Valsartan reduces serum cystatin C and the renal vascular resistance in patients with essential hypertension.

A high level of albuminuria and increased renal vascular resistance are associated with hypertensive renal damage. In this study, the authors investigated the effect of the angiotensin II receptor blocker, valsartan, on renal function and intrarenal hemodynamics in non-diabetic patients with essential hypertension. A prospective three-month study of the effects of valsartan, 40-80 mg/day, was performed in 30 hypertensive patients. As an assessment of renal function, serum creatinine, urine albumin/creatinine (Alb/Cr) ratio, and serum cystatin C levels were evaluated. Doppler ultrasonography of the kidney was performed for the evaluation of renal hemodynamics. Peak-systolic, end-diastolic, and mean velocities of interlobar arteries were evaluated, and the pulsatility index (PI) and resistive index (RI) were calculated. It was determined that patients with microalbuminuria had higher levels of serum cystatin C, PI, and RI compared to patients without microalbuminuria. Valsartan treatment significantly reduced systolic and diastolic blood pressure and decreased the Alb/Cr ratio. Serum creatinine was not changed, whereas serum cystatin C levels were significantly reduced. Valsartan treatment significantly decreased the PI in all patients and both PI and RI in patients with microalbuminuria. These results suggest that the angiotensin II receptor blocker, valsartan, is able to improve renal function by reducing renal vascular resistance in hypertensive patients, especially in patients with microalbuminuria, and may prevent future renal failure in patients with essential hypertension.

Interactions of a nonpeptidic drug, valacyclovir, with the human intestinal peptide transporter (hPEPT1) expressed in a mammalian cell line.

The results of previous work performed in our laboratory using an in situ perfusion technique in rats and rabbit apical brush border membrane vesicles have suggested that the intestinal uptake of valacyclovir (VACV) appears to be mediated by multiple membrane transporters. Using these techniques, it is difficult to characterize the transport kinetics of VACV with each individual transporter in the presence of multiple known or unknown transporters. The purpose of this study was to characterize the interaction of VACV and the human intestinal peptide transporter using Chinese hamster ovary (CHO) cells that overexpress the human intestinal peptide transporter (hPEPT1) gene. VACV uptake was significantly greater in CHO cells transfected with hPEPT1 than in cells transfected with only the vector, pcDNA3. The optimum pH for VACV uptake was determined to occur at pH 7.5. Proton cotransport was not observed in hPEPT1/CHO cells, consistent with previously observed results in tissues and Caco-2 cells. VACV uptake was concentration dependent and saturable with a Michaelis-Menten constant and maximum velocity of 1.64 +/- 0.06 mM and 23.34 +/- 0.36 nmol/mg protein/5 min, respectively. A very similar Km value was obtained in hPEPT1/CHO cells and in rat and rabbit tissues and Caco-2 cells, suggesting that hPEPT1 dominates the intestinal transport properties of VACV in vitro. VACV uptake was markedly inhibited by various dipeptides and beta-lactam antibiotics, and Ki values of 12.8 +/- 2.7 and 9.1 +/- 1.2 mM were obtained for Gly-Sar and cefadroxil at pH 7.5, respectively. The present results demonstrate that VACV is a substrate for the human intestinal peptide transporter in hPEPT1/CHO cells and that although transport is pH dependent, proton cotransport is not apparent. Also, the results demonstrate that the hPEPT1/CHO cell system has use in investigating the transport kinetics of drugs with the human intestinal peptide transporter hPEPT1; however, the extrapolation of these transport properties to the in vivo situation requires further investigation.

Amino acid transport in cerebral microvessels during Plasmodium yoelii infection in mice.

Plasmodium yoelii infected cerebral microvessels of mice had an enhanced time-dependent, temperature-sensitive, and saturable uptake of [14C]-amino acid. viz. leucine, valine and glycine. Metabolic inhibitors caused a noticeable inhibition of amino acid uptake in normal microvessels as compared to infected cerebral microvessels indicating that the uptake of [14C]-L-leucine, [14C]-L-valine and [14C]-glycine is an energy dependent process.

