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Amino Acids: The Forum for Amino Acid, Peptide and Protein Research (v.24, #4)

Neuronal transmembrane chloride electrochemical gradient: A key player in GABA_A receptor activation physiological effect by A. Cupello (pp. 335-346).

It has long been accepted that GABA is the main inhibitory neurotransmitter in the mammalian brain, acting via GABA_A or GABA_B receptors. However, new evidences have shown that it may work as an excitatory transmitter, especially in the brain of newly-born animals and acting via GABA_A receptors. The difference in the end results of GABA_A receptors activation in the two cases is not due to the receptor associated channels, which in both cases are chloride channels. The different physiological effect in the two cases is due to different electrochemical gradients for chloride. When GABA acting via GABA_A receptors is inhibitory, either there is no transmembrane electrochemical gradient for chloride or there is one forcing such negative ions into the nerve cell, once chloride channels are open. Viceversa, GABA is excitatory when the electrochemical gradient is such to make chloride ions flow outside the cell, upon opening of the GABA activated chloride channels.In this review this concept is discussed in details and evidence in the scientific literature for the existence of different types of chloride pumps (either internalizing or extruding chloride) is compiled.

Keywords: Key words: Chloride ion; Electrochemical gradient; Neurone; GABAA receptors; Physiological effect

Regulation of renal amino acid (AA) transport by hormones, drugs and xenobiotics – a review by C. Fleck; M. Schwertfeger; P. M. Taylor (pp. 347-374).

Major advances have recently been made in our understanding of the mechanisms and functions of amino acid transport in mammalian cells: – from the whole organism to transporter molecular structure. In this article, we present a brief overview of current knowledge concerning amino acid transporters, followed by a detailed discussion of the relevance of this new information to our broader understanding of the physiological regulation of amino acid handling in the kidney. We focus especially on the influence of hormones and xenobiotics on renal amino acid transport systems. In a growing number of cases, it now seems possible to correlate the effects of hormones, drugs, and xenobiotics with the capacity of renal amino acid transporters. This topic is of clinical relevance for the treatment of many amino acid reabsorption disorders. For example, under suitable conditions glucocorticoids and thyroid hormones stimulate renal reabsorption of amino acids and might therefore be of benefit in the treatment of different kinds of aminoaciduria. Hormonal regulation also underlies the postnatal development of renal amino acid reabsorption capacity, which can be stimulated to mature earlier after exogenous administration of e.g. glucocorticoids. In contrast, many compounds (e.g. heavy metal complexes) selectively damage renal amino acid transporters resulting in urinary amino acid loss. These types of phenomena (stimulation or inhibition of amino acid transporters in the kidney) are reviewed from the perspectives of our new molecular understanding of transport processes and of clinical relevance.

Keywords: Keywords: Amino acids; Transport; Kidney; Hormones; Xenobiotics; Stimulation; Inhibition

The low nanomolar levels of N^G-monomethylarginine in serum and urine of patients with chronic renal insufficiency are not significantly different from control levels by A. Torremans; B. Marescau; R. Vanholder; R. De Smet; J.-M. Billiouw; P. P. De Deyn (pp. 375-381).

There are no reliable mean values of N^G-monomethylarginine (NMMA) in blood and urine of patients with renal insufficiency available in the literature. Therefore we investigate whether the NMMA levels are changed in blood and urinary excretion of nondialysed and dialysed patients with chronic renal insufficiency to evaluate whether NMMA may reach sufficiently increased concentrations in blood of the patients to exert toxic biological activity.In nondialysed as well as in dialysed patients we find no significant difference in serum concentration of NMMA between patients and controls. In nondialysed patients (all with a residual creatinine clearance lower than 15 ml/min), we find 94.5 ± 26.1 nM (mean ± SD) versus 94.6 ± 19.5 nM in controls. Similar levels are found in serum of haemodialysed patients (each with serum creatinine levels >700 μM): 83.0 ± 20.2 nM. The urinary excretion of NMMA in nondialysed patients is also not significantly different from the excretion of controls: 123 ± 110 in patients versus 157 ± 117 nmol/24 hrs in controls. Furthermore, the clearance of NMMA is much lower compared to the clearance of the dimethylarginine derivatives.Based on the literature, the low nanomolar levels of NMMA found in blood of patients with renal insufficiency do not support the statement that NMMA proper may act as a uremic toxin.

Keywords: Keywords: NG-monomethylarginine; Guanidino compounds; Methylated arginine residues; Renal insufficiency; Uraemia; Nitric oxide (NO); Nitric oxide synthase (NOS)

Effects of phenylalanine and phenylpyruvate on ATP-ADP hydrolysis by rat blood serum by B. Rücker; J. P. Oses; I. B. Kirst; S. L. Berti; C. D. Bonan; A. M. O. Battastini; J. J. F. Sarkis (pp. 383-388).

