Pathways for angiotensin-(1—7) metabolism in pulmonary and renal tissues

2000 ◽  
Vol 279 (5) ◽  
pp. F841-F850 ◽  
Author(s):  
Alicia J. Allred ◽  
Debra I. Diz ◽  
Carlos M. Ferrario ◽  
Mark C. Chappell
Keyword(s):  
Brush Border Membrane ◽  
Ace Inhibitor ◽  
Renal Cortex ◽  
Combined Treatment ◽  
Kinetic Studies ◽  
Ace Inhibition ◽  
Alternate Pathway ◽  
Renal Brush Border Membrane ◽  
Rate Of Hydrolysis ◽  
Hydrolysis Of

Two of the primary sites of actions for angiotensin (ANG)-(1—7) are the vasculature and the kidney. Because little information exists concerning the metabolism of ANG-(1—7) in these tissues, we investigated the hydrolysis of the peptide in rat lung and renal brush-border membrane (BBM) preparations. Radiolabeled ANG-(1—7) was hydrolyzed primarily to ANG-(1—5) by pulmonary membranes. The ANG-converting enzyme (ACE) inhibitor lisinopril abolished the generation of ANG-(1—5), as well as that of smaller metabolites. Kinetic studies of the hydrolysis of ANG-(1—7) to ANG-(1—5) by somatic (pulmonary) and germinal (testes) forms of rat ACE yielded similar values, suggesting that the COOH-domain is responsible for the hydrolysis of ANG-(1—7). Pulmonary metabolism of ANG-(1—5) yielded ANG-(3—5) and was independent of ACE but may involve peptidyl or dipeptidyl aminopeptidases. In renal cortex BBM, ANG-(1—7) was rapidly hydrolyzed to mono- and dipeptide fragments and ANG-(1—4). Aminopeptidase (AP) inhibition attenuated the hydrolysis of ANG-(1—7) and increased ANG-(1—4) formation. Combined treatment with AP and neprilysin (Nep) inhibitors abolished ANG-(1—4) formation and preserved ANG-(1—7). ACE inhibition had no effect on the rate of hydrolysis or the metabolites formed in the BBM. In conclusion, ACE was the major enzymatic activity responsible for the metabolism of ANG-(1—7) in the lung, which is consistent with the ability of ACE inhibitors to increase the half-life of circulating ANG-(1—7) and raise endogenous levels of the peptide. An alternate pathway of metabolism was revealed in the renal cortex, where increased AP and Nep activities, relative to ACE activity, promote conversion of ANG-(1—7) to ANG-(1—4) and smaller fragments.

scholarly journals Kinetic studies on the acid hydrolysis of the methyl ketoside of unsubstituted and O-acetylated N-acetylneuraminic acid

1973 ◽  
Vol 133 (4) ◽  
pp. 623-628 ◽  
Author(s):  
A. Neuberger ◽  
Wendy A. Ratcliffe
Keyword(s):  
Sialic Acid ◽  
Acid Hydrolysis ◽  
Model Compound ◽  
Kinetic Studies ◽  
Order Rate Constant ◽  
Neuraminic Acid ◽  
Acetylneuraminic Acid ◽  
Rate Of Hydrolysis ◽  
Ph Range ◽  
Hydrolysis Of

The hydrolysis of the model compound 2-O-methyl-4,7,8,9-tetra-O-acetyl-N-acetyl-α-d-neuraminic acid and neuraminidase (Vibrio cholerae) closely resembled that of the O-acetylated sialic acid residues of rabbit Tamm–Horsfall glycoprotein. This confirmed that O-acetylation was responsible for the unusually slow rate of acid hydrolysis of O-acetylated sialic acid residues observed in rabbit Tamm–Horsfall glycoprotein and their resistance to hydrolysis by neuraminidase. The first-order rate constant of hydrolysis of 2-methyl-N-acetyl-α-d-neuraminic acid by 0.05m-H2SO4 was 56-fold greater than that of 2-O-methyl-4,7,8,9-tetra-O-acetyl-N-acetyl -α-d-neuraminic acid. Kinetic studies have shown that in the pH range 1.00–3.30, the observed rate of hydrolysis of 2-methyl-N-acetyl-α-d-neuraminic acid can be attributed to acid-catalysed hydrolysis of the negatively charged CO2− form of the methyl ketoside.