Oxiracetam and D-pyroglutamic acid antagonize a disruption of passive avoidance behaviour induced by the N-methyl-D-aspartate receptor antagonist 2-amino-5-phosphonovalerate.

Intracerebroventricular administration (6 micrograms/2 microliters) of D-2-amino-5-phosphonovalerate (AP-5), a specific antagonist of the NMDA receptors, prior to training impaired the passive avoidance in a retention test in rat. Pretreatment with oxiracetam and D-pyroglutamic acid at doses ranging from 50 to 500 mg/kg SC dose-dependently prevented the disruptive effect of AP-5. This finding indicates that an interaction with excitatory amino acid NMDA type receptors may be important in behavioural effects of the two pyrrolidinone derivatives.

Comparison of the properties of [3H]-D-2-amino-5-phosphonopentanoic acid and [3H]-DL-2-amino-7-phosphonoheptanoic acid binding to homogenates of rat cerebral cortex.

1. The pharmacology and ionic regulation of [3H]-2-D-2-amino-5-phosphonopentanoic acid ([3H]-D-AP5) and [3H]-DL-2-amino-7-phosphonoheptanoic acid ([3H]-DL-AP7) binding to homogenates of rat cerebral cortex were examined using radioligand binding methodology. 2. Both [3H]-D-AP5 and [3H]-DL-AP7 labelled a single population of binding sites with dissociation constants of 0.39 and 1.8 mumol/l, respectively. The density of binding sites found with [3H]-DL-AP7 was 13 times greater than that found with [3H]-D-AP5. 3. The ionic requirements of the [3H]-D-AP5 binding site in the presence of chloride were such that calcium acetate enhanced binding, while magnesium and sodium acetate both decreased binding. In the absence of chloride both calcium and chloride ions stimulated binding. 4. In a chloride-free buffer calcium acetate stimulated binding of [3H]-DL-AP7 in a biphasic manner. Chloride ions (ammonium salt) enhanced binding slightly at low concentrations (0.1-1.0 mmol/l) above which binding was reduced to non-specific levels. The ionic dependence of [3H]-DL-AP7 binding had some similarities to the previously defined GLU-C site. 5. The pharmacological profile of the site labelled by [3H]-D-AP5 was consistent with that of a recognition site for N-methyl-D-aspartate (NMDA) as defined in electrophysiological experiments. [3H]-DL-AP7 did not label an NMDA site as several non-NMDA ligands displaced binding with high affinity and the binding was not stereospecific as found for [3H]-D-AP5. Moreover, the pharmacological profile of the [3H]-DL-AP7 site did not correspond to any excitatory amino acid receptor as presently defined.

Capillary gas chromatographic/mass spectrometric analysis of abnormal metabolites in hypoglycin-treated rat urine.

Numerous abnormal metabolites were identified in large amounts in the urine of hypoglycin-treated rats using capillary gas chromatography/mass spectrometry-computer analysis. These metabolites are not detectable in significant amounts in normal rats' urine. Ten of them have not been previously associated with hypoglycin administration: these are several hydroxy compounds, including those from the valine and isoleucine pathways, 2-oxo-adipic acid, n-butyrylglycine and isovaleryl glucuronide. These results indicate that the pathways of isoleucine and valine metabolism are inhibited at their respective acyl-CoA dehydrogenation steps, as is the case for fatty acid, leucine and lysine metabolism, as previously shown. The mass spectra of the trimethylsilyl derivatives of cis, cis-4,7-decadiene-1,10-dioic, cis-4-decene-1,10-dioic, cis-4-octene-1,8-dioic acids, and (methylenecyclopropyl)acetylglycine, which were previously identified using nuclear magnetic resonance and oxidative cleavage or acid hydrolysis, are presented for the first time.

Verapamil counteracts the masking of long-lasting potentiation of hippocampal population spike produced by 2-amino-5-phosphonovalerate.