The nucleotide (ATP-ADP)/nucleoside (adenosine) ratio in the circulation can modulate the processes of vasoconstriction, vasodilatation and platelet aggregation. The main objective of the present study with rat blood serum was to evaluate the possibility of changes in nucleotide hydrolysis by phenylalanine (Phe) and phenylpyruvate (PP), the levels of which could increase in the circulation of individuals with phenylketonuria. Results demonstrated that Phe in the range 1.0–5.0 mM inhibited the ADP hydrolysis by rat serum. The effect of inhibition by Phe on ATP hydrolysis appeared only at a concentration of 5.0 mM. PP had no significant effect upon nucleotide hydrolysis. Kinetic analysis indicated that the inhibition of ADP and ATP hydrolysis by Phe in rat blood serum is uncompetitive. Conversely, Phe and PP did not affect the hydrolysis of p-nitrophenyl-5′-TMP by rat serum.

Keywords: Keywords: ATP Diphosphohydrolase; Apyrase; Phenylalanine; Phenylpyruvate; Phenylketonuria; Circulatory problems

l-Homoarginine suppresses exocrine pancreas in rats by T. Hira; S. Ohyama; H. Hara (pp. 389-396).

Previously, we found that guanidinated casein, a l-homoarginine-containing protein, was a more potent stimulator of pancreatic enzyme secretion than intact casein in rats. In this study, we examined secretory response and adaptation of the exocrine pancreas to the administration of free l-homoarginine in normal and bile-pancreatic juice (BPJ)-diverted rats. An intraperitoneal injection of l-homoarginine (10 mg/rats) produced immediate and transient reduction in pancreatic secretion in BPJ-diverted rats, but not in normal rats. The BPJ-diverted rats were fed with either a 25% casein, 45% casein, or 45% casein diet supplemented with l-homoarginine (19 g/kg diet) for 4 days. Feeding of a diet containing l-homoarginine inhibited the pancreatic adaptation induced by the high-protein diet. These results indicate that l-homoarginine has an inhibitory effect on the secretion and production of exocrine pancreatic enzyme in BPJ-diverted rats, and l-homoarginine may have an antagonistic effect on CCK receptors.

Keywords: Keywords: l-Homoarginine; Pancreatic secretion; Pancreatic hypertrophy; Bile-pancreatic juice diversion; Hypercholecystokinemia; Rat

The role of ionotropic receptors of glutaminic acid in cardiovascular system by E. M. Sitniewska; R. J. Wiśniewska; K. Wiśniewski (pp. 397-403).

The aim of our study was to estimate the involvement of the peripheral N-methyl-D-aspartate receptors in regulation of cardiovascular function. For this purpose we examined the effects of intravenous injection of the agonists – NMDA (0.025; 0.05 and 1.0 mg/kg iv) and 1R-3R-ACPD (0.025; 0.05 and 1.0 mg/kg iv) – and antagonist of NMDA receptors DL-AP7 (0.02; 0.07 and 0.2 mg/kg iv). To determine if the effects of NMDA come from central or peripheral action we observed the effect during blockade of autonomic ganglion by using the nicotinic receptor antagonist – chlorisondamine (1.25 mg/kg iv). Administration of NMDA in three doses evoked slight hypotension after injection of the medium dose, 0.05 mg/kg. In the condition of pretreatment with 1.25 mg/kg chlorisondamine the hypotensive effect of NMDA was markedly reduced, what might suggest that NMDA-induced hypotension raised from the action within the brain. The competetive NMDA receptor antagonist DL-AP7 slightly increased the blood pressure. None of the injected drug had an influence on the heart rate in our in vivo study.It is concluded that the peripherally localized NMDA receptors may take a part in regulation of cardiovascular system, since their stimulation or blockade evoked the changes of systemic pressure.

Keywords: Key words: NMDA receptors; Systemic administration; Blood pressure; Heart rate

Optimized conventional synthesis of “RGD” and “RGDS” peptides and their sarcosine mimics as integrin GP IIb/IIIa antagonists by M. Abo-Ghalia; S. Abd El-Rahman; A. El-Kafrawy; A. Kalomuch (pp. 405-411).

Synthetic arginyl-glycyl-α-aspartyl “RGD” and arginyl-glycyl-α-aspartyl-serinyl “RGDS” peptide sequences, which are originally located in matrix proteins, are confirmed to be as versatile integrin GP IIb/IIIa antagonists. Since integrins, as cell surface glycoprotein receptors are implicated in several physiological mechanisms, these peptides are recently specially considered in the design of new therapeutics.Replacing glycine by sarcosine, as its more lipophilic isomer, in RGD peptides seemed, accordingly, interesting in revealing some structural/biological activity relationships.To render “RGD” peptides more conveniently available, an ameliorated quasi-gram yield conventional synthesis in solution of the parent “RGD” and “RGDS” [8, Scheme 1A & 15, Scheme 1B] and their sarcosine analogues, [8′, Scheme 1A & 15′, Scheme 1B] respectively, is herein described.A compilation of the mild hydrogenolysis removable Z and NO₂ groups and/or the acidiolytic removable Boc group were manipulated for the amino temporary protecting steps. Both the DCCI/HOBt and MA methodologies served well as peptide coupling methods.

