Renal excretion of N'1-methylnicotinamide in the rat

1975 ◽  
Vol 228 (6) ◽  
pp. 1641-1645 ◽  
Author(s):  
CR Ross ◽  
F Diezi-Chomety ◽  
F Roch-Ramel
Keyword(s):  
Renal Clearance ◽  
Renal Excretion ◽  
Plasma Concentrations ◽  
Competitive Inhibitor ◽  
Proximal Tubules ◽  
Free Flow ◽  
Minor Role ◽  
Distal Tubules ◽  
A Minor

The renal excretion of N'1-methylnicotinamide (NMN) was studied in the rat. Renal clearance experiments clearly demonstrated that: 1) NMN is secreted; 2)a tubularmaximum (Tm), 7 mumol/min per kg, could be reached; and 3)NMN secretion is inhibitedby a competitive inhibitor, mepiperphenidol. In free-flow micropuncture experiments, animals were infused with plasma concentrations of NMN ABOVE Tm; the TF/P NMNto TF/P inblin ratio for proximal and distal samples was 2.34 and 2.28, respectively, indicating that NMN is secreted in the proximal tubules and is not secreted orreabsorbed in the distal tubules. This finding was further confirmed by intratubularmicroinjections of ['14C]NMN into rats. In diuretic animals approxiamately 10%of the NMN injected into early proximal tubules was reabsorbed, but no reabsorption could be detected after distal injections. The nondiuretic animals showed no significant reabsorption of NMN. It was concluded that NMN transport is a carrier-mediated process and that reabsorption, if it occurs, plays only a minor role.

Renal excretion of uric acid in the rat: a micropuncture and microperfusion study

1976 ◽  
Vol 230 (3) ◽  
pp. 768-776 ◽  
Author(s):  
F Roch-Ramel ◽  
F Diezi-Chomety ◽  
D De Rougemont ◽  
M Tellier ◽  
J Widmer ◽  
...  
Keyword(s):  
Uric Acid ◽  
Renal Excretion ◽  
Proximal Tubules ◽  
Free Flow ◽  
Collecting Ducts ◽  
Order Of Magnitude ◽  
Plasma Urate ◽  
Distal Tubules

Free-flow micropuncture experiments were done in rats of three strains infused with small amounts of urate [plasma urate (P urate) = 95 +/- 8 muM]. Urate concentrations in tubular fluid were measured by an accurate chemical fluorometric ultramicromethod. In fluid from surface glomeruli, the glomerular fluid-to-plasma urate ratio [GF/P) urate] was 0.99 +/- 0.03 (n=11), i.e., lower than expected for total ultrafiltrability of plasma urate. Along proximal convolutions, net reabsorption of 55% of filtered urate was demonstrated. Small amounts of urate may have been reabsorbed between late proximal and early distal sites. Net transepithelial movements of urate did not occur in distal tubules or collecting ducts. In microperfusion experiments on proximal tubules, both a reabsorptive flow of urate (loss of perfused [2-14C]urate) and a secretory flow (entrance of cold urate into perfusate) of the same order of magnitude were demonstrated. Neither flow was influenced by simultaneous water movements. Microperfusion of Henle's loops indicated a significant but very small net reabsorption.

13C-NMR study of the inhibition of δ-chymotrypsin by a tripeptide-glyoxal inhibitor

2002 ◽  
Vol 362 (2) ◽  
pp. 339-347 ◽  
Author(s):  
Aleksandra DJURDJEVIC-PAHL ◽  
Chandralal HEWAGE ◽  
J. Paul G. MALTHOUSE
Keyword(s):  
13C Nmr ◽  
Exchange Process ◽  
Competitive Inhibitor ◽  
Minor Role ◽  
Oxyanion Hole ◽  
Inhibitor Complex ◽  
Rapid Exchange ◽  
Nmr Study ◽  
A Minor ◽  
Hydroxy Groups