In transversely sectioned rat hippocampal slices the effects of 2-amino-5-phosphonovalerate (APV), presumably a selective N-methyl-DL-aspartate antagonist, were examined on the development of long-lasting potentiation (LLP) of the CA1 population spike produced by Schaffer collateral tetanization (100 Hz, 1 s). APF (100 nA, 5 min), when applied 150-200 micron away from the CA1 cell bodies (apical dendritic area), had no significant effect if the population spike was evoked at 0.1 Hz, but produced a depression of the population spike if a 100 Hz tetanus was given during its iontophoresis. This depressant effect of APV was counteracted by verapamil (0.33 microM, 3 min) and LLP induced by the 100 Hz tetanus was unmasked. It is suggested that APV does not antagonize LLP, but only masks it by allowing CA++ influx into CA1 neurones that induces a depression. The results also raise doubts as to the selectivity of APV as an amino acid antagonist.

[Mutagenic action of nitroso compounds on Escherichia coli cells]. / Izuchenie mutagennogo deistviia nitrozosoedineniia na kletki Escherichia coli.

An attempt to induce some forward and back mutations in two Escherichia coli strains (his- and HfrH requiring thiamine) under the action of the carcinogenic nitrosamines--dimethylnitrosamine (DMN) and diethylnitrosamine (DEN)--is described. For this purpose the cells of E. coli were treated with 5% DMN or 1% DEN for 1 hour at 37 degrees C in 0.14 M NaCl. It was shown that the sensitivity of both strains to both nitrose compounds was not the same. DEN was 5-fold as toxic as DMN for the E. coli cells. DMN and DEN induced neither mutations of resistance to 10(-3) M valine, nor reversions in histidine-dependent strain. These mutations were obtained after the cells were treated with 0.1 M NaNO2. Lethal effects of DMN increased more than in 5 times and the toxicity of DEN did not change in hydroxylating mixture, in which nitrosamines derived to active compounds. Under these conditions both carcinogenes showed a mutagenic activity. DEN proved to be about twice as strong mutagenically as DMN. Thus, in our experiments we could see that DMN and DEN could induce both forward and back mutations in E. coli.

[L-valine transport by the actinomycete Actinomyces species 26-115, the producer of actinomycin C]. / Transport L-valina aktinomitsetom Actinomyces species 26-115--produtsentom aktinomitsina C

Transport of L-valine by Actinomyces species 26-115, an organism producing actinomycin C depended on L-valine concentration in the medium and temperature and required a source of intrinsic energy. Km for L-valine transport was 3.5.10(-6)--6.0.10(-6) M. It somewhat differed from experiment to experiment. The above system transported also other neutral amino acids. L-isoleucine was a competing inhibitor of L-valine transport. The transport of L-valine was stereospecific. The activity of the transport system was regulated by the intracellular content of L-valine. Probably because of this the amino acid transport depended on the culture age, so far as the level of free valine in the mycelium at various stages of development was different.

Studies on convulsants in the isolated frog spinal cord. I. Antagonism of amino acid responses.

1. The isolated frog spinal cord was used to study the effects of picrotoxin, bicuculline, and strychnine on the responses of primary afferents to amino acids. Recording was by sucrose gap technique. 2. A series of neutral amino acids was found to depolarize primary afferents. Optimal activity was obtained by an amino acid whose carboxyl and amino groups were separated by a three-carbon chain length (i.e. GABA). Amino acids with shorter (i.e. beta-alanine, glycine) or longer (i.e. delta-aminovaleric acid, epsilon-aminocaproic acid) distances between the charged groups were less potent. Imidazoleacetic acid was the most potent depolarizing agent tested. 3. Picrotoxin and bicuculline antagonized the primary afferent depolarizations of a number of amino acids tested with equal specificity. Depolarizing responses to standard (10- minus 3 M) concentrations of beta-alanine and taurine were completely blocked by these convulsants, while depolarizations to 10- minus 3 gamma-aminobutyric acid (GABA) were only partially antagonized. Glycine responses were unaffected by these agentsk; Strychnine completely blocked beta-alanine and taurine depolarizations and incompletely antagonized several other neutral amino acids. GABA, glutamate, and glycine depolarizations were not affected. 5. These results suggest that there are at least three distinct populations of neutral amino acid receptors on primary afferent terminals: a GABA-like receptor, a taurine/beta-alanine receptor, and a glycine-like receptor. The strychnine resistance of the glycine responses indictaes that the primary afferent receptors for glycine differ from those on the somata of spinal neurones.