Pyrazinoate excretion in the chimpanzee. Relation to urate disposition and the actions of uricosuric drugs.
(33/56)
These experiments were designed to define the renal disposition of pyrazinoic acid in a nonhuman primate that is phylogenetically close to man and to relate this to the effects of pyrazinoate on urate excretion. The renal clearance of pyrazinoate was almost always greater than the simultaneous glomerular filtration rate at plasma concentrations ranging from 1.9 to 960 mug/ml. Some inhibitors of tubular secretion, probenecid, MK-282 (an experimental, potent uricosuric drug), p-aminohippurate, iodopyracet, sulfinpyrazone, and mersalyl, reduced clearances of pyrazinoate to values far below filtration rate. Chlorothiazide, allopurinol, and salicylate did not. The clearance of pyrazinoate was not influenced by changes in urine flow. It is concluded that pyrazinoate is actively secreted and actively reabsorbed. Pyrazinoate had a dual effect on urate excretion. At concentrations in plasma less than 10 mug/ml there was a concentration related fall in urate/inulin clearance ratio, reaching values of 10-20% of control. Over the range of 10-100 mug/ml in plasma, the clearance of urate remained maximally depressed. At higher concentrations of pyrazinoate there was a concentration related increase in urate/inulin clearance ratio such that at pyrazinoate levels above 600 mug/ml a definite uricosuric response was obtained. Prior administration of pyrazinoate to give plasma levels of 20-140 mug/ml completely or almost completely prevented uricosuric responses to probenecid, PAH, chlorothiazide, and sulfinpyrazone. Iodopyracet, mersalyl, salicylate and N-acetyl-4-dibutylsulfamoyl-3-trifluoromethylbenzenesulfonamide (MK-282) retained significant uricosuric action, but the activities were probably less than normal. The results are consistent with a model of urate transport involving high rates of bidirectional transtubular flux. (+info)
Micropuncture study of diuretic effects on sodium and calcium reabsorption in the dog nephron.
(34/56)
A close relationship has been observed between the clearance rates of sodium and calcium under a variety of diuretic conditions. The thiazide diuretics act differently in dissociating the renal tubular reabsorption of sodium and calcium. This phenomenon has been further investigated using recollection micropuncture and clearance techniques in a group of 14 dogs subjected to three consecutive experimental phases: expansion to 3% of body weight (BWt) with Ringer's solution, chlorothiazide infusion at 20 mg/kg/h, and furosemide in a prime of 10 mg/kg/ and a 10 mg/kg/h infusion. Diuretic losses were balanced with infusion of equal volumes of Ringer's solution throughout the experiment. Chlorothiazide increased the fractional excretion (FE) of sodium almost threefold while FE(Ca) was not significantly altered. Furosemide increased FE(Na) and FE(Ca) to an approximately equal, and more marked, degree. This dissociation of sodium and calcium reabsorption after chlorothiazide was also evident in the superficial distal tubule, where (tubule fluid/plasma sodium) (TF/P(Na)) increased from 0.32 to 0.49 (P < 0.01) and TF/(ultrafiltrate)UF(Ca) was unchanged (0.35-0.31). Furosemide markedly reduced the transtubular concentration gradient for both sodium (0.86) and calcium (0.94). TF/P(Inul in) decreased progressively from 3.79 to 2.78 to 2.33 in three phases. In the late proximal tubule, chlorothiazide induced a fall of TF/P(Inul in) from 1.57 to 1.44 (P < 0.01), but the ratio TF/UF(Ca): TF/P(Na) was unchanged. Furosemide had no significant proximal effect. It is concluded that acute administration of chlorothiazide reduces sodium reabsorption in the distal hephron, presumably the cortical diluting segment, without affecting calcium reabsorption. (+info)
On the hypocalciuric action of chlorothiazide.
