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PubMed1988

Conjugative clearance of 1-naphthol and disposition of its glucuronide and sulfate conjugates in the isolated perfused rat kidney.

Extensive extrahepatic metabolism of 1-naphthol (1-N) was shown to occur in the rat in vivo (clearance = 377 ml/min/kg). The renal contribution to the metabolism of 1-N was investigated in the isolated perfused rat kidney (IPK). 1-N was metabolized to its sulfate (1-NS) and glucuronide (1-NG) conjugate by the IPK. The renal clearance of 1-N ranged from 5.36 to 6.24 ml/min/kidney and was 80 to 95% of the p-aminohippuric acid clearance by the IPK. This indicated that the renal extraction ratio of 1-N was 0.80 to 0.95, showing an important contribution of renal metabolic clearance to the total clearance. Nonlinear kinetics, due to saturation of the metabolic pathways, was shown at 1-N concentrations higher than 10 microM. 1-NS and 1-NG are both secreted in the urine and perfusate, although the urinary excretion of 1-NS is very small whereas the excretion of 1-NG into the urine is extensive, due to differences in the active secretion and protein binding of both conjugates.

Animals↗
PubMed1988

Influence of blood components on the tissue uptake indices of cyclosporin in rats.

The effect of blood components on the transfer of cyclosporin into brain, salivary gland, liver and kidney was measured in rats by an an vivo double isotope, tissue-sampling single injection technique. The brain-, salivary gland- and liver extraction of [3H] cyclosporine relative to [14C]butanol were studied with an intracarotid and a portal vein injection technique; the kidney extraction of [3H]cyclosporin relative to p[14C]aminohippuric acid was measured after a rapid injection in the aorta. The injection vehicles were a Ringer's solution [Ringer-4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid], rat plasma, human plasma, human red blood cells (RBC) suspension and human blood. The brain extraction (1-4%), the salivary extraction (25-74%) and the kidney extraction (8-47%) varied markedly depending on which blood components were added to the injection solution. The effect of RBC binding on tissue extraction was by far more pronounced than that of plasma protein binding. The binding of cyclosporin to RBC retards particularly the uptake of this drug by kidney. Moreover the kidney penetration of cyclosporin was confirmed by thaw-mount autoradiography after injection of the labeled drug in the aorta; the micrographs showed that the renal clearance of cyclosporin was restricted largely to the glomerular route. In contrast the hepatic extraction of [3H]cyclosporin was high (48-84%) and generally nonlimited by its binding to blood components; this could explain the high concentrations of drug observed in this tissue. In summary, cyclosporin binding to RBC and plasma proteins reduces drug uptake by brain, kidney and salivary gland, but causes little inhibition of hepatic uptake of cyclosporin.

Animals↗
PubMed1987

Renal functions following hyperbaric oxygen toxicity in conscious rats.

The after-effects of renal function were studied in rats exposed to hyperbaric oxygen (HBO) at either 4.8 ATA for 60 min or 6.8 ATA until the onset of convulsions. Only the rats which suffered from HBO convulsions were found to have alterations in renal function. It was observed that 4 hr after convulsions, there was a decrease in urinary excretion of urea and creatinine, which resulted in an elevation of blood urea nitrogen (BUN) and creatinine. Clearances of inulin and p-aminohippuric acid showed a decrease in the glomerular filtration rate and effective renal blood flow 4 hr after HBO convulsions. These parameters nearly returned to normal in 24 hr after convulsions. The renal handling of a large volume of infused saline was also retarded 4 hr after HBO convulsions, but by the end of 24 hr after HBO convulsions, it was much improved. Therefore, it was concluded that the renal function was altered after HBO convulsions, but nearly recovered in 24 hr.

Animals↗
PubMed1987

[Measuring blood flow and catheterization technic in the acute and chronic dog model].

Metabolic studies under in vivo conditions may require a simultaneous catheterization of various organs. Because of phylogenetic relationships, pigs or dogs are best suitable for metabolic investigations. Organ-specific flow rates and substrate balances can be determined by means of dye dilution techniques (indocyanine green - ICG, para-aminohippuric acid - PAH, bromsulphthalein - BSP). An easy method for catheter insertion under anesthesiological and operative conditions is described.

Animals↗
PubMed1986

Early changes in renal function following chemically induced nephropathy.