A new inhibitor, Z-Ala-Pro-Phe-glyoxal (where Z is benzyloxycarbonyl),has been synthesized and shown to be a competitive inhibitor of δ-chymotrypsin, with a Ki of 25±8nM at pH7.0 and 25°C. Z-Ala-Pro-[1-13C]Phe-glyoxal and Z-Ala-Pro-[2-13C]Phe-glyoxal have been synthesized, and 13C-NMR has been used to determine how they interact with δ-chymotrypsin. Using Z-Ala-Pro-[2-13C]Phe-glyoxal we have detected a signal at 100.7p.p.m. which we assign to the tetrahedral adduct formed between the hydroxy group of Ser-195 and the 13C-enriched keto-carbon of the inhibitor. This signal is in a pH-dependent slow exchange with a signal at 107.6p.p.m. which depends on a pKa of ∼ 4.5, which we assign to oxyanion formation. Thus we are the first to detect an oxyanion pKa in a reversible chymotrypsin—inhibitor complex. A smaller titration shift of 100.7p.p.m. to 103.9p.p.m. with a pKa of ∼ 5.3 is also detected due to a rapid exchange process. This pKa is also detected with the Z-Ala-Pro-[1-13C]Phe-glyoxal inhibitor and gives a larger titration shift of 91.4p.p.m. to 97.3p.p.m., which we assign to the ionization of the hydrated aldehyde hydroxy groups of the enzyme-bound inhibitor. Protonation of the oxyanion in the oxyanion hole decreases the binding efficiency of the inhibitor. From this decrease in binding efficiency we estimate that oxyanion binding in the oxyanion hole reduces the oxyanion pKa by 1.3 pKa units. We calculate that the pKas of the oxyanions of the hemiketal and hydrated aldehyde moieties of the glyoxal inhibitor are both lowered by 6.4–6.9 pKa units on binding to chymotrypsin. Therefore we conclude that oxyanion binding in the oxyanion hole has only a minor role in decreasing the oxyanion pKa. We also investigate how the inhibitor breaks down at alkaline pH, and how it breaks down at neutral pH in the presence of chymotrypsin.

scholarly journals The synthetic RGDS peptide inhibits the binding of fibrinogen lacking intact alpha chain carboxyterminal sequences to human blood platelets

Blood ◽  
1987 ◽  
Vol 69 (3) ◽  
pp. 950-952 ◽  
Author(s):  
EI Peerschke ◽  
DK Galanakis
Keyword(s):  
Platelet Aggregation ◽  
Human Blood ◽  
Blood Platelets ◽  
Adenosine Diphosphate ◽  
Competitive Inhibitor ◽  
Minor Role ◽  
Solution Ph ◽  
Alpha Chain ◽  
A Minor ◽  
Human Blood Platelets

Abstract The alpha chain 572–574 Arg-Gly-Asp sequence of fibrinogen appears to play only a minor role in platelet aggregation based on the ability of fibrinogen preparations lacking alpha chain carboxyterminal segments to support platelet aggregation, but synthetic Arg-Gly-Asp-Ser (RGDS) peptides are capable of inhibiting platelet aggregation and fibrinogen binding. The present study thus examined the ability of RGDS peptides to inhibit platelet interactions with a plasmic degradation product of fibrinogen (8D–50) that resembles an intermediate fragment X. Gel- filtered, human blood platelets suspended in 0.01 mol/L HEPES-buffered modified Tyrode's solution, pH 7.5, were stimulated with 20 mumol/L adenosine diphosphate and the binding of 125I-labeled 8D–50 or intact fibrinogen (0.01 to 0.6 mg/mL) assessed in the presence of 0 to 117 mumol/L RGDS. The data revealed that RGDS decreased the apparent affinity of 8D–50 and intact fibrinogen for platelets but did not affect the maximum number of binding sites. RGDS thus appears to be a competitive inhibitor not only of intact fibrinogen (Ki = 12 +/- 2 mumol/L) but also of 8D–50 (Ki = 15 +/- 3 mumol/L) (mean +/- SD, n = 3).

The pharmacokinetics of azacitidine following subcutaneous treatment in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7087-7087
Author(s):  
E. Laille ◽  
R. Ward ◽  
A. Nasser ◽  
M. Stoltz ◽  
C. Cogle ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Plasma Concentrations ◽  
Hepatic Metabolism ◽  
Volume Of Distribution ◽  
Adverse Event Reporting ◽  
Myelogenous Leukemia ◽  
Minor Role ◽  
Renal Elimination ◽  
Drug Concentrations ◽  
A Minor

7087 Background: 5-azacitidine (AZA), through its effects on DNA metabolism, gene expression, and cell differentiation, has proven beneficial in treatment of MDS and AML and AZA therapy significantly increases survival in higher-risk MDS and AML compared to conventional care. Few studies have evaluated the pharmacokinetics (PK) of AZA and the renal elimination of AZA has not been previously published to our knowledge. Plasma PK of AZA are herein reported in patients receiving SC doses of 75 mg/m2. This study was designed to also assess the contribution of renal elimination to the overall clearance of AZA. Methods: Adult patients with MDS or AML and ECOG status 0–2 were treated with 7 consecutive daily SC doses of 75 mg/m2 AZA during their first treatment cycle. PK parameters of AZA were derived from drug concentrations in plasma and urine collected after the first and last dose (day 7) of AZA. Safety was evaluated by adverse event reporting (NCI-CTC). Results: Currently, 18 patients have been treated with SC AZA. AZA was rapidly absorbed and reached peak plasma concentrations (concs) within 0.5 hr post dosing. The AUCinf after SC doses was 1170 hr*ng/mL. The AZA concs declined in a pseudo bi-phasic manner with an elimination half-life of 1.25 hours. The plasma PK profiles after the first and last dose were superimposable. The apparent total clearance (CL/F) and volume of distribution (Vd/F) were 143 L/hr and 318 L, respectively. AZA recovery in urine was very small relative to dose (<2%). AZA was well tolerated and no unexpected toxicities were observed. Conclusions: The AZA AUCinf after SC doses is similar to the published AUC value (1044 hr*ng/mL) after 75 mg/m2 IV doses indicating approximating 100% systemic bioavailability. After SC dosing, CL/F exceeded hepatic blood flow indicating extra-hepatic metabolism. Vd/F was 4–5 fold greater than total body water suggesting extensive AZA tissue distribution. Renal elimination appears to play a minor role in the overall clearance of AZA. [Table: see text]