(35/56)
Clearance experiments were performed in female mongrel dogs, either intact or thyro-parathy-roidectomized (T-PTX), under pentobarbital anesthesia, to examine the unusual hypocalciuric property of thiazide diuretics. The relationship between calcium clearance (C(Ca)) and sodium clearance (C(Na)) was determined in normal dogs, C(Ca) = 0.79 C(Na); constant infusion of chlorothiazide (CTZ) to provide drug concentrations in plasma of approximately 40 mug/ml modified this relationship; C(Ca) = 0.30 C(Na) (P < 0.001). The magnitude of the dissociating effect of CTZ on the urinary Ca/Na relationship was found to be most highly correlated with urinary drug concentration. Infusion of CTZ (1 mg/min) into one renal artery caused a unilateral decrease (25%) in C(Ca)/GFR while producing a unilateral increase (80%) in C(Na)/GFR. The same dose of CTZ in T-PTX dogs produced an increase in C(Na)/GFR without causing a change in C(Ca)/GFR. The defective response in T-PTX dogs could be ascribed to poor tubular secretion of the drug; when urinary drug concentrations were elevated in T-PTX dogs to the levels found in intact dogs (by infusing more drug), C(Ca)/GFR fell to an equivalent extent. T-PTX dogs showed substantially lower renal extraction of CTZ (42%) than intact dogs (57%); PTH administration to T-PTX dogs increased extraction toward normal (49%). The defective secretion of CTZ could not be attributed to either a decreased tubular maximum or a decreased renal blood flow. (+info)
A comparison of the effects of chlorothiazide, quinethazone and placebo on student volunteers and on rats: a teaching exercise.
(36/56)
Medical student participation in a controlled doubleblind clinical bioassay provides an effective introduction to clinical pharmacology and perhaps the best stimulus to the future rational evaluation and use of drugs. In one such exercise, 27 volunteers were divided into three groups: one received 50 mg. quinethazone, one 500 mg. chlorothiazide and the third a lactose placebo. Urine was collected for three 90-minute periods, volume and pH being recorded; sodium and potassium were measured with a flame photometer, and chloride by the Volhard technique. Although this study was primarily a comparative bioassay of two established diuretics against a placebo, no previous direct comparisons of these diuretics could be found in the literature. The diuretic activity of chlorothiazide and quinethazone compared to placebo therapy was confirmed in both humans and rats, the use of controls was illustrated, and a higher mean sodium-potassium ratio for quinethazone than for chlorothiazide was demonstrated. (+info)
Effects of increased sodium delivery on distal tubular sodium reabsorption with and without volume expansion in man.
(37/56)
The separate effects of volume expansion and of increased delivery of sodium on sodium reabsorption in the diluting segment of the distal nephron were studied in man. In six normal subjects during a sustained water diuresis, sodium delivery to the distal nephron was increased without volume expansion by the administration of acetazolamide. In these subjects, free water clearance rose linearly as a function of urine flow. In five patients with complete, central diabetes insipidus, distal sodium delivery was increased by the infusion of hypertonic saline during a sustained water diuresis. In four of these five patients, changes in free water clearance were also observed during hypertonic saline diuresis in the presence of distal blockade of sodium reabsorption with chlorothiazide. At high rates of distal delivery the following observations were made: (a) free water clearance was lower and fractional sodium excretion higher during saline diuresis compared to acetazolamide diuresis; (b) although free water clearance was moderately reduced by chlorothiazide at low rates of urine flow, there was no difference in free water clearance between saline loading alone and saline plus chlorothiazide at high rates of urine flow; and (c) during saline loading free water clearance rose without evidence of a limit when increased distal delivery was accompanied by spontaneous increases in glomerular filtration rate, but tended toward a limit when glomerular filtration rate remained constant. The data indicate that during acute volume expansion with saline, there is a decrease in the fraction of delivered sodium reabsorbed in the distal nephron when compared to the response of the distal nephron to comparable increases in distal sodium delivery in the absence of volume expansion. (+info)
Idiopathic hypercalciuria and hyperparathyroidism.