The functional changes in the rat kidney 24 h after administration of 2-bromoethanamine hydrobromide (BEA) have been extensively described. There is, however, little information regarding earlier alterations. The present study was designed to measure early changes in renal function in order to clarify further pathomechanisms of the BEA-induced lesion. Experiments were performed in two groups of Wistar rats with different infusion rates during the first 3 h following injection of 100 mg/kg BW BEA compared to sham-injected rats. Analysis included measuring urine flow, osmolality, urea, sodium and potassium as well as inulin and para-aminohippuric acid clearance. Our studies show a tubular as well as a glomerular involvement in BEA-induced nephropathy. A significantly higher urine flow occurred already in the first 30 min following injection of BEA. Urine osmolality began to decrease after 90 min, Na excretion was elevated at 3 h, K excretion was not significantly different from the control group, urea excretion was increased after 30 min. Contrary to other studies we found a continuously decreasing glomerular filtration rate and PAH clearance during the first 3 h. Our results suggest an early effect of BEA on tubular function (increasing sodium excretion), papillary concentration capacity (increasing urine flow combined with decreasing osmolality) and glomerular function (decreasing glomerular filtration rate).

Animals↗
PubMed1986

Effective renal blood flow and renal energy charge in murine peritonitis.

The temporal sequence of physiological derangements preceding acute renal failure (ARF) observed in overwhelming bacterial septicemia remains controversial. In order to examine the relationship of renal circulatory alterations and cellular dysfunction in murine sepsis, effective renal plasma flow (ERPF), renal tissue metabolites, and energy charge ratios were determined in Sprague-Dawley rats at 10 and 20 hours following induction of peritonitis by cecal ligation and perforation (CLP) or cecal manipulation alone (sham). Tissue levels of adenine nucleotides, lactate, and pyruvate were assayed after freeze-clamping kidneys unilaterally followed by enzymatic determinations. Cardiac outputs were determined by thermodilution and ERPF by p-aminohippuric acid (PAH) clearance. Results indicate in this model, despite an increase in cardiac output (P less than 0.05), ERPF was significantly decreased at both 10 hours (P less than; 0.05) and 20 hours (P less than 0.01) following induction of peritonitis. Further, although tissue pyruvate/lactate ratios showed significant decreases by 10 hours (P less than 0.05), diminished energy charge ratios were not observed until 20 hours following septic insult. These findings support the hypothesis of diminished renal perfusion as contributory and antecedent to cellular dysfunction in septicemic ARF.

Adenine Nucleotides↗
PubMed1985

Measurement of portal and hepatic blood flows using a modified method for surgical placement of catheters in the major splanchnic vessels of sheep.

A modified catheterization and para-aminohippurate dye dilution technique was used to measure portal and hepatic blood flows in sheep. Blood flows (mean +/- 1SD) for 7 healthy sheep were 1.54 +/- 0.71 L/min and 1.98 +/- 0.75 L/min for portal and hepatic flows, respectively. Blood flow measurement was facilitated when dye injection rates produced blood para-aminohippurate acid concentrations greater than 15 mg/L. Uniform mixing of dye with blood was confirmed in 1 sheep with 2 portal vein catheters. Surgery to place the catheters was facilitated by using a ventral para-costal approach. Blood gas analysis was useful in confirming the placement of the catheters. Useful catheter life in this experiment was 41 days, which was longer than in previous reports. Treating the catheters with an organo-silane preparation, protecting the catheters against dislodgement, and use of a belly bandage to minimize damage to the external parts of the catheter may have prolonged catheter life in this experiment.

Animals↗
PubMed1985

Renal clearance of fluoride in children and adolescents.

Renal function and fluoride excretion have been studied in 38 children. The children were divided into three groups according to their glomerular filtration rate: normal (92 to 136 mL/min/1.73 m2 of body surface area [BSA]), low (less than 92 mL/min/1.73 m2 BSA, and super-normal (greater than 136 mL/min/1.73 m2 BSA). Standard clearance technique with infusion of inulin and p-aminohippuric acid during water diuresis was used. Mean renal fluoride clearance was 45.0 +/- 9.8 (SD) mL/min in the group of children with normal glomerular filtration rates and 31.4 +/- 8.8 mL/min in the group with low glomerular filtration rates. This difference was statistically significant. There was a close linear relationship between renal fluoride clearance and glomerular filtration rate, urinary flow, and free water clearance. The fractional fluoride excretion did not differ between the groups. About 60% of the filtered fluoride was reabsorbed. No evidence for tubular secretion exceeding the reabsorption could be found. The results suggest that children have lower renal fluoride clearance rates than adults and indicate that a moderate impairment of the renal function could lead to increased retention of fluoride.

Adolescent↗
PubMed1985

Renal secretion of phenolsulfonphthalein: analysis of its vectorial transport in normal and mutant analbuminemic rats.

