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Biomedical subjects

I M Weiner

Publications and source records attributed to I M Weiner.

At least 19 recordsLinked to original sources
PubMed1984

Effects of p-aminohippurate and pyrazinoate on urate excretion in Cebus monkeys.

Changes in the fractional excretion of urate (FEurate) induced by various concentrations of p-aminohippurate (PAH) and pyrazinoate in plasma were evaluated in anesthetized Cebus monkeys using the standard clearance technique. PAH at concentrations between 2 and 40 micrograms/ml produced modest uricosuria (delta FEurate, ca 50%). At higher concentrations of PAH (up to 1200 micrograms/ml) the values of FEurate were not different from controls. Pyrazinoate at concentrations between 1 and 700 micrograms/ml reduced FEurate. The depressant effect of pyrazinoate was not influenced by the presence of PAH. These results are consistent with the idea that the secretory component for urate is distinct from that for PAH in this monkey.

Aminohippuric Acids↗
PubMed1983

Function of proximal tubule carbonic anhydrase defined by selective inhibition.

The specific role of luminal carbonic anhydrase in bicarbonate reabsorption by the proximal tubule has not been established because it has been difficult to inhibit selectively the luminal enzyme without simultaneous inhibition of the cytoplasmic enzyme. The present experiments employed in vivo microperfusion, microcalorimetry, and microelectrode techniques to determine the effects of luminal application of a dextran-bound carbonic anhydrase inhibitor (DBI) on bicarbonate reabsorptive rate (JtCO2) and intraluminal pH in the rat proximal convoluted tubule. Tubules were perfused at 20 nl/min with an artificial ultrafiltrate. Aminoethyl dextran (AED) with no enzyme-inhibitor activity was added to the control perfusate, and the effects of the parent inhibitor STZ not bound to dextran were also determined. Both DBI and STZ significantly reduced JtCO2 from 138 +/- 10 pmol X mm-1 X min-1 (control) to 30 +/- 4 and 30 +/- 9, respectively. In contrast to the indistinguishable effects on JtCO2, intraluminal pH measured close to the site of perfusion was 6.80 +/- 0.02 during DBI perfusion, whereas with STZ perfusion the pH was 7.24 +/- 0.04 (P less than 0.001). Using the collected perfusate total CO2 concentration and a renal cortical PCO2 of 60 mmHg, the calculated equilibrium pH for this solution was 7.27. DBI inhibited only luminal carbonic anhydrase, therefore. We conclude that luminal carbonic anhydrase is in functional contact with proximal tubule fluid and is necessary for at least 80% of bicarbonate reabsorption by this segment.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Equilibrium↗
PubMed1983

Effects of pyrazinoate and p-aminohippurate on renal urate excretion by the dog and guinea pig.

In anesthetized dogs, pyrazinoate reduced the fractional excretion of urate when the concentration of the drug in plasma ranged from 3 to 300 micrograms/ml. At higher concentrations, fractional excretion rose progressively. p-Aminohippurate at concentrations in plasma ranging from 1 to 1000 micrograms/ml had no effect on the fractional excretion of urate. In guinea pigs, pyrazinoate exerted only a faint uricosuric action and p-aminohippurate was without effect. Both substances were tested over the range of 1 to 1000 micrograms/ml of plasma. The results in dogs help explain some previous reports of negative experiments with pyrazinoate; the doses used were not optimal for detecting responses. The results in guinea pigs suggested that urate secretion in this animal does not fit either of two previously recognized mechanisms.

Aminohippuric Acids↗
PubMed1981

Renal excretion of cimetidine.

