Changes in renal haemodynamics and electrolyte excretion during acute hyperkalemia in conscious adrenalectomized sheep. (1/75)

The p-aminohippurate (PAH) clearance, inulin clearance and the excretion of electrolytes by 10 adrenalectomized sheep were measured before, during and after the infusion of 0-43 M-KCl at 2 ml./min for 2 hr. The PAH clearance increased as the plasma potassium concentration increased up to approximately 6-0 m-mole/l. Further increases in plasma potassium were associated with a progressive return of the PAH clearance to or below the pre-infusion levels. At its maximum the PAH clearance was 1-228 +/- 0-032 (S.E. of mean) times the pre-infusion levels. The inulin clearance increased to reach a mazimum coincident with or subsequent to the maximum PAH clearance. The maximum level of inulin clearance during the hyperkalaemia was 1-158 +/- 0-020 times the pre-infusion clearance. The increments in the clearance of potassium and of bicarbonate rose rapidly to exceed the increment in inulin clearance during the hyperkalaemia in all experiments. The increments in the clearance of sodium and of chloride exceeded the increment in inulin clearance in more than half the experiments. It was concluded that although hyperkalaemia was associated with increased glomerular filtration much of the increased excretion of sodium, chloride and bicarbonate was derived from depressed tubular reabsorption of the ions. When the infusion experiments were repeated on the same animals the sheep demonstrated an improved ability to control the rise in plasma potassium concentration which was similar to potassium adaptation described in other species. There were no apparent differences between sheep maintained on 1-5 mg and 5 mg deoxycorticosterone acetate daily in their adaptation to potassium loading and the effect was tentatively attributed to the level of steroid maintenance being chronically high. The toxicity of hyperkalaemia was not lessened by this adaptation to potassium loading.  (+info)

Renal excretion of monovalent cations during functional adrenalectomy in conscious sheep. (2/75)

In sheep with both adrenals removed and one re-implanted in the neck, functional adrenalectomy was produced in conscious undisturbed animals by occluding the blood supply to the transplanted gland. Functional adrenalectomy caused a fall in potassium excretion and a very large increase in sodium excretion and was reversed by aldosterone. Hydrocortisone infusions slightly increased potassium excretion and reduced solute-free water reabsorption. Preliminary evidence suggests that potassium secretion into urine was still occurring during the 8 hr period of adrenal occlusion and functional adrenalectomy.  (+info)

The transport of para-aminohippuric acid by the ciliary body and by the iris of the primate eye. (3/75)

Para-aminohippuric acid (PAH) accumulates against a concentration gradient in the ciliary body and independently in the iris of the rhesus monkey eye. This accumulation is inhibited by incubation of 0 degrees C and shows saturation kinetics in both tissues. Cyanide, ouabain, dinitrophenol, iodopyracet, and probenecid effectively depress PAH uptake in both tissues, but anaerobic incubation conditions have little effect on uptake in either tissue. The washout of preaccumulated PAH occurs 2.5 times faster from the iris than from the ciliary body. The effects on washout of 10(-4)M PAH, 0 degrees C, and 10(-5)M dinitrophenol are consistent with washout occurring by a diffusional mechanism in both tissues, with some reaccumulation occurring in the ciliary body only. In addition, nonsaturable uptake of PAH, studied in both tissues under high PAH concentrations, also occurs significantly faster in the iris than in the ciliary body. The kinetic analysis of active PAH uptake in both tissues is discussed in terms of initial uptake and in terms of a steady-state model. This steady-state model compensates for some technical problems in applying in vitro incubation techniques to primate tissues and also includes a correction for the additional exchange processes that affect the two tissues differently. Results of the kinetic analysis suggest that, at least to an order of magnitude, iris uptake is significant with respect to ciliary body uptake.  (+info)

Inhibition of renal tubular transport of methotrexate by probenecid. (4/75)