scholarly journals Further evidence for an allosteric model for ribonuclease

1976 ◽  
Vol 153 (2) ◽  
pp. 329-337 ◽  
Author(s):  
E J Walker ◽  
G B Ralston ◽  
I G Darvey
Keyword(s):  
Conformational Change ◽  
Equilibrium Dialysis ◽  
Kinetic Studies ◽  
Experimental Systems ◽  
Substrate Analogues ◽  
Multiple Binding ◽  
Rate Of Hydrolysis ◽  
Hydrolysis Of ◽  
Cyclic Cmp ◽  
Allosteric Model

Evidence is presented from three experimental systems to support the allosteric model of Walker et al. (1975) (Biochem. J. 147, 425-433) which explains the substrate-concentration-dependent transition observed in the RNAase (ribonuclease)-catalysed hydrolysis of 2‘:3’-cyclic CMP (cytidine 2‘:3’-cyclic monophosphate). 1. Kinetic studies of the initial rate of hydrolysis of 2‘:3’-cyclic CMP show that the midpoint of the transition shifts to lower concentrations of 2‘:3’-cyclic CMP in the presence of the substrate analogues 3′-CMP, 5′-CMP, 3′-AMP, 3′-UMP and Pi; 2′-CMP and 2′-UMP do not cause such a shift. 2. Trypsin-digestion studies show that a conformational change in RNAase to a form less susceptible to tryptic inactivation is induced in the presence of the substrate analogues 3′-CMP, 5′-CMP, 3′-AMP, and 3′-UMP. 2′-CMP, 2′-AMP and 2′-UMP do not induce this conformational change. 3. Equilibrium-dialysis experiments demonstrate the multiple binding of molecules of 3′-CMP, 3′-AMP and 5′-AMP to a molecule of RNAase. 2′-CMP binds the ratio 1:1 over the analogue concentration range studied.

Effect of glucocorticoids on renal cortical NHE-3 and NHE-1 mRNA

1994 ◽  
Vol 267 (3) ◽  
pp. F437-F442 ◽  
Author(s):  
M. Baum ◽  
O. W. Moe ◽  
D. L. Gentry ◽  
R. J. Alpern
Keyword(s):  
Proximal Tubule ◽  
Mammalian Cells ◽  
Brush Border Membrane ◽  
Renal Cortex ◽  
Membrane Vesicles ◽  
Mrna Abundance ◽  
Renal Brush Border Membrane ◽  
Acute Increase ◽  
Glucocorticoid Deficiency ◽  
Convoluted Tubules

Glucocorticoids play an important role in modulating proximal tubule acidification. Chronic systemic administration of dexamethasone increases the rate of bicarbonate absorption in isolated perfused proximal convoluted tubules and Na+/H+ antiporter activity in renal brush-border membrane vesicles. The proximal tubule expresses mRNA corresponding to two known Na+/H+ antiporter isoforms: NHE-3, an amiloride-resistant apical membrane Na+/H+ antiporter; and NHE-1, an amiloride-sensitive Na+/H+ antiporter found on most mammalian cells. Administration of dexamethasone for 1 and 2 days (600 micrograms/kg twice daily and 2 h before animals were killed) increased NHE-3 mRNA abundance 1.3- and 2.5-fold, respectively, but had no effect on NHE-1 mRNA abundance. Aminoglutethimide-induced glucocorticoid deficiency had no effect on NHE-1 or NHE-3 mRNA abundance. Incubation of proximal tubules for 3 h with 10(-5) M dexamethasone increased proximal tubule Na+/H+ antiporter activity from 0.69 +/- 0.04 to 0.92 +/- 0.03 pH units/min (P < 0.01); however, there was no increase in NHE-3 or NHE-1 mRNA abundance. Similarly, there was no effect on NHE-3 or NHE-1 mRNA abundance in rabbit renal cortex 4 h after intravenous administration of 600 micrograms/kg dexamethasone. Thus chronic dexamethasone increases NHE-3 but not NHE-1 mRNA abundance. The acute increase in Na+/H+ antiporter activity induced by dexamethasone occurs by mechanisms independent of changes in NHE-1 and NHE-3 mRNA abundance.

Betaine transport in rabbit renal brush-border membrane vesicles

1993 ◽  
Vol 264 (6) ◽  
pp. F948-F955 ◽  
Author(s):  
T. M. Wunz ◽  
S. H. Wright
Keyword(s):  
Brush Border ◽  
Brush Border Membrane ◽  
Renal Cortex ◽  
Membrane Vesicles ◽  
Brush Border Membrane Vesicles ◽  
Maximal Rate ◽  
Transport Pathways ◽  
Organic Osmolyte ◽  
Renal Brush Border Membrane ◽  
Renal Brush Border

