and ketoacidotic diabetic animals.

Animals↗
PubMed1984

Metabolic machinery of the alligator kidney.

Crocodilians such as caimans and alligators are uricotelic and ammoniotelic animals. They are carnivorous but they excrete ammonium ions in an alkaline urine. The metabolic organization of the kidney of the Mississippi alligator was studied by measuring the renal metabolite profile, the activities of enzymes, and the behavior of kidney tubules in vitro. The liver and tail muscle were also studied. Both awake and anesthetized animals were in a state of low plasma bicarbonate and low blood pH with high plasma lactate concentration. This did not prevent the excretion of an alkaline urine (pH 7.76). alpha-Ketoglutarate was low in all three tissues and lactate was high. Glutamate concentration and glutamate dehydrogenase activity were highest in the kidney with a low equilibrium constant for alanine aminotransferase (KGPT). Glutaminase I was found only in the kidney. It could not be detected in liver or muscle. Glutamine synthetase was found only in the liver. Phosphoenolpyruvate carboxykinase (PEPCK) was present in both liver and kidney. Alanine aminotransferase and malic enzyme showed high activity in the kidney but were inconspicuous in liver and muscle. Malate dehydrogenase and lactate dehydrogenase were present in all three tissues. Renal tubules incubated with glutamine and alanine were ammoniagenic and gluconeogenic. Lactate was gluconeogenic. Enzyme activities were measured at both 30 and 37 degrees C. The studies on renal tubules were also performed at these two temperatures. Temperature had little effect on the data including acid-base values in the blood. Our findings demonstrate that the kidney of the alligator is perfectly equipped for various metabolic functions and especially for ammoniagenesis and gluconeogenesis.

Acid-Base Equilibrium↗
PubMed1983

Comparison of mu-, delta- and kappa-receptor binding sites through pharmacologic evaluation of p-nitrophenylalanine analogs of opioid peptides.

For the purpose of comparing the structural requirements of opioid receptor subsites interacting with phenylalanine residues of opioid peptides, analogs containing p-nitrophenylalanine (Phe(pNO2) ) were synthesized and tested in the guinea pig ileum (GPI) and mouse vas deferens (MVD) assay as well as in mu- and delta-receptor selective binding assays. Whereas substitution of Phe(pNO2) in position 4 of the mu-selective analog H-Tyr-c[-N epsilon-D-Lys-Gly-Phe-Leu-] and of the delta-selective analog H-Tyr-D-Ser-Gly-Phe-Leu-Thr-OH produced a significant potency increase in all assays, the corresponding substitution in the kappa-selective dynorphin-(1-13) fragment resulted in a decreased potency in the GPI-assay. These findings suggest that the electronic requirements of the Phe4 binding site at the mu- and delta-receptor are identical, but different from those of the corresponding site at the kappa-receptor. The observation that Phe(pNO2) substitution in position 3 of morphiceptin and dermorphin also produces a drastic potency drop indicates that the Phe3 side-chain of the latter peptides at the mu- and delta-receptor may bind to a site different from that interacting with the Phe4 side-chain of enkephalins.

Animals↗
PubMed1982

Synthesis and pharmacological characterization in vitro of cyclic enkephalin analogues: effect of conformational constraints on opiate receptor selectivity.

Using a combination of solid-phase and solution methods, we synthesized a series of cyclic [Leu5]enkephalin analogues by substitution of D-alpha, omega-diamino acids in position 2 of the enkephalin sequence and cyclization of the omega-amino group to the C-terminal carboxy group of leucine. Cyclic analogues containing D-alpha, beta-diaminopropionic acid (1), D-alpha, gamma-diaminobutyric acid (2), D-ornithine (3), or D-lysine (4) in position 2 and the [D-Leu5] and [des-Leu5] analogues of 4 (5 and 6) showed, in general, high potency in the guinea pig ileum (GPI) assay and low potency in the mouse vas deferens (MVD) assay. IC50 (MVD)/IC50 (GPI) ratios ranging from 3.1 to 29.4 were obtained, indicating the preference of the cyclic analogues for mu receptors over delta receptors. With two exceptions, preferential affinity for mu receptors is reflected in the Ki ratios determined in parallel binding assays using [3H]naloxone and [3H] [D-Ala2, D-Leu5]enkephalin as mu and delta receptor selective radioligands, respectively. Comparison of the pharmacological profiles of the cyclic analogues 1-4 with those of their corresponding open-chain analogues, [D-Ala2, Leu5]enkephalinamide (1a), [D-Abu2, Leu5]enkephalinamide (2a), [D-Nva2, Leu5]enkephalinamide (3a), and [D-Nle2, Leu5]enkephalinamide (4a), revealed that the pronounced mu character of compounds 1-4 is a direct consequence of the conformational constraints introduced by cyclization. This finding is in agreement with the concept of different conformational requirements of mu- and delta-opiate receptors and raises the possibility of manipulating opiate receptor selectivity by varying the type and degree of conformational restriction.

Animals↗
PubMed1981

Electronic, steric, and hydrophobic factors influencing the action of enkephalin-like peptides on opiate receptors.

The requirements of opiate receptors for electronic, steric, and hydrophobic properties of the amino acids in Pos. 4 and 5 of enkephalin-like peptides were studied. A series of [D-Ala2]-enkephalins containing carboranylalanine, adamantylalanine, t-butylglycine and p-nitrophenylalanine were synthesized and their pharmacological activities in the guinea pig ileum and their naloxone displacement in rat brain homogenates determined. An electronegative (-E) aromatic character of the amino acid in Pos. 4 strongly enhanced potency, overruling steric effects. The enhancement was not caused by exceptional enzyme resistance. Amino acid in Pos. 5 contributed to potency mainly through its effect on overall hydrophobicity. The two C-terminal amino acids seem to function as potentiator and address elements in the enkephalins.

Animals↗
PubMedDate not supplied

Subtleties of structure-agonist versus antagonist relationships of opioid peptides and peptidomimetics.

The development of novel delta opioid antagonists and delta opioid agonists structurally derived from the prototype delta antagonist TIPP (H-Tyr-Tic-Phe-Phe-OH), is reviewed. Both delta antagonists and delta agonists with extraordinary potency and unprecedented delta receptor selectivity were discovered. Some of them are already widely used as pharmacological tools and are also of interest as potential therapeutic agents for use in analgesia. The results of the performed structure-activity studies revealed that the delta antagonist versus delta agonist behavior of this class of compounds depended on very subtle structural differences in diverse locations of the molecule. These observations can be best explained with a receptor model involving a number of different inactive and active receptor conformations.

Animals↗