Transtubular transport of many organic anions, such as p-aminohippuric acid and phenolsulfonphthalein (PSP), from plasma into urine is an important renal function. Most of these nephrophilic ligands strongly bind to albumin in the circulation. To investigate a possible function of plasma albumin in vectorial transport of these organic anions, plasma clearance and urinary excretion of PSP, on one hand, and its interaction with serum proteins, on the other, were studied in normal and mutant Nagase analbuminemic rats (NAR). Intravenously administered PSP rapidly disappeared from the circulation, followed by its urinary excretion in both NAR and normal rats. However, its plasma clearance was significantly larger in NAR (53.9 ml/min/kg body weight) than in normal animals (4.7 ml/min/kg body weight). Gel exclusion Sephadex G-100 chromatography and ultrafiltration analysis revealed that the PSP binding capacity of serum proteins was considerably lower in NAR than in normal rats; 32.0% and 12.5% of the ligand bound to NAR serum protein and 94.4% and 84.2% to normal rat serum protein (predominantly albumin) at 0.1 and 0.5 mmol/L ligand concentrations, respectively. Despite the greater PSP clearance in NAR, its urinary excretion was lower in NAR than in the normal animals; 20.9% +/- 2.5% and 46.0% +/- 12.6% of the administered dose appeared in NAR and normal rat urine, respectively, within 3 hours of administration. Injection of PSP with equimolar albumin resulted in a decrease in plasma clearance and an increase in urinary excretion of PSP in NAR; more than 31.4% +/- 3.3% of the injected dose appeared in the urine within 3 hours of administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Albumins↗
PubMed1979

Effect of renal vein ligation with or without suprarenal inferior vena cava ligation on sodium and phosphate excretions during acute extracellular volume expansion in the rat.

Right nephrectomy with or without inferior vena cava (IVC) ligation was performed in rats 1 week after left renal vein ligation. Left kidney function and sodium and phosphate excretions by volume expansion were investigated. Inulin (CIN) and para-aminohippuric acid (CPAH) clearances and fractional excretions of sodium (FENa) and phosphate (FEP) were examined before and after volume expansion was induced by normal saline. Kidney functions were well preserved with development of collateral venous channels; biochemical parameters returned to the normal ranges. However, CIN and CPAH were reduced to 33 to 25 per cent of control values and the filtration fraction was elevated. After volume expansion, a marked increment of FENa was observed in cases of IVC ligation but the increment in animals without IVC ligation was less than in the control group. FEP was also increased in experimental groups but the magnitude of phosphaturia was not so prominent compared to the control group. The increment of FEP was not comparable to that of FENa. Thus, from the aspect of kidney function, this experiment showed the rationality of left renal vein ligation with contralateral nephrectomy. From the pathophysiologic aspect, the magnitude of natriuresis and phosphaturia by volume expansion was not prominent and a reduced reabsorptive capacity for sodium and phosphate may exist in a solitary kidney with a ligated renal vein. When suprarenal IVC ligation was also done, prominent natriuresis was observed with saline infusion.

Animals↗
PubMed1981

Atrial volume receptors. Demonstration of an effective "threshold" of left atrial distension by an inflated balloon to induce increased diuresis in the anesthetized dog.

1. The intraatrial balloon technique was used to study the effect of distension of the left atrium on the urinary flow of anesthetized dogs. The balloon was inflated with 0.3, 0.4 or 0.5 ml saline/kg body weight, respectively, in three experimental groups, each containing 10 mongrel dogs. Intraatrial pressure, arterial blood pressure, ECG and respiratory excursions were continuously monitored in all experiments. Urine flow, inulin and p-aminohippuric acid clearance, urine osmolarity, total sodium and total potassium excretion were measured during the control period, after inflation of the balloon and 30 min after deflation. 2. Left atrial distension with 0.3 ml/kg caused essentially no increase in diuresis. Inflation with 0.4 ml/kg induced a 60% increase of mean urinary flow with respect to the control period. Inflation with 0.5 ml/kg elicited a mean increase in diuresis of 110%. 3. When it occurred, increased diuresis was accompanied by a decrease of urine osmolarity that was compatible with a decrease of antidiuretic hormone activity, and by an increase in total sodium excretion. There were no statistically significant changes in glomerular filtration rate and effective renal plasma flow. 4. The demonstration of a "threshold" for the distension of the left atrium that is capable of inducing diuresis in the anesthetized dog and of overcoming strong opposing hemodynamic effects provides additional indirect evidence for the role of the left atrial stretch receptors in the regulation of body fluid volume.

Anesthesia↗
PubMedDate not supplied

Metabolism of procainamide in the perfused rat liver.