The renal excretion and certain pharmacokinetic properties of cimetidine were studied in anesthetized rats undergoing moderate osmotic diuresis. When cimetidine concentrations in plasma (Pcim) were low, ca. 2 micrograms/ml, the clearance of cimetidine (Ccim) was 2.64-fold greater than the glomerular filtration rate (GFR). Ccim was lower at higher concentrations, e.g., at ca. 200 micrograms/ml, Ccim/GFR was 1.24. When animals with low Pcim were alkalotic (bicarbonate infusion), Ccim/GFR was 1.82 (different from control, P less than 0.01). In nonalkalotic animals, Ccim/GFR was not influenced by changes in urine flow rate. High levels of Pcim completely blocked net secretion of the cation, tetraethylammonium ion, but did not inhibit the secretion of the anion p-aminohippurate. The half-time of cimetidine in plasma was 43 to 49 min. The apparent volume of distribution was 3.6-fold greater than estimated total body water. We conclude that cimetidine is secreted by the renal organic cation transport mechanism and that it probably undergoes passive reabsorption (nonionic diffusion) to a modest extent when the urine is alkaline. The relatively long half-life of the drug in the body, despite its very high renal clearance, is attributable to the large volume of distribution.

Animals↗
PubMed1981

Dextran-bound inhibitors of carbonic anhydrase.

High molecular weight inhibitors of carbonic anhydrase were synthesized and tested in isolated perfused rat kidneys. One such inhibitor, dextran-bound inhibitor (DBI), had a mean molecular mass of 6700 daltons. Its renal clearance was equal to the clearance of inulin and its intrarenal volume of distribution was close to that of inulin. The maximal effect of DBI on bicarbonate excretion was the same as that of acetazolamide. This action could not be attributed to breakdown products of DBI. DBI does not enter erythrocytes. Another inhibitor, extra-large inhibitor, had a mean molecular mass of 99,000 daltons. It was scarcely filterable. It did not increase bicarbonate excretion when added to perfusates in concentrations greater than effective concentrations of DBI. It is concluded that activity of carbonic anhydrase bound to luminal membranes of renal cells is critical for normal reabsorption of bicarbonate.

Animals↗
PubMed1980

A micropuncture study of urate excretion by Cebus monkeys employing high performance liquid chromatography with amperometric detection of urate.

Net renal reabsorption of endogenous urate was studied by the micropuncture technique in Cebus monkeys in the absence of osmotic diuresis. Most of filtered urate (more than 70%) was reabsorbed in the proximal convoluted tubules. Samples from early distal tubules contained 9% of filtered urate; approximately 18% being reabsorbed between the late proximal and early distal segments. There was no detectable reabsorption along the distal tubule. Fractional delivery of urate to late distal tubules was greater than fractional excretion, implying reabsorption of some 4% of filtered urate in the collecting system. However, we cannot exclude nephron heterogeneity as the cause of the difference. The foregoing results were obtained using the method of Pachla and Kissinger for the determination of urate. Urate is separated by high performance liquid chromatography and detected by an amperometric technique. We found the method to be sufficiently sensitive, precise and specific for renal micropuncture samples.

Animals↗
PubMed1979

Urate transport in the nephron.

This paper summarizes the literature on the sties of urate transport, secretory and reabosrptive, in the nephron. In the animals studied thus far the bulk of urate transport occurs in the proximal tubules. Two patterns of transport have been uncovered. In one, urate is secreted and reabsorbed throughout the convoluted tubule (perhaps the pars recta as well). The direction of net transport depends on the kind of animal studied and in some instances on the experimental conditions. In the second pattern there is a strong secretory process in the pars recta, and net secretion of urate, when it occurs, is attributable to that segment. In some but not all animals it is clear that urate secretion in the proximal tubules occurs by a mechanism separate from that which secretes p-aminohippurate (PAH). One important unresolved question is: How general is the occurrence of separate secretory mechanisms for PAH and urate? Another unresolved question is: What are the magnitudes of the unidirectional fluxes of urate in the segments in which bidirectional transport occurs?

Animals↗
PubMed1979

Urate excretion: drug interactions.

