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PubMed1973

Renin-like activity of the rat submaxillary gland: characterization and the effect of several drugs and stimuli.

1. Renin-like activity was found in rat submaxillary glands.2. This activity was destroyed by boiling, was non-dialyzable and showed an optimum at approximately 50 degrees C.3. Renin-like activity in the submaxillary gland was not diminished 24 h after nephrectomy but was considerably reduced after ligature of the submaxillary duct.4. Renin-like activity in the submaxillary gland was reduced following food-deprivation, water-deprivation or hypovolemia.5. Renin-like activity in the rat submaxillary gland was increased after isoproterenol administration but not following pilocarpine.6. Renin-like activity in the rat submaxillary gland was increased considerably by administration of NaCl or KCl, as well as following adrenalectomy.7. Chlorothiazide and ouabain increased submaxillary renin-like activity but diazoxide did not affect this activity.

Adrenal Glands↗
PubMed1992

Thiazide therapy for ACTH-induced hypercalciuria and nephrolithiasis.

A one-year-old boy presented with hypercalciuria and nephrolithiasis following a course of ACTH therapy for infantile spasms. After a successful cystolithotripsy, therapy with chlorothiazide was followed by regression of the hypercalciuria within 42 months. Neither nephrolithiasis nor nephrocalcinosis recurred. Therapy with thiazides to prevent hypercalciuria caused by ACTH is proposed.

Adrenocorticotropic Hormone↗
PubMed1982

Mechanism of drug dissolution rate enhancement from beta-cyclodextrin-drug systems.

The influence of beta-cyclodextrin on the physicochemical properties of bendrofluazide, chlorothiazide, hydrochlorothiazide and hydroflumethiazide was investigated using solubility, X-ray powder diffraction, differential scanning calorimetry (DSC) and intrinsic dissolution rate methods. The solubility of each drug was enhanced in the presence of beta-cyclodextrin, the effect being greatest with bendrofluazide. X-ray diffraction data on equimolar freeze dried systems indicated the formation of solid state inclusion complex only in the case of bendrofluazide. The relative increase in initial dissolution rate of drug from freeze dried systems varied from sixty fold for bendrofluazide to three fold for hydroflumethiazide. The observed dissolution rates were intermediate between those predicted by the classical two component soluble complex model and a carrier controlled model. It was concluded that the enhanced drug dissolution rates, which are above those predicted by the soluble complex model, are due to an extension of carrier phase dissolution control to higher drug weight fractions than predicted by the soluble complex model and that this was a consequence of the disparate solubilities of the carrier and drug.

Bendroflumethiazide↗
PubMed1968

Factors influencing the electrical potential across the mucosa of rat colon.

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.

Acetazolamide↗
PubMed1974

Relationship between glucose and sodium excretion in the new-born dog.