scholarly journals The synthetic RGDS peptide inhibits the binding of fibrinogen lacking intact alpha chain carboxyterminal sequences to human blood platelets

Blood ◽  
1987 ◽  
Vol 69 (3) ◽  
pp. 950-952
Author(s):  
EI Peerschke ◽  
DK Galanakis
Keyword(s):  
Platelet Aggregation ◽  
Human Blood ◽  
Blood Platelets ◽  
Adenosine Diphosphate ◽  
Competitive Inhibitor ◽  
Minor Role ◽  
Solution Ph ◽  
Alpha Chain ◽  
A Minor ◽  
Human Blood Platelets

The alpha chain 572–574 Arg-Gly-Asp sequence of fibrinogen appears to play only a minor role in platelet aggregation based on the ability of fibrinogen preparations lacking alpha chain carboxyterminal segments to support platelet aggregation, but synthetic Arg-Gly-Asp-Ser (RGDS) peptides are capable of inhibiting platelet aggregation and fibrinogen binding. The present study thus examined the ability of RGDS peptides to inhibit platelet interactions with a plasmic degradation product of fibrinogen (8D–50) that resembles an intermediate fragment X. Gel- filtered, human blood platelets suspended in 0.01 mol/L HEPES-buffered modified Tyrode's solution, pH 7.5, were stimulated with 20 mumol/L adenosine diphosphate and the binding of 125I-labeled 8D–50 or intact fibrinogen (0.01 to 0.6 mg/mL) assessed in the presence of 0 to 117 mumol/L RGDS. The data revealed that RGDS decreased the apparent affinity of 8D–50 and intact fibrinogen for platelets but did not affect the maximum number of binding sites. RGDS thus appears to be a competitive inhibitor not only of intact fibrinogen (Ki = 12 +/- 2 mumol/L) but also of 8D–50 (Ki = 15 +/- 3 mumol/L) (mean +/- SD, n = 3).

The Cation Transporters rOCT1 and rOCT2 Interact with Bicarbonate but Play Only a Minor Role for Amantadine Uptake into Rat Renal Proximal Tubules

2002 ◽  
Vol 303 (3) ◽  
pp. 959-968 ◽  
Author(s):  
Kerry B. Goralski ◽  
Ganlu Lou ◽  
Matthew T. Prowse ◽  
Valentin Gorboulev ◽  
Christopher Volk ◽  
...  
Keyword(s):  
Proximal Tubules ◽  
Minor Role ◽  
Renal Proximal Tubules ◽  
Cation Transporters ◽  
A Minor

Renal urate excretion at various plasma concentrations in the rat: a free-flow micropuncture study

1976 ◽  
Vol 231 (2) ◽  
pp. 387-392 ◽  
Author(s):  
D De Rougemont ◽  
M Henchoz ◽  
F Roch-Ramel
Keyword(s):  
Plasma Concentrations ◽  
Proximal Tubules ◽  
Free Flow ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Micropuncture Study ◽  
Plasma Urate ◽  
Pelvic Urine

Free-flow micropuncture experiments were performed in male Sprague-Dawley rats undergoing moderate mannitol diuresis and infused with urate-containing solutions. The resulting plasma urate concentrations ranged from 37.5 +/- 2.4 to 601.2 +/- 23.8 muM. With urate loading, the fraction of filtered urate excreted in pelvic urine increased from 0.32 +/- 0.02 to 0.92 +/- 0.05 mu M, but net secretion was not observed. At normal urate levels net reabsorption occurred along superficial proximal tubules, whereas net secretion could be demonstrated at the highest plasma urate levels. Net movements of urate did not appear to occur across the walls of the lower segments of nephrons.

