Effects of mercurial diuretics on renal transport of urate in the chimpanzee

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“…Fannelli et a1 have used mersalyl in the chimpanzee as another pharmacologic tool for the study of renal urate transport (14). In the chimpanzee, a species with physiologic and pharmacologic similarities to man insofar as handling of urate by the kidney is concerned (15), urate excretion normally is far less than the amount filtered under control clearance conditions.…”

Section: Thomas H Steelementioning

confidence: 99%

“…In the chimpanzee, a species with physiologic and pharmacologic similarities to man insofar as handling of urate by the kidney is concerned (15), urate excretion normally is far less than the amount filtered under control clearance conditions. Yet, following the administration of mersalyl, net secretion of urate was clearly demonstrable (14). T h e apparent magnitude of secretion was surprisingly great, for urate clearances after mersalyl occasionally achieved values nearly double the glomerular filtration rate (14).…”

Section: Thomas H Steelementioning

confidence: 99%

“…T h e magnitudes of intrarenal urate secretory and reabsorptive fluxes probably have been greatly underestimated in the more traditional interpretations of results from clearance studies. T h e selective inhibition of urate reabsorption can unmask very large secretory fluxes (14). Conversely, it seems possible that total intrarenal urate reabsorp tion may decline when tubular secretion is selectively inhibited, as a consequence of diminished urate delivery to postsecretory reabsorptive sites.…”

Section: Thomas H Steelementioning

confidence: 99%

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Renal excretion of uric acid

Steele

1975

Arthritis & Rheumatism

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I n earlier years of renal physiology study, the developnient of the inulin clearance for the estimation of the glomerular filtration rate (GFR) allowed a precise comparison between the excretion and filtration rates of many urinary solutes. Although it soon was realized that many members of a large group of weak organic acids are avidly bound by the kidney and undergo net tubular secretion, studies in several species including man indicated that the rate of uric acid excretion was far less than its rate of filtration. Even though the possibility was raised that polymerized or protein-bound aggregates of urate not amenable to glomerular filtration might exist in plasma (l), the prevailing opinion was that urate simply underwent complete glomerular filtration and partial tubular reabsorption. Extensive studies were reported in 1950 by Berliner et al (Z), in which urate titration procedures were performed in an attempt further to characterize urate reabsorption within the normal kidney. During the progressive infusion of urate, the difference between the rates of filtration and excretion of urate increased progressively. Berliner and his coworkers ultimately concluded that a maximum urate reabsorption rate probably exists in normal man, but that the ap- parent capacity for urate reabsorption is so great that it would not become fully saturated under normal conditions (2). Although Praetorius and Kirk (3) described a hypouricemic patient who demonstrated net urate secretion in 1950, the possible existence of a significant amount of tubular secretion of urate in man was not widely accepted. Subsequently, renewed interest in renal urate secretion occurred, largely as a result of work from the laboratory of the late Dr. Alexander Gutman. Gutman and Y u raised the question of the existence of urate secretion in man based on observations during clearance studies in gouty patients and normal persons (4). Even in their early reports, they hypothesized that large transtubular fluxes of urate might exist, for if secretion of urate did occur then the calculated net reabsorptive rates of urate would be too low. Subsequent observations elucidating the remarkable "paradoxical actions" of certain pharmacologic agents on urate excretion (5) and also the antiuricosuric effect of pyrazinamide (PZA) administration (6) raised the possibility that inhibition of the tubular secretion of urate could substantially reduce urate excretion. Although Gutman and his colleagues acknowledged that an enhanced rate of urate reabsorption could also have produced an antiuricosuric effect, they visualized that if virtually complete reabsorption of the filtered urate occurred within the nephron and if the urinary uric acid were derived primarily from

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Section: Thomas H Steelementioning

confidence: 99%

Section: Thomas H Steelementioning

confidence: 99%

Section: Thomas H Steelementioning

confidence: 99%

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Renal excretion of uric acid

Steele

1975

Arthritis & Rheumatism

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“…These differences will be discussed shortly. Studies i n our laboratories over previous years (23)(24)(25)(26), some in collaboration with I. M. Weiner, State University of New York at Syracuse, were specifically directed at trying to elucidate some of the physiologic and pharmacologic aspects of renal urate transport i n a unique and very close phylogenetic relative to man, the chimpanzee. This species, like man, has suffered the mutational loss of uricase, and its renal handling of urate is superficially very similar to that of man (23).…”

Section: George M Fanelli Jrmentioning

confidence: 99%

“…A carrier-mediated reabsorptive flux has as yet eluded experimental verification. However it is thought that there is a simultaneous active reabsorption of probenecid, salicylate, sulfinpyrazone, etc, that competitively inhibits urate reabsorption and thereby produces a uricosuric effect T h e uricosuric action of the organomercurial diuretic, mersalyl, is so intense i n the chimpanzee that net tubular secretion was readily demonstrable (25). T h e urate secretory component is large and is apparently inhibited by probenecid, salicylate, and various other organic anions.…”

Section: George M Fanelli Jrmentioning

confidence: 99%

Uricosuric agents

Fanelli

1975

Arthritis & Rheumatism

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By definition a uricosuric agent is one that facilitates the renal excretion of uric acid presumably by specific inhibition of its tubular reabsorption and secretion. Even though in most instances (with possible exceptions to be discussed shortly) both transport systems are inhibited to some degree, the predominant pharmacologic effect is on urate reabsorption at the luminal membrane with the net effect being uricosuria. An excellent review on uricosuric drugs has been published by the late Dr. Alexander B. Gutman Basic to the understanding of the mechanism of action of uricosuric agents and renal urate transport in general are the following postulates formulated by Weiner and Fanelli (2): a) Most of urate reabsorption occurs in the proximal tubule. b) Uricosuric agents act by depressing proximal reabsorption of urate. c) Drugs that depress urate reabsorption do so from the luminal aspect of the tubule. d) Uric acid is secreted in the proximal tubule. e) T h e secretory flux for urate (and consequently the reabsorptive flux) is large. f) A variety of compounds, uricosuric or not, inhibit the secretory flux. g) T h e urate secretory mechanism is probably different from the p-amino-(1).

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Diuretic and Uricosuric Agents

Fink

McKenna

Werner

2003

Burger's Medicinal Chemistry and Drug Discovery

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Herein is presented the development and therapeutic use of diuretic agents, a topic that constitutes one of the most significant advances in medicine made during the twentieth century. Diuretics are among the most frequently prescribed therapeutic agents for the treatment of edema, hypertension, and congestive heart failure and they act primarily by inhibiting the reabsorption of sodium ions from the renal tubules in the kidney. Recent advances in renal and ion‐transport research have led to a more precise understanding of the cellular mechanisms of actions of the various classes of diuretic agents. This understanding has aided the design of newer and more effective agents. Today diuretics are grouped as loop, potassium‐sparing, thiazide, or osmotic diuretics and include compounds that have combined diuretic and uricosuric properties. Uricosuric agents increase the excretion of uric acid, a principal product of purine metabolism; and because hyperuricemia is an adverse effect sometimes observed with diuretic treatment, arising from decreased extracellular volume and increased urate reabsorption, this combined property is advantageous. However, given that diuretics themselv are convenient, inexpensive, and generally are well tolerated, they will probably continue to play a role in the treatment of hypertension.

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Effects of mercurial diuretics on renal transport of urate in the chimpanzee

Cited by 34 publications

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Renal excretion of uric acid

Renal excretion of uric acid

Uricosuric agents

Diuretic and Uricosuric Agents

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