We have previously produced evidence that procainamide forms a reactive metabolite. This study of the metabolism of procainamide in a perfused rat liver was aimed at providing clues to the identity of this reactive metabolite. Several metabolites were found that had not been previously described and three of these were identified. Probably the most significant of these metabolites is the phenol, N-acetyl-3-hydroxyprocainamide. This phenol could have been formed from either a hydroxylamine or an arene oxide intermediate and either of these could represent a reactive metabolite. In contrast to the metabolism of procainamide, the phenol metabolite, N-acetyl-3-hydroxyprocainamide, is not formed in significant quantities from N-acetylprocainamide. This implies that oxidation of procainamide to 3-hydroxyprocainamide precedes acetylation to give N-acetyl-3-hydroxyprocainamide. As N-acetylation of procainamide decreases both its toxicity and the formation of the oxidative phenol metabolite, among the hypotheses to be explored is relationship between the formation of the phenol metabolite and the toxicity of procainamide. The other metabolites that were identified were N-acetylprocainamide N-oxide and N-acetyl-4-aminohippuric acid.

Acecainide↗
PubMed1983

Net absorption of 3-methylindole and indole in cattle after oral administration of L-tryptophan.

The time course and quantity of 3-methylindole (3MI) and indole absorbed after oral administration of L-tryptophan (TRP) was determined in 2 steers. The relationship between the appearance of 3MI and indole in the rumen and blood plasma to absorption of 3MI and indole was also studied. Two Hereford X Angus steers with portal vein, mesenteric vein, and femoral (steer 1) or iliac (steer 2) artery catheters were used. Absorption rates from the portal drained viscera (net absorption) of 3MI and indole were determined by the product of portal and arterial concentration difference and blood flow. Blood flow was determined by primed continuous infusion of p-aminohippuric acid into a mesenteric vein. Three absorption measurements 30 minutes apart were taken at midpoint times of 0, 12, 24, 36, and 48 hours after oral administration of 0.4 g of TRP/kg of body weight. Steer 1 was dosed twice resulting in a total of 45 absorption measurements. Net absorption of 3MI and indole peaked at an average of 1.05 and 0.81 g/hr, respectively. By 48 hours, 29.2% and 15.3% of the TRP dose were accounted for by 3MI and indole absorption, respectively. Closed system in vitro incubations of TRP with ruminal fluid from the same 2 steers resulted in a TRP to 3MI conversion of 23.2% and a TRP to indole conversion of 10.7%. Net absorption of 3MI and indole closely followed and was correlated with concentration of 3MI and indole in ruminal fluid and blood plasma.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1981

Effects of differential changes in rat hepatic and renal cytochrome P-450 concentrations on hepatotoxicity and nephrotoxicity of chloroform.

Cytochrome P-450 concentrations in rat liver and kidney were differentially altered by pretreatment with phenobarbital (PB), cadmium or fasting. The rats were then challenged with chloroform. The consequent hepatotoxicity was assayed by alanine amino transferase activity (AlaAT); the nephrotoxicity by inhibition of p-aminohippuric acid (PAH) uptake in vitro and both by histopathology. Fasting increased renal and hepatic cytochromes P-450 and chloroform-mediated necrosis in both organs. PB induction increased and cadmium decreased the liver cytochrome P-450 concentrations and the hepatotoxicity mediated by chloroform. PB and cadmium had no effect on renal cytochrome P-450 concentrations or the nephrotoxicity of chloroform. These results strongly suggest that the nephrotoxic metabolite of chloroform is produced within the kidney and the hepatotoxic metabolite in the liver.

Animals↗
PubMed1980

Renal handling of [14C]allantoin in the rabbit.

Rabbit renal cortical slices were incubated at 25 degrees C, pH 7.4, for 2 hr under 100% O2 in a phosphate-buffered medium. [14C]allantoin was accumulated to a tissue water/medium ratio of 1.38 +/- 0.03 (mean +/- S.E., n = 22). Under 100% N2, the tissue water/medium ratio fell significantly to 0.90 +/- 0.02 (n = 14, P less than .001). Probenecid (an anion) inhibited the uptake of allantoin at doses which had no effect on the water content of the slices, i.e., did not appear to have a toxic effect on the tissue. Its effect was specific. In contrast, salicylate (another anion) and quinine (a cation) inhibited the uptake of allantoin only at concentrations which simultaneously increased the water content of the slices. These results suggest a toxic effect on cell metabolism. Salicylate (an anion) and quinine (a cation), in dosage which inhibited allantoin uptake, also inhibit the uptake of the para-aminohippuric acid (an anion) and tetraethylammonium bromide (a cation). Net secretion of allantoin was observed in urinary clearance experiments on anesthetized rabbits acutely loaded with allantoin, under mannitol diuresis. At flow rates less than 1 ml/kg.min, fractional excretion of [14C]allantoin was 0.85 +/- 0.03 (n = 27 clearance periods) indicating significant net reabsorption. When urine flow was increased above 1 ml/kg.min, fractional excretion of [14C]allantoin reached 1.07 +/- 0.03 (n = 18 clearance periods), i.e., net secretion.

Allantoin↗