A derivative of probenecid, 2-nitroprobenecid, was studied in chimpanzees and Cebus monkeys. The uricosuria induced by the drug could be diminished by the infusion of p-aminohippurate (chimpanzee) or hippurate (monkey). Both hippurates inhibited the secretion of the drug and it is likely that the diminished response was the result of decreased access of 2-nitroprobenecid to its site of action. In contrast, pyrazinoate diminished the response to 2-nitroprobenecid without disturbing its renal disposition (both species). This action of pyrazinoate is attributed to its ability to inhibit the secretory flux of urate. The effect of pyrazinoate is diminished at high levels of 2-nitroprobenecid, i.e., it appears as if pyrazinoate causes a shift to the right of the concentration-response curve of 2-nitroprobenecid. A mathematical model is developed which seems to explain this apparent shift in the concentration-response curve. This model requires that the transepithelial fluxes for urate be very large. In the chimpanzee the action of salicylate resembles that of pyrazinoate but it is less prominent.

Animals↗
PubMed1978

The effects of 2,4,6-triaminopyrimidine (TAP) on sodium and potassium excretion by the rat kidney: comparison with amiloride.

2,4,6-Triaminopyrimidine (TAP) has been reported to be a blocker of the cation-specific paracellular conductance pathways of several epithelia. The compound is also known to inhibit sodium transport in the frog skin. Its effects on renal function were studied in clearance experiments in anesthetized rats and in isolated perfused rat kidneys and compared with the effects of amiloride. The effects of both compounds on electrical resistance of the frog gallbladder were also evaluated. Both TAP and amiloride caused modest natriuresis and a marked reduction in potassium excretion. Amiloride is approximately 1000 times more potent than TAP when compared on the basis of drug concentration in the urine. The concentrations of both substances in urine (at effective doses) correspond to concentrations reported to be effective against sodium transport in amphibian membranes. The urinary concentrations of TAP also correspond to the concentrations required to inhibit paracellular cation movement in the gallbladder. Amiloride at the level tested (10(-3) M) did not seem to influence the paracellular pathway. The results neither establish nor disprove a role of the paracellular pathway in potassium secretion. Both TAP and amiloride are secreted by the renal tubules.

Amiloride↗
PubMed1978

Salicylate excretion in the rat; free flow micropuncture experiments.

As in other animals, the renal clearance of salicylate in the rat is greater when the urine is alkaline than when it is acid. In none of the present experiments was the rate of salicylate excretion greater than the rate of its glomerular filtration. Nevertheless, net secretion of salicylate was observed in the proximal tubules of alkalotic, nonalkalotic diuretic, and normal hydropenic animals when the plasma concentration of salicylate was below 150 microgram/ml. Alkalosis enhanced the salicylate content of proximal tubular fluid (approximately 30%). The enhancement is less than would be expected from published reports of proximal tubular fluid pH, if non-ionized salicylate were the only permeant form of the drug. In the absence of alkalosis and at high plasma concentrations, net reabsorption in the proximal tubule was observed. In some circumstances there is net reabsorption of salicylate between the end of the accessible portion of the proximal tubule and the beginning of the distal. Salicylate is reabsorbed from the distal tubule. There was only a small difference in distal reabsorptive rate between normal and alkalotic animals.

Animals↗
PubMed1977

Diuretic-induced uricosuria: interaction with pyrazinoate transport in man.

We investigated the acute effect of an orally administered uricosuric natriuretic agent (SKF-62698) on renal urate transport in paired clearance studies in seven normal men. The participants received SKF-62698 on two separate occasions. Prior to the second study, each received pyrazinamide (PZA) in order to inhibit the tubular secretion of urate. Within 3 hours, SKF-62698 significantly decreased the plasma urate and trebled the rate of urate excretion in the studies without PZA. In contrast, after PZA pretreatment. SKF-62698 did not diminish the plasma urate appreciably and elicited only 60% of the previous increase in urate excretion. Sodium excretion quadrupled after SKF-62698, irrespective of the presence of PZA. Plasma concentrations of pyrazinoate, the renally active metabolite of PZA, were at levels previously shown in the chimpanzee to primarily inhibit the tubular secretion of urate. Therefore, intact tubular secretion of urate probably was necessary in order for SKF-62698 to elicit its maximum uricosuric response. SKF-62698 appeared to inhibit the tubular secretion of pyrazinoate, but the observed changes in urate transport could not be explained on that basis.

Adult↗
PubMed1976

The role of volume contraction in the hypocalciuric action of chlorothiazide.