Keywords: Keywords: RGD; RGDS; Peptides; Sarcosine; GP IIb/IIIa Antagonists

Serum amino acid concentrations in aging men and women by H. T. Pitkänen; S. S. Oja; K. Kemppainen; J. M. Seppä; A. A. Mero (pp. 413-421).

The age and gender related differences in serum amino acid concentrations have been assessed in 72 (23–92 years) medically screened healthy men and women who were divided into three male and three female groups according to age. Free-time physical activity and food intake were analysed from the 5-day diaries. The subjects were instructed to eat according to their normal dietary habits and to avoid any clinical complementary nutritional products or other products that could increase protein or energy intake. The blood samples (5 ml) taken from the antecubital vein after an over-night fast were analysed for their amino acid contents by chromatography. In total nutrient intake of energy (P < 0.001), protein (P < 0.001), alcohol (P < 0.05), water (P < 0.01), sodium (P < 0.001) and fiber P < 0.001) decreased significantly with age. The concentration of total amino acids (P < 0.01), essential amino acids (P < 0.001), non-essential amino acids (P < 0.05) and branched-chain amino acids (P < 0.05) decreased, whereas citrulline (P < 0.001) and cysteine (P < 0.001) were the only amino acids, which increased with aging. In addition, men had significantly higher concentrations than women of essential amino acids (P < 0.001), branched-chain amino acids (P < 0.001), and 10 of the 22 individual amino acids assayed (P < 0.01). Women had significantly higher concentrations of aspartate (P < 0.05), glycine (P < 0.01), serine (P < 0.001) and taurine (P < 0.01) than men. It is concluded that the decrease in serum total amino acid concentration is associated with decreased energy and protein intake with aging and men have higher essential amino acid concentration in serum than women.

Keywords: Keywords: Amino acids; Non-athletes; Age; Gender; Nutrition

Synthesis of new α-heterocyclic α-aminoesters by A. Bentama; E. M. El Hadrami; A. El Hallaoui; A. Elachqar; J.-P. Lavergne; M.-L. Roumestant; Ph. Viallefont (pp. 423-426).

α-Heterocyclic α-aminoesters were obtained in good yields by reaction of a glycine cation equivalent and different heterocyclic nucleophiles; diastereoselectivity using a carbohydrate (galactopyranose) as N-protecting group was modest.

Keywords: Keywords: Heterocyclic α-aminoesters; Chiral auxiliary; Galactopyranose

Phosphate-dependent glutaminase in enterocyte mitochondria and its regulation by ammonium and other ions by B. Masola; E. Zvinavashe (pp. 427-434).

The effects of ammonium and other ions on phosphate dependent glutaminase (PDG) activity in intact rat enterocyte mitochondria were investigated. Sulphate and bicarbonate activated the enzyme in absence and presence of added phosphate. In presence of 10 mM phosphate, ammonium at concentrations <1 mM inhibited the enzyme. This inhibition was reversed by increased concentration of phosphate or sulphate. The inhibition of PDG by ammonium in presence of 10 mM phosphate was biphasic with respect to glutamine concentration, its effect being through a lowering of V_max at glutamine concentration of ≤5 mM, and increased K_m for substrate concentration above 5 mM. The activation of the enzyme by bicarbonate was through an increase in V_max. Ammonium and bicarbonate ions may therefore be important physiological regulators of PDG. It is suggested that phosphate and other polyvalent ions may function by preventing product inhibition of the enzyme through promotion of PDG dimer formation. The dimerized enzyme may have a high affinity for glutamine and reduced sensitivity to inhibition by ammonium ions.

Keywords: Keywords: Glutaminase; Ammonium; Bicarbonate; Mitochondria; Enterocyte

Metabolic interactions between restraint stress and l-lysine: The effect on urea cycle components by M. Smriga; K. Torii (pp. 435-437).

We studied the effects of l-lysine on wrap-restraint stress-induced changes in ureagenesis. An exposure to wrap-restraint stress did not affect the plasma concentration of l-lysine, but did decrease plasma urea and arginine. Oral l-lysine (1 g/kg) blocked the effect of stress on ureagenesis, and enhanced the effect of stress on l-arginine. No influence of l-lysine were found in controls. The results imply a stress-specific, ureagenesis-stimulating effect of l-lysine, and suggest an increased requirement for l-arginine during the above conditions.

Keywords: Keywords: Wrap-restraint stress; Urea; Arginine; Lysine; Rat

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Amino Acids: The Forum for Amino Acid, Peptide and Protein Research (v.24, #4)