The mechanism of excretion of methotrexate (MTX) has been investigated in the monkey. Under steady-state conditions of varied plasma levels of MTX, it was determined that MTX was excreted by renal tubular transport as well as by glomerular filtration. The maximum rate of renal tubular transport of MTX (81 mug/min) was attained at plasma levels of MTX from 6 to 8 mug/ml. Correspondingly, the rate of clearance of MTX from plasma was shown to diminish from a value that was 3-fold greater than the glomerular filtration rate at plasma levels of MTX from 6 to 32 mug/ml. Pretreatment of animals with probenecid (700 mg/sq m) totally inhibited renal tubular transport of MTX when MTX was administered in doses from 1.8 to 621 mg/sq m. Following inhibition of renal tubular transport of MTX by probenecid, steady-state plasma levels of MTX in animals pretreated with probenecid (700 mg/sq m) was reduced by a factor of 2.6 from values determined in non-probenecid-pretreated control animals receiving similar varied doses of MTX (1.8 P to greater than 600 mg/sq m). The mode of i.v. injection of MTX was seen to effect the concentration of MTX in plasma. Initial loading followed by continuous sustaining infusion of MTX provided stable and higher levels of MTX in plasma than was determined in controls or in experimental animals pretreated with probenecid and receiving identical doses of MTX by single bolus injection.  (+info)

Characterization of tubular functional capacity in humans using para-aminohippurate and famotidine. (5/75)

BACKGROUND: Renal drug excretion by glomerular filtration and active tubular secretion may be altered by factors such as acute and chronic renal disease, nephrotoxins, and drug interactions. Thus, accurate and reproducible methods for quantitation of glomerular filtration rate (GFR) and tubular functional capacity are critical. METHODS: We utilized a four-step sequential infusion method to characterize anionic [para-aminohippurate (PAH)] and cationic (famotidine) tubular functional capacity in healthy volunteers. Filtration and secretion rates were quantitated from renal clearance and iothalamate-derived GFR determinations. RESULTS: Concentration-dependent renal clearance of PAH was observed at plasma concentrations> 100 mg/L; renal clearances were 442 +/- 131 (mean +/- SD), 423 +/- 94, 233 +/- 45, and 152 +/- 18 mL/min/1.73 m2 at plasma concentrations of 18 +/- 2, 92 +/- 5, 291 +/- 47 and 789 +/- 28 mg/L, respectively. The apparent affinity (Km) and maximum secretory capacity (TmPAH) were 141 +/- 70 mg/L and 71 +/- 16 mg/min/1.73 m2, respectively. The unbound renal clearance and tubular secretory clearance of famotidine were 384 +/- 70 and 329 +/- 78 mL/min/1.73 m2, respectively, and were not significantly correlated with the unbound plasma concentrations, which ranged from 126 to 2659 ng/mL. The rate of tubular secretion was linear at unbound plasma concentrations up to 2659 ng/mL. CONCLUSIONS: These data indicate that a sequential infusion method using PAH may be used to characterize the anionic secretory component of proximal tubular function. The tubular clearance of famotidine may be a suitable index of the cationic secretory capacity of the proximal tubule in humans. Saturation of the cationic secretory pathway was not observed, and further investigation into parallel pathways of cationic secretion, such as p-glycoprotein, may be warranted.  (+info)

Renal intracortical blood flow distribution, function, and sodium excretion in unanesthetized dogs following vena caval ligation. (6/75)

We studied the renal function and the intrarenal blood flow of nine dogs whose thoracic inferior vena cava had been previously ligated (caval dogs) and nine other dogs. Following preparative surgery which included placement of a left atrial catheter, a femoral artery catheter, and bilateral ureteral catheters, the caval dogs gained an average of 2.1 kg of fluid weight, whereas the normal dogs gained no weight. Although neither the caval dogs' blood pressure (114 plus or minus 7 vs 120 plus or minus 4 mm Hg) nor their inulin clearance (0.64 plus or minus 0.06 vs. 0.79 plus or minus 0.06 ml/min g-1 kidney weight) was significantly reduced, their estimated renal blood flow (Cpah/[1-hematocrit]) was considerably lower (2.30 plus or minus 0.24 vs. 3.25 plus or minus 0.15 ml/min g-1). During the clearance study, the caval dogs' excretion of sodium (79 plus or minus 18 vs. 158 plus or minus 17 muEq/min) and their fractional clearance of sodium (2.0 plus or minus 0.4 vs. 3.4 plus or minus 0.5%) were reduced. Studies with microspheres failed to demonstrate a selective decrease in blood flow. However, comparison studies of nine other dogs (five caval and four normal) demonstrated that microsphere results were less reproducible in caval dogs than they were in normal dogs. We have concluded taht reduced blood flow is the only consistent alteration of renal function in this edematous animal model and that previous suggestions of altered distribution are not supported by these studies.  (+info)