1. The relationship between renal glucose and sodium excretion was studied in thirty-three new-born dogs aged 1-14 days and in ten adult dogs.2. Glucose was infused into the animals at rates sufficient to produce an amount of filtered glucose at least 1.5 times the tubular transport of glucose (saturating glucose load). In both puppies and adults tubular glucose reabsorption at saturating glucose loads varied directly with the glomerular filtration rate (r = 0.54 and 0.73 respectively, P < 0.01 for both).3. In the puppy, as the fraction of filtered sodium excreted (C(Na)/C(In)) increased from 0.05 to 0.45, the ratio, renal tubular glucose transport divided by glomerular filtration rate at saturating glucose loads, (T(G)/GFR)(m), decreased from 3.7 to 1.7 mg/ml. (r = -0.75, P < 0.01). In the adult C(Na)/C(In) was below 0.08 in all experiments and (T(G)/GFR)(m) was within the 95% confidence limits predicted by regression analysis of the data from puppies. Although mean (T(G)/GFR)(m) was greater in the adult than in the puppy (P < 0.01), when puppies had C(Na)/C(In) similar to that for adults, they had (T(G)/GFR)(m) values equivalent to that for the adult.4. There was excellent correlation between glucose excretion and water excretion for both adult and new-born dogs (r = 0.93 and 0.87, respectively). However, for any glucose loss, water loss was greater in the puppy than in the adult (P < 0.01).5. During the control period total sodium excretion (per gram kidney) and C(Na)/C(In) were similar in the new-born and adult dog. However, during glucose loading, the puppies excreted more sodium and had a higher C(Na)/C(In) than did the adult, although glucose excretion was greater in the adult than in the puppy (P < 0.01 for all comparisons).6. Glomerular blood flow, as measured by radioactive microspheres, was redistributed towards inner cortical nephrons during glucose loading in the puppy. There was no such redistribution of glomerular blood flow in the adult.7. Sodium reabsorption beyond the proximal tubule was blocked with ethacrynic acid and chlorothiazide. In the puppy, the increase of C(Na)/C(In) following a glucose load was the same whether the glucose load followed control or distal blockade collections, suggesting that reductions of sodium reabsorption following a glucose load probably came from the proximal tubule. C(Na)/C(In) during glucose loading plus distal blockade was significantly (P < 0.01) higher in the puppy (0.598) than in the adult (0.280), indicating that glucose diuresis produced a greater inhibition of proximal tubular sodium reabsorption in the new-born than in the adult dog. These results support the hypothesis that the high sodium excretion rate during glucose diuresis in the new-born dogs appears to be due to the greater sensitivity of the neonatal proximal tubule to the osmotic effect of glucose. When presented with a glucose osmotic load the new-born dog diminishes net proximal sodium reabsorption more than does the adult and thus depresses tubular glucose reabsorption to a greater extent. The lower values of maximal glucose transport rates found in new-born animals may be related, therefore, to the higher fractional sodium excretion rates during glucose diuresis rather than to a diminished intrinsic glucose transport capacity in the new-born kidney.

Age Factors↗
PubMed1970

Idiopathic hypercalciuria and hyperparathyroidism.

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.

Adenoma↗
PubMed1981

Maintenance of glomerulotubular balance for bicarbonate during carbonic anhydrase inhibition in the dog.

Studies were performed to examine the possible effects of carbonic anhydrase (CA) inhibition on the glomerulotubular balance for bicarbonate in anesthetized dogs. Maximal CA inhibition was achieved by acetazolamide infusion and glomerular filtration rate (GFR) was reduced in a stepwise fashion by progressive clamping of the left renal artery. A close relationship (R equals 0.973) was maintained between the amount of filtered and reabsorbed bicarbonate in normal dogs with CA inhibition. A similar relationship was observed between GFR and bicarbonate reabsorption during CA inhibition in normal dogs (R equals 0.957) as well as in sodium bicarbonate loaded dogs (R equals 0.867). In these two groups, GFR in the clamped kidney was reduced to values ranging respectively from 99 to 5% and from 96 to 3%. Distal tubular blockade with ethacrynic acid and chlorothiazide, performed in normal dogs and in sodium bicarbonate loaded dogs, did not abolish glomerulotubular balance for bicarbonate during CA inhibition. This study demonstrates that the glomerulotubular balance for bicarbonate is maintained during CA inhibition whether or not distal tubular blockade is superimposed. A proportionate decrease in both fractions of bicarbonate reabsorption, either CA dependent or not mediated by CA, or an adaptive increase in the fraction of bicarbonate reabsorption not mediated by CA can explain the maintenance of glomerulotubular balance for bicarbonate.

Acetazolamide↗
PubMed1975

Renal sodium reabsorption during saline loading and distal blockade in newborn dogs.

The ability of the proximal tubule to respond to saline expansion and varying filtered sodium loads was studied in 27 neonatal dogs aged 1-23 days. Sodium reabsorption beyond the proximal tubule was blocked with ethacrynic acid and chlorothiazide. When puppies received an intravenous load of 0.9% saline for 1.5 h, fractional sodium reabsorption averaged 0.985. After the addition of distal blockade to the saline infusion fractional Na reabsorption fell to 0.512. During distal blockade alone fractional Na reabsorption was 0.701, and after 1.5 h of saline expansion added to distal blockade fractional Na reabsorption fell to 0.493. Thus, there was a significant decrease in proximal tubular fractional Na reabsorption after saline expansion in neonatal dogs, and the high fractional Na reabsorption and low Na excretion during saline loading without distal blockade must be due to a large distal Na reabsorption. When filtered sodium load was varied by raising and lowering the glomerular filtration rate during distal blockade, there was excellent correlation between amount of filtered and reabsorbed sodium (r = 0.92). Thus, glomerulotubular balance exists in newborn dogs when there is no saline expansion.