Transport of the organic osmolyte betaine was characterized in brush-border membrane vesicles (BBMV) isolated from rabbit renal cortex. Inwardly directed gradients of either Na+ or H+ supported concentrative uptake in a manner consistent with the presence of parallel Na(+)-betaine and H(+)-betaine cotransport processes. Concentrative uptake occurred in the presence of membrane potential alone, indicating that betaine transport is electrogenic. Accumulation of betaine was not dependent on chloride in the medium. Whereas L-proline inhibited both the H(+)- and Na(+)-sensitive components of betaine transport, glycine blocked the H(+)-sensitive pathway and had little effect on Na(+)-sensitive betaine transport. Both pathways were adequately described by Michaelis-Menten kinetics. Under Na(+)-gradient conditions (pH equilibrium), the maximal rate of total betaine transport (Jmax) = 50.8 +/- 13.3 nmol.mg-1.min-1 and the concentration of total betaine producing half-maximal uptake (Kt) = 4.1 +/- 0.5 mM. Under H(+)-gradient conditions (Na+ free), Jmax = 102.5 +/- 10.5 nmol.mg-1.min-1 and Kt = 2.8 +/- 0.3 mM. Imposition of both Na+ and H+ gradients increased Jmax (142 +/- 25.5 nmol.mg-1.min-1) to a level significantly greater than that noted in the presence of a Na+ gradient alone. We conclude that betaine transport in renal BBMV involves two distinct transport pathways that are differentiated on the basis of sensitivity to either Na+ or H+ and by their specificity to proline and glycine.

Kinetic studies on the imines derived from reaction of 2-Amino-2-hydroxymethylpropane-1,3-diol with 2-Hydroxybenzaldehyde and with 1-Hydroxy-2-naphthaldehyde. Hydrolysis kinetics, and evidence for catalysis by the phenolate (ortho-O-) group in the imine formation reaction

1983 ◽  
Vol 36 (11) ◽  
pp. 2327 ◽  
Author(s):  
RMB Singh ◽  
L Main
Keyword(s):  
Deuterium Oxide ◽  
Kinetic Studies ◽  
Base Catalysis ◽  
Rate Coefficients ◽  
Contributing Factors ◽  
Formation Reaction ◽  
Rate Of Hydrolysis ◽  
Rate Profile ◽  
Solvent Isotope ◽  
Hydrolysis Of

pH-rate profiles are reported for the hydrolysis of 2-[[{2-hydroxy-1,1-di(hydroxymethyl)ethyl}-imino]methyl]phenol (1) and 1-[[{2-hydroxy-1,1-di(hydroxymethyl)ethyl}imino]methyl]-2-naphthol (2). Rate coefficients for possible contributing reactions are established and compared. Measurement of the rate of hydrolysis in deuterium oxide of (1) in the neutral plateau region of the pH-rate profile shows that the imine (1) is about 1.6 times more reactive in H2O than in D2O, and possible contributing factors to this solvent isotope effect are considered. Also reported are rate data for formation of (1) from 2-amino-2-hydroxymethylpropane-1,3-diol and 2-hydroxybenzaldehyde which show the latter to be almost as reactive in the anionic as in the neutral form; this suggests a base catalysis role by the phenolate oxygen in imine formation.

Role of megalin in renal handling of aminoglycosides

2001 ◽  
Vol 281 (2) ◽  
pp. F337-F344 ◽  
Author(s):  
Junya Nagai ◽  
Hiroaki Tanaka ◽  
Naoki Nakanishi ◽  
Teruo Murakami ◽  
Mikihisa Takano
Keyword(s):  
Brush Border Membrane ◽  
Renal Cortex ◽  
Renal Medulla ◽  
Bolus Administration ◽  
Renal Tubules ◽  
Vitamin D Binding Protein ◽  
Renal Handling ◽  
Renal Brush Border Membrane

The role of megalin in tissue distribution of aminoglycosides was examined in normal rats and maleate-treated rats that shed megalin from the renal brush-border membrane. In normal rats, amikacin administered intravenously accumulated most abundantly in the renal cortex, followed by the renal medulla. No amikacin was detected in other tissues. Tissue distributions of amikacin were well correlated with megalin levels in each tissue. Bolus administration of gentamicin increased urinary excretion of megalin ligands (vitamin D binding protein and calcium), suggesting the competition between gentamicin and these megalin ligands in renal tubules. Ligand blotting showed that binding of45Ca2+ to megalin was inhibited by aminoglycosides. Both megalin levels and amikacin accumulation in renal cortex were decreased by maleate injection. Then, amikacin accumulation recovered proportionate to megalin levels. These findings suggest that megalin is involved in the renal cortical accumulation of aminoglycosides in vivo. In addition, the interaction between aminoglycosides and calcium in the kidney may be due to the competition among these compounds to bind to megalin.