Thiazide-induced hypocalciuria usually requires two to four days of drug treatment for its full expression. The present experiments were designed to test the possibility that an immediate hypocalciuria could be produced in subjects whose extracellular volumes were already contracted. In previously untreated subjects, chlorothiazide (2 g/day) did not produce hypocalciuria on the first day of treatment. Hypocalciuria occurred on the second day and was somewhat enhanced on the third and fourth days of treatment. In subjects pretreated with furosemide (40 mg two or three times a day for two days), chlorothiazide produced hypocalciuria on the first day of its use. Under the influence of chlorothiazide, there was a strong linear correlation between the changes in the excretion of calcium and sodium. The results are consistent with the idea that chlorothiazide enhances the ratio of calcium to sodium reabsorptions and that this tendency for absolute hypocalciuria can be overridden by a large natriuretic response to the drug. Volume contraction, which minimizes the natriretic response to diuretics, allows a more immediate and pronounced hypocalciuric response to thiazides.

Adult↗
PubMed1976

Relationship between clearances of Ca and Na: effect of distal diuretics and PTH.

One of the objectives of this study was to determine whether or not the absence of parathyroid hormone (PTH) modifies quantitatively the acute action of chlorothiazide (CTZ) to lower the clearance ratio, CCa/CNa. The same group of dogs was studied with standard clearance techniques before and after thyroparathyroidectomy (T-PTX), and after T-PTX during the infusion of PTH. There was no significant difference in the response to CTZ before or after T-PTX, or during the infusion of PTH. The effects of PTH and a maximally effective dose of CTZ were additive. A second objective of this work was to ascertain whether or not two other diuretics which act on the distal tubule, amiloride and triamterene, had actions on CCa/CNa similar to that of CTZ. Amiloride caused a reduction in CCa/CNa which, even at maximally effective doses, was much smaller than the effect of CTZ. Maximally effective doses of amiloride and CTZ had additive actions. Triamterene was evaluated at only one dose; it also lowered the ratio CCa/CNa.

Amiloride↗
PubMed1975

Dissociation of calcium and sodium clearances in patients with hypoparathyroidism by infusion of chlorothiazide.

Previous reports have identified a deficient hypocalciuric response to chronic treatment with thiazide diuretics in patients with hypoparathyroidism. The present study was designed to ascertain if the acute response to thiazide diuretics is impaired in hypoparathyroidism. Five normal subjects and five patients with hypoparathyroidism were studied with the renal clearance technique during water diuresis. In normal subjects the clearance of calcium/clearance of sodium was 0.98 +/- 0.14 before, and 0.33 +/-0.03 during the intravenous infusion of chlorothiazide. In patients with hypoparathyroidism the corresponding ratios were 1.69 +/- 0.27 and 0.57 +/- 0.10. In both groups the drug-induced fall in clearance was 65% of control. The concentration of chlorothiazide in plasma and its rate of excretion were comparable in both groups. It is concluded that the acute action of thiazides is not impaired in hypoparathyroidism.

Adolescent↗
PubMed1975

Inhibition of urate excretion by pyrazinoate: a micropuncture study.

Anesthetized monkeys (Cebus albifrons) undergoing moderate mannitol diuresis were treated with infusions containing lithium urate to elevate the urate concentration in plasma to 45-68 mug/ml and containing the uricosuric drug, 2-nitroprobenecid, to enhance the renal clearance or urate. The urate/inulin clearance ratio was 0.55 +/- 0.03. When pyrazinoate was added to the infusion the clearance ratio fell to 0.26 +/- 0.02. Analysis of free-flow micropuncture samples revealed a major effect of pyrazinoate in the proximal tubule, although an additional, smaller action in the distal tubule could not be definitely excluded. When droplets containing [14C]urate and [3H]inulin were streaked on the surface of the left kidney more urate than inulin appeared in the urine from that kidney (but not the other) within the first 3 min after application. This "excess" excretion of urate could be largely eliminated by pretreatment with pyrazinoate. The results suggest that pyrazinoate inhibits secretion of urate in the proximal tubule.

Animals↗