The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. (7/75)

The effects of insulin on the renal handling of sodium, potassium, calcium, and phosphate were studied in man while maintaining the blood glucose concentration at the fasting level by negative feedback servocontrol of a variable glucose infusion. In studies on six water-loaded normal subjects in a steady state of water diuresis, insulin was administered i.v. to raise the plasma insulin concentration to between 98 and 193 muU/ml and infused at a constant rate of 2 mU/kg body weight per min over a total period of 120 min. The blood glucose concentration was not significantly altered, and there was no change in the filtered load of glucose; glomerular filtration rate (CIN) and renal plasma flow (CPAH) were unchanged. Urinary sodium excretion (UNaV) decreased from 401 plus or minus 46 (SEM) to 213 plus or minus 18 mueq/min during insulin administration, the change becoming significant (P smaller than 0.02) within the 30-60 min collection period. Free water clearance (CH2O) increased from 10.6 plus or minus 0.6 to 13 plus or minus 0.5 ml/min (P smaller than 0.025); osmolar clearance decreased and urine flow was unchanged. There was no change in plasma aldosterone concentration, which was low throughout the studies, and a slight reduction was observed in plasma glucagon concentration. Urinary potassium (UKV) and phosphate (UPV) excretion were also both decreased during insulin administration; UKV decreased from 66 plus or minus 9 to 21 plus or minus 1 mueq/min (P smaller than 0.005), and tupv decreased from 504 plus or minus 93 to 230 plus or minus 43 mug/min (P smaller than 0.01). The change in UKV was associated with a significant reduction in plasma potassium concentration. There was also a statistically significant but small reduction in plasma phosphate concentration which was not considered sufficient alone to account for the large reduction in UPV. Urinary calcium excretion (UCaV) increased from 126 plus or minus 24 to 200 plus or minus 17 mug/min (P smaller than 0.01). These studies demonstrate a reduction in UNaV associated with insulin administration that occurs in the absence of changes in the filtered load of glucose, glomerular filtration rate, renal blood flow, and plasma aldosterone concentration. The effect of insulin on CH2O suggests that insulin's effect on sodium excretion is due to enhancement of sodium reabsorption in the diluting segment of the distal nephron.  (+info)

Dependence of p-aminohippurate transport on calcium in canine renal cortical slices. (8/75)

1. Experiments were conducted on renal cortical slices from sixty-one adult mongrel dogs in order to evaluate the relationship between p-aminohippurate (PAH) transport and calcium. Tissues were found to be viable for at least 180 min.2. PAH uptake and the slice/medium (S/M) concentration ratio increased in normal tissues from 3 to 90 min whether data were expressed on a tissue weight or protein content basis. PAH uptake increased with time in calcium-depleted tissues, but all values were lower than normal. At 90 min, PAH S/M in calcium-depleted tissues (4.20 +/- 0.18) was reduced 40% compared to normal tissues (6.90 +/- 0.23).3. Over the time period of 3-90 min incubation, protein concentration ranged from 89.4 to 99.4 mg/g cortex in calcium-depleted tissues. During the same time period in normal tissues, protein concentration ranged from 105 to 117.6 mg/g cortex. No change was observed in medium protein concentration of calcium-depleted tissues.4. Lineweaver-Burke analysis showed similar values for K(m) in normal and calcium-depleted tissues (0.45-0.50 mumole ml.(-1)) although V(max) fell from control values of 0.082 to 0.052 mumole g(-1) min(-1) during calcium depletion.5. After 90 min incubation, addition of EGTA (7, 14 or 21 x 10(-3)M) to media containing calcium was associated with decreased S/M and uptake rates compared to control values from the same animals. The decreases observed were similar to those seen in tissues incubated in calcium-free media.6. Increased cell volume in the presence of calcium was not associated with decreased PAH uptake. Removal of calcium in association with constant cell volume was associated with reduced PAH uptake. Replacement of calcium, but not magnesium, is associated with a return of uptake to normal rates.7. It is concluded that (a) calcium removal causes increased water uptake into cells, (b) calcium removal causes a reduced V(max), (c) calcium is required for maintenance of intracellular PAH, (d) the effect of calcium on PAH is specific and reversible, and (e) the effect of calcium is not mediated by volume changes.  (+info)

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