Phosphonoformic acid blunts adaptive response of renal and intestinal Pi transport

1993 ◽  
Vol 265 (6) ◽  
pp. F756-F763 ◽  
Author(s):  
M. Loghman-Adham ◽  
M. Levi ◽  
S. A. Scherer ◽  
G. T. Motock ◽  
M. T. Totzke
Keyword(s):  
Drinking Water ◽  
Adaptive Response ◽  
Brush Border Membrane ◽  
Membrane Vesicles ◽  
Kinetic Studies ◽  
Phosphonoformic Acid ◽  
Pi Transport ◽  
Renal Brush Border Membrane ◽  
Kinetics Of ◽  
Renal Brush Border

Parenteral administration of phosphonoformic acid (PFA) results in phosphaturia, but the effects of oral PFA on Pi handling are not known. To assess this effect, PFA was administered in drinking water for 5 days to rats stabilized on normal (NPD) or low (LPD) phosphorus diets. In renal brush-border membrane vesicles (BBMV), kinetic studies showed a higher apparent Vmax for Pi in rats on LPD compared with rats on NPD (1,840 +/- 274 vs. 1,111 +/- 192 pmol.mg-1.5 s-1, respectively, P < 0.05, n = 5). In LPD rats, PFA reduced the apparent Vmax for Pi to 1,047 +/- 191 pmol.mg-1.5 s-1 (P < 0.05, n = 5) with no change in the apparent Km. Similarly, there was a higher apparent Vmax for Pi in intestinal BBMV from rats on LPD compared with rats on NPD. In LPD rats, PFA reduced the apparent Vmax for Pi with no change in the apparent Km. Oral PFA had no effect on the kinetics of Pi transport in renal or intestinal BBMV from rats on NPD. Pi-protectable [14C]PFA binding was lower in renal BBMV from PFA-treated LPD rats, but membrane fluidity was not different. Orally administered PFA can blunt the adaptive response of the renal and intestinal BBM to an LPD. The downregulation of Na(+)-Pi cotransport is mediated through a reduction in the number of Na(+)-Pi cotransporters.

Chronic K depletion stimulates rat renal brush-border membrane Na-citrate cotransporter

1991 ◽  
Vol 261 (5) ◽  
pp. F767-F773 ◽  
Author(s):  
M. Levi ◽  
L. A. McDonald ◽  
P. A. Preisig ◽  
R. J. Alpern
Keyword(s):  
Brush Border ◽  
Brush Border Membrane ◽  
Apical Membrane ◽  
Kinetic Studies ◽  
Maximal Activity ◽  
Linear Rate ◽  
Renal Brush Border Membrane ◽  
Low K ◽  
K Depletion ◽  
Renal Brush Border

Chronic K depletion (KD) causes hypocitraturia. In the present studies, the effect of KD, induced by a low-K diet for 14 days (serum [K] 4.1 +- 0.1, control vs. 2.2 +/- 0.1 meq/l, KD, P less than 0.01), on renal cortical brush-border membrane (BBM) Na-citrate cotransporter activity was examined. KD significantly decreased fractional citrate excretion (3.90 +/- 0.68 vs. 0.53 +/- 0.10%, P less than 0.01). This was paralleled by a significant increase in the initial linear rate of BBM Na-dependent citrate transport (81 +/- 4 vs. 141 +/- 6 pmol citrate.5 s-1.mg protein-1, P less than 0.01). Kinetic studies varying extravesicular citrate concentration demonstrated that KD increased the maximal activity (Vmax) (152 +/- 17 vs. 296 +/- 14 pmol citrate.5 s-1.mg protein-1, P less than 0.01) with no difference in citrate affinity (118 +/- 23, control vs. 135 +/- 22 microM citrate, KD). Similarly, when extravesicular Na concentration was varied, KD increased the Vmax (132 +/- 9 vs. 206 +/- 6 pmol citrate.5 s-1.mg protein-1, P less than 0.01) with no difference in Na affinity (29 +/- 3, control vs. 28 +/- 1 mM Na, KD). The effect of KD on Na-citrate cotransport was specific in that KD did not alter Na-glucose (84 +/- 12, control vs. 89 +/- 5 pmol glucose.5 s-1.mg protein-1, KD) or Na-proline (87 +/- 3, control vs. 84 +/- 5 pmol proline.5 s-1.mg protein-1, KD) cotransport. In conclusion, KD increases the Vmax of the proximal tubule apical membrane Na-citrate cotransporter.(ABSTRACT TRUNCATED AT 250 WORDS)

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