Age Factors↗
PubMed1975

Effect of sodium nitrate loading on electrolyte transport by the renal tubule.

Effects of sodium nitrate were compared with sodium chloride loading on transport of electrolytes by the nephron. Maximal levels of free water clearance/clomerular filtration rate (CH2O/GFR) averaged 8.4% with nitrate loading and 14.4% with saline loading. Since ethacrynic acid and chlorothiazide exert their major natriuretic effect in the distal nephron, the increment in Na ad Cl reabsorbed beyond the proximal tubule. The administration of these agents resulted in an increase in fractional sodium excretion (CNa/GFR) of 21.1%, urinary sodium excretion (UNaV) of 1,126 mueq/min, and urinary chloride excretion (UClV) of 848 mueq/min during nitrate loading compared with an increase in CNa/GFR of 37.6%, UNaV of 2,362 mueq/min, and UClV of 2,397 mueq/min during saline loading. The smaller diuretic-induced increment in Na and Cl excretion in the nitrate studies suggests, as do the hydrated studies, that less Cl and Na are reabsorbed in the distal nephron during nitrate than saline loading. At every level of UNaV, fractional bicarbonate reabsorption was higher, urine pH was lower, and urinary potassium excretion (UKV) was higher in the nitrate studies. Thus, compared with saline loading, sodium nitrate decreases chloride and sodium reabsorption in the distal nephron. The higher hydrogen and potassium secretion in the nitrate studies may be consequent to the decreased ability of the distal nephron to reabsorb chloride.

Animals↗
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↗
PubMed2004

Effect of thiazide on renal gene expression of apical calcium channels and calbindins.

Thiazide diuretics are specific inhibitors of the Na-Cl cotransporter in the distal convoluted tubule (DCT). In addition to producing diuresis and natriuresis, they have a hypocalciuric effect. Recently, two apical calcium channels have been identified, transient receptor potential vanilloid 5 (TRPV5) and TRPV6; both are expressed in the DCT. We studied the effects of thiazides on mouse renal calcium handling and renal gene expression of TRPV5 and TRPV6, as well as calbindin-D(28k) and calbindin-D(9k), both of which are calcium transport facilitators located in the DCT. Upregulation of renal TRPV5 was found 4 h after intraperitoneal injection of chlorothiazide (CTZ) at both 25 and 50 mg/kg, but not at 100 mg/kg. Chronic treatment with CTZ at 25 mg/kg twice daily for 3 days, with or without salt supplementation of 0.8% NaCl and 0.1% KCl in the drinking water, caused hypocalciuria, but the gene expression patterns were different. Without salt supplementation, mice developed volume contraction and there were no changes in gene expression. When volume contraction was prevented by salt supplementation, there was a significant increase in gene expression of TRPV5, calbindin-D(28k), and calbindin-D(9k). Salt supplementation alone also induced significant upregulation of TRPV5, TRPV6, and both calbindins. The upregulation of TRPV5 by CTZ and salt supplementation and salt alone was further confirmed with immunofluorescent staining studies. Our studies suggest that thiazides induce hypocalciuria through different mechanisms depending on volume status. With volume contraction, increased calcium reabsorption in the proximal tubule plays the major role. Without volume contraction, hypocalciuria is probably achieved through increased calcium reabsorption in the DCT by the activation of a transcellular calcium transport system and upregulation of apical calcium channel TRPV5, calbindin-D(28k), and calbindin-D(9k).

Animals↗
PubMed1978

Calcium and sodium transport by the distal convoluted tubule of the rat.