(38/56)
With provocative tests of parathyroid activity based on phosphate deprivation and the administration of chlorothiazide 8 out of 19 patients with idiopathic hypercalciuria developed hypercalcaemia. Five of the eight underwent exploration of the neck and four of them had parathyroid adenomas; the fifth patient had "normal" glands but responded satisfactorily to subtotal parathyroidectomy. One patient who failed to develop hypercalcaemia had primary chief cell hyperplasia of the parathyroids. (+info)
Factors influencing the electrical potential across the mucosa of rat colon.
(39/56)
1. An investigation has been carried out into various factors which influence the transmucosal potential difference (p.d.) of rat colon in vivo when the p.d. is either high (> 30 mV) or low (< 20 mV).2. The p.d. was uninfluenced by short duration anaesthesia with ether or pentobarbitone. When anaesthesia was prolonged for several hours, p.d. rose steadily. The gradient of p.d. along the descending colon which developed and its elimination by adrenalectomy suggested that the rise was due to increased secretion of adrenal steroids.3. P.d. was increased by Na depletion after a delay of about 18 hr and fell again following Na repletion with a similar time delay. A characteristic gradient of p.d. along the descending colon was seen.4. Both haemorrhage and anoxia caused a rapid fall of p.d. P.d. was restored rapidly to its previous level when anoxia was corrected.5. Vasopressin (I.V.) in low dose was without effect; in high dose it caused a transient fall of p.d. associated with intense vasoconstriction of gut blood vessels.6. The following factors studied were without effect on p.d.: presence of glucose within the lumen; considerable osmotic gradients across the mucosa; variation of luminal pH over the range 5.2-9.8; intravenous administration of acetazolamide, chlorothiazide, frusemide, triamterene, ethacrynic acid or ouabain. Ouabain in the luminal solution also had no effect in all but two rats in which a small fall of p.d. was seen.7. 2,4-dinitrophenol, 10(-2)M, in the lumen caused a small fall of p.d. only if the p.d. was high.8. Experiments were done to determine the effect on p.d. of altering the ionic composition of the luminal solution. When the p.d. was low (< 20 mV) alteration of [Na], [K] or [Cl] produced small absolute changes of the p.d., all of comparable magnitude. The changes could be interpreted as due to diffusion potentials resulting from the ionic gradients across the mucosa. When the p.d. was high (> 30 mV), it showed a striking dependence on the luminal [Na] only, consistent with the presence of a large p.d. due to active Na transport. (+info)
Effects of hypotonic saline loading in hydrated dog: evidence for a saline-induced limit on distal tubular sodium transport.
(40/56)
We performed studies on dogs under hydrated conditions, utilizing the rate of free water formation (C(H2O)) as an index of the rate of distal tubular sodium transport. Since C(H2O) could be progressively increased with no evidence of a maximal rate during loading with hypotonic (2.5%) mannitol, it was concluded that there is no limit on distal tubular sodium transport during mannitol loading. In contrast, during hypotonic (0.45%) saline loading C(H2O) rose initially, but as urine flow (V) exceeded 25% of the filtered load C(H2O) attained maximal levels (up to 20% of the filtered load) and remained stable as V increased to 50% of the filtered load. It was concluded that saline loading progressively inhibits proximal sodium reabsorption. Initially, the distal tubule absorbes a large fraction of the proximal rejectate and sodium excretion rises slightly. Eventually, an alteration in distal sodium transport appears which culminates in a maximal rate or transport limit. This distal transport limit provoked by saline loading could not be characterized by a classical Tm as seen with glucose and does not seem to be consequent to high rates of flow through the distal tubule. Regardless of the precise nature of this limit, the major increment in sodium excretion develops during saline loading only after saline alters the capacity of the distal tubule to transport sodium. (+info)