Urate-2-14C transport in the rat nephron

Kramp, R.; Lassiter, William E.; Gottschalk, Carl W.

doi:10.1172/jci106482

Cited by 61 publications

(22 citation statements)

References 36 publications

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“…The net flux of uric acid in the renal tubules of rats has been well studied, but the results are inconsistent (1,(8)(9)(10)(11) (12) reported that the rats infused with oxonate and mannitol showed a high level of FEuric acid like that of urate-loaded animals. The level and the overall function in the kidneys were similar to those of the present study.…”

Section: Discussionmentioning

confidence: 99%

Effects of uricosuric drugs and diuretics on uric acid excretion in oxonate-treated rats.

Yonetani

Iwaki

1983

Jpn.J.Pharmacol

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Abstract-A practical procedure for evaluating uricosuric agents was demonstrated using clearance experiments with potassium oxonate-treated rats. The fractional excretion value of uric acid showed a reabsorptive net flux of uric acid in the renal tubules of the animal, though the value was obviously higher than those of primates such as men, chimpanzees and cebus monkeys. However, the rats responded well to uricosuric drugs and diuretics. Probenecid and uricosuric diuretics such as tienilic acid induced hyper uricosuria due to the increase of fractional excretion of uric acid and/or the increase of the filtered amount of uric acid with the rise of plasma uric acid. On the other hand, furosemide had no effect on uric acid excretion at a low dose with moderate diuresis, while a higher dose decreased the fractional excretion of uric acid with elevation of plasma uric acid. Benzothiazides were also uricosuric at the lower doses, but the high dose, as in the case of the so-called uricosuric drugs, had no effect on the uric acid excretion and plasma uric acid level. Thus, oxonate-treated rats were useful for evaluating drug effects on uric acid excretion.Because of species differences in the metabolism and excretion of uric acid, animal experiments have contributed little to the evaluation of drug activities on the renal handling of uric acid, except for those using primates such as chimpanzees and cebus monkeys. The urinary excretion of uric acid, however, has been well studied with various nonhuman mammalia in order to find useful animals for the evaluation, resulting in some successful examples (1). The rat is such an animal because it shows a reabsorptive net flux of uric acid in the renal tubules, though the animal handles uric acid by both hepatic metabolism and renal excretion. On the other hand, useful inhibitors of urate oxidase have already been developed to create the disease model of hyperuricemia (2-4), but the inhibitor-treated animals have not been utilized enough for evaluating uricosuric agents. A practical procedure for evaluating the drugs with potassium oxonate treated rats is reported here. Materials and MethodsTen-week-old male Slc-Wistar rats were used. To determine uric acid and inulin clearance, the animals were given potassium oxonate, 250 mg/kg i.p., and then the right femoral artery, left femoral vein and urinary bladder were cannulated for blood collection, infusion and urine collection, respectively, under anesthesia with sodium pentobarbital, 50 mg/kg i.p., within 2 hr after the adminis tration of oxonate. The same dose of oxonate was given again just 2 hr after the first administration, and then 60% urethane, 2 ml/kg, and 15% inulin, 4 ml/kg, were administered subcutaneously. The animals were then infused with 4% mannitol-1.5% inulin-0.9% sodium chloride solution at the flow rate of 0.1 ml/min on a hot plate at

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Section: Discussionmentioning

confidence: 99%

Effects of uricosuric drugs and diuretics on uric acid excretion in oxonate-treated rats.

Yonetani

Iwaki

1983

Jpn.J.Pharmacol

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“…Tissue slice studies on the rat kidney have failed to demonstrate uric acid uptake, although uptake could be demonstrated in animals such as the chicken, the rabbit, and the guinea pig, which show unequivocal evidence of net secretion in vivo (19). Precession studies in the rat utilizing [2-14C]urate have also failed to demonstrate evidence for a urate secretory mechanism in this species (9). By contrast, evidence for urate secretion in the rat has been advanced by Greger, Lang, and Deetjen, who were able to demonstrate that the proximal tubular fluid-to-plasma urate ratio divided by the tubular fluidto-plasma inulin ratio exceeded unity.…”

Section: Analytic Methodsmentioning

confidence: 99%

The influence of the extracellular fluid volume on the tubular reabsorption of uric acid.

Weinman¹,

Eknoyan²,

Suki³

1975

J. Clin. Invest.

135

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A B S T R A C T Changes in tubular reabsorption of uric acid in response to alterations in the extracellular fluid volume (ECFV) were examined in rats by clearance studies and by direct intratubular microinjections. Contraction of the ECFV led to a rise in the serum uric acid concentration and a 47% decrease in the clearance of uric acid. The ratio of uric acid to inulin clearance also fell, indicating an increase in the net tubular reabsorption of urate. Volume expansion resulted in an increase in the urate clearance and a 37% decrease in the net tubular reabsorption of uric acid.To localize the site in the nephron where these changes occur, microinjections of [2-1"C]urate were performed.

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“…Recently it has been shown that very large doses of PZh are uricosuric in the dog and chimpanzee, a result suggesting that PZA in large doses inhibits uric acid reabsorption as well as secretion (14). Micropuncture studies have also tlemonstrated that PZA inhibits uric acid reabsorption in the proximal nephron of the rat (15). O n the other hand, clearance studies in the Cebus monkey have shown that the tubular reabsorptive maximum for uric acid is increased following PZA administration (16).…”

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confidence: 99%

“…Therefore the "pyraLinamide suppression test" would indicate that probenecid increased uric acid secretion. However it is known from more direct studies that probenecitl inhibits, rather than stimulates, uric acid secretion and that its uricosuric effect results from a decrease in uric acid reabsorption (10,11,13,(15)(16)(17). From this analysis it seems clear that pyrazinamide cannot be used to determine the mechanism by which a drug increases uric acid excretion.…”

mentioning

confidence: 99%

“…This result implies that during maximum responses to probenecid a large amount of uric acid is secreted by the tubule. However, it is known from direct studies in the rabbit, guinea pig, clog, rat, monkey, and chimpanzee that probenecitl itself is a potent inhibitor of uric acid secretion (10,11,(13)(14)(15). If probenecitl inhibited uric acid secretion as effectively in man as i t did in other species, i t is difficult to imagine how i t could be a potent uricosuric drug in a model such as the one proposed by the postsecretory reabsorptive site hypothesis.…”

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confidence: 99%

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