Effect of histamine on the secretion of pro-opiomelanocortin derived peptides in rats

1988 ◽  
Vol 119 (2) ◽  
pp. 312-319 ◽  
Author(s):  
Ulrich Knigge ◽  
Flemming W. Bach ◽  
Steen Matzen ◽  
Peter Bang ◽  
Jørgen Warberg
Keyword(s):  
Receptor Antagonist ◽  
Anterior Pituitary ◽  
Plasma Concentrations ◽  
Gel Filtration ◽  
Male Rats ◽  
Minor Role ◽  
Plasma Acth ◽  
Intracerebroventricular Infusion ◽  
A Minor ◽  
Two Peaks

Abstract. In conscious male rats intracerebroventricular infusion of histamine increased the plasma concentrations of ACTH and β-endorphin immunoreactivity 2.5-fold (P < 0.01). Gel filtration of plasma revealed two peaks of β-endorphin immunoreactivity corresponding to β-endorphin and β-lipotropin. The two fractions increased almost equally in histamine-stimulated animals, whereas most of the circulating β-endorphin immunoreactivity in control animals corresponded to β-endorphin. Central infusion of the H1-receptor agonist 2-thiazolylethylamine and of the H2-receptor agonists dimaprit or 4-methylhistamine increased the plasma ACTH and β-endorphin immunoreactivity concentrations 2- and 3-fold, respectively (P < 0.01). Infused intracerebroventricularly, the H2-receptor antagonists cimetidine or ranitidine prevented the histamine-induced increase in plasma ACTH and β-endorphin immunoreactivity (P < 0.01), whereas the H1-receptor antagonist mepyramine inhibited the peptide responses by 70% (P < 0.01). Infused intra-arterially cimetidine or ranitidine inhibited the histamine-induced increase in plasma ACTH by 80% (P < 0.01) and plasma β-endorphin immunoreactivity by 45% (P < 0.05), whereas mepyramine or the other H1-receptor antagonist SKF-93944 inhibited the ACTH response by 50% (P < 0.05), but had no effect on the β-endorphin immunoreactivity. The results indicate that histamine increases the release of the pro-opiomelanocortin derived peptides ACTH, β-lipotropin and β-endorphin from the anterior pituitary lobe, whereas an effect of histamine on the release of β-endorphin from the neurointermediate lobe is possible. The effect of histamine seems primarily mediated by H2-receptors, whereas H 1-receptors appear to play a minor role.

Micropuncture study of renal excretion of water, K, Na, and Cl in Necturus

1962 ◽  
Vol 203 (4) ◽  
pp. 662-666 ◽  
Author(s):  
Phyllis A. Bott
Keyword(s):  
Renal Excretion ◽  
Distal Tubule ◽  
Sodium Concentration ◽  
Great Variability ◽  
Proximal Tubules ◽  
Kidney Tubules ◽  
Sodium Potassium ◽  
Micropuncture Study ◽  
Distal Tubules

Inulin, sodium, potassium, and chloride were determined on identical samples of serum and fluid collected from the kidney tubules of Necturus under urethan anesthesia. Inulin fluid-serum ratios obtained were as follows: highest ratios for proximal tubules approximated 2, indicating a reabsorption of about 50%, of filtered water; highest ratios for distal tubules were near 3.4; ratios for sodium remained near 1 in proximal tubules, tending to be lowest near the ends of the segments. There was an abrupt drop in sodium concentration in the early part (thin segment) of the distal tubules, which may be made possible by the better oxygen supply in this region. Chloride ratios rose to 1.12 in the proximal tubules and chloride concentrations fell over the same region, as did sodium. Potassium ratios remained close to 1 in the proximal tubules, indicating that up to one-half of the filtered potassium may be reabsorbed there. Distal tubule potassium ratios showed great variability, some being higher and some lower than 1.

The Effect of Path Length and Display Size on Memory for Spatial Information

2012 ◽  
Vol 59 (3) ◽  
pp. 147-152 ◽  
Author(s):  
Katherine Guérard ◽  
Sébastien Tremblay
Keyword(s):  
Path Length ◽  
Potential Role ◽  
Spatial Information ◽  
Recall Performance ◽  
Minor Role ◽  
Length Effect ◽  
Serial Memory ◽  
Fixed Reference ◽  
A Minor

In serial memory for spatial information, some studies showed that recall performance suffers when the distance between successive locations increases relatively to the size of the display in which they are presented (the path length effect; e.g., Parmentier et al., 2005) but not when distance is increased by enlarging the size of the display (e.g., Smyth & Scholey, 1994). In the present study, we examined the effect of varying the absolute and relative distance between to-be-remembered items on memory for spatial information. We manipulated path length using small (15″) and large (64″) screens within the same design. In two experiments, we showed that distance was disruptive mainly when it is varied relatively to a fixed reference frame, though increasing the size of the display also had a small deleterious effect on recall. The insertion of a retention interval did not influence these effects, suggesting that rehearsal plays a minor role in mediating the effects of distance on serial spatial memory. We discuss the potential role of perceptual organization in light of the pattern of results.

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