Experimental studies on the excretion of uric acid in rabbit
The excretion of uric acid in man has been of great interest because of its importance as an end product in purine metabolism as well as of its role in causing gout. There are many differences in the modes of renal handling of urate among various species of animals. Uric acid actively secreted by the renal tubules of most vertebrate including amphibians, reptiles, and birds. On the other hand, in most mammals net tubular reabsorption of urate appears to be occurred with some exception, such as Dalmatian dog. In the rabbits, however, the mechanism of renal excretion of uric acid has long been a subject of controversial results. Within a given group it was possible to find individuals wish either net secretion or net reabsorption of urate depend on the experimental conditions.
Excretion of urate can be depressed or enhanced hy a variety of drugs belonging mainly to the aromatic acid group. Diodrast, probenecid, cinchophen and salicylates have been reported as uricosuric agents, on the other hand, lactate, benzoate, pyrazinoic acid, acetazolamide and chlorothiazide are known to be contraindicated to use for the patient with gout since theme agents depress the excretion of uric acid from the kidney. However, complex and sometimes the paradoxical effects on the
urate excretion by those above mentioned drugs are not uncommon.
The experiments were designed to investigate the mechanisms of renal handling of crate as well as the effects of variety of drugs on the tubular transport of uric acid in the rabbits.
Male or female white rabbits, from 1.5 to 2.5 kg in weight, were used. The experimental methods used in these studios were clearance, stop-flow, and retrograde injection techniques. The effects of saline, salicylate, chlorothiazide and probenecid were investigated in each experimental conditions.
Results of the experiments ware summarized as follows;
1. In the rabbits, the rate of urate clearance was always lower than the rate of inulin clearance. The filtration fraction of the urate was one third on an average, therefore, it is estimated that approximately two thirds of filtered crate was reabsorbed.
2. In the kidneys of rabbits, the crate clearance was increased significantly by administration of chlorothiazide and decreased by probenecid. The administration of salicylate had no effect on the rate of urate clearance. The filtration fraction of urate was increased by chlorothiazide and decreased by probenecid.
3. In the strop-flow studies, the U/P ratio of urate was higher than the U/P ratio of inulin in the proximal region, indicating the secretion of uric acid in the proximal tubuleg. The proximal peak was increased by chlorothiazide and inhibited by probenecid.
4. In the retrograde injection studies, the reabsorption of urate in the proximal reigon was observed, and these reabsorptive transport of urate was depressed by either probenecid or by chlorothiazide.
5. No distal tubular activity was observed under any of these experimental conditions concerning urate transeort.
The results of these experiments show that probenecid inhibits both secretory and reabsorptive transport of uric acid in the kidney of the rabbits. The enhancement of secretory transport of urate by chlorothiazide in the clearance study was due to the secondary action of chlorothiazide which inhibits the reabsorptive transport of urate in the proximal tubules. It is evident that the urate transport in the kidneys of rabbits is bidirectional nondiffusive flux both secretory and reabsorptive directions in the proximal tubules.