Calcium and sodium transport were studied in the distal convoluted tubule of the rat by micropuncture and microperfusion techniques. The animals received either control infusions, 0.9% saline at 0.02 ml/min, or chlorothiazide (CTZ), 0.5 mg/min-kg. In free-flow micropuncture, distal calcium reabsorption occurred against an electrochemical gradient; it was 9% of the filtered load in the controls and 13.8% in the CTZ-treated rats. The drug dissociated calcium and sodium transport along the distal tubule. Absolute reabsorptive rates for calcium and sodium, measured in pump perfusion experiments, were proportional to the distal loads. CTZ, acting from the lumen, enhanced net calcium (P less than 0.01) and reduced net sodium (P less than 0.01) reabsorption. In stationary microperfusion experiments, sodium backflux produced rapid establishment of a steady-state concentration of 50 mM. In contrast, net backflux of calcium was negligible. With calcium in the luminal perfusion fluid, there was a concentration-dependent reabsorptive efflux which was not saturated at a luminal calcium concentration of 9.5 mM and which was enhanced by CTZ.

Animals↗
PubMed1979

Calcium transport in the nephron.

Ionized and complexed calcium are filtered at the glomerulus and more than 95% of the filtered load is reabsorbed along the length of the nephron. In the proximal convoluted tubule calcium is absorbed in proportion to sodium and water, suggesting a passive mechanism. The high permeability of this segment is compatible with passive transport, but evidence for active transport has been advanced. A role for Ca2+-ATPase and/or for a Ca2+/Na+ antiport has also been proposed. The straight portion of the proximal tubule appears to transport calcium actively but little is known about the mechanism and regulation of calcium absorption in this segment. Both passive and active transport of calcium in the thick ascending limb have been demonstrated, and heterogeneity in the function of medullary and cortical segments has been proposed. Definite evidence has been advanced for avid active calcium absorption in the distal convoluted tubule. Both chlorothiazide and parathyroid hormone enhance the transport of calcium in this segment. The granular portion of the collecting tubule resembles in its properties and function the distal convoluted tubule. The light portion, however, is incapable of transporting calcium. The distal tubule and collecting tubule may be the final regulators of urinary excretion of calcium but much more data are required before this view can be adopted.

Absorption↗
PubMed1987

Thiazide-sensitive sodium chloride cotransport in early distal tubule.

At least two pathways mediate sodium absorption across the luminal membrane of the renal distal tubule. One pathway is a conductive channel and the other appears to be a coupled Na-Cl cotransport pathway. The distal tubule comprises three segments: the distal convoluted tubule, the connecting tubule, and the initial collecting duct. To provide information about cellular locations of the proposed sodium transport pathways, we perfused early (14-38% of whole distal length) and late (61-83% of whole distal length) segments of whole distal tubules separately in vivo in anesthetized rats. When perfused with a solution that resembles fluid normally arriving at the distal tubule (75 mM Na, 68 mM Cl), rates of sodium absorption were similar in early and late segments (early 68 +/- 29.6, late 67 +/- 27.5 pmol X min-1 X mm-1). When perfused with a solution that resembles interstitial fluid (148 mM Na, 110 mM Cl), sodium transport was significantly higher in early than in late segments (276 +/- 28.4 vs. 113 +/- 29.7 pmol X min-1 X mm-1). Chlorothiazide (10(-3) M), which blocks sodium and chloride absorption in whole distal tubules, reduced sodium and chloride transport to zero in early distal tubules but had no significant effect in late distal tubules. Removing all chloride from perfusion solutions reduced sodium transport in early but not late distal segments.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Dietary protein restriction and renal injury in the spontaneously hypertensive rat.

We examined the influence of a low-protein diet on the course of the renal injury in spontaneously hypertensive rats (SHR) and SHR given antihypertensive drug therapy (SHRD). Antihypertensive drug treatment was hydralazine, reserpine, and chlorothiazide. Wistar-Kyoto (WKY) rats served as normotensive controls. SHR, SHRD, and WKY were each placed on a 24, 14, and 10% protein diet at 5 wk and followed to 80-90 wk of age. Untreated SHR showed a steady rise in protein excretion from 5 to 70 wk regardless of dietary protein content. Protein excretion in SHRD on a 24% protein diet was similar to untreated SHR. However, SHRD on a 14 or 10% diet had a more moderate increase in protein excretion. Glomerular, tubular, and vascular pathology in untreated SHR was not influenced by dietary protein intake. Despite successful antihypertensive therapy, kidney pathology in SHRD on a 24% diet was not significantly different from untreated SHR. In contrast, SHRD on 14 or 10% protein diets had less segmental glomerulosclerosis and vascular pathology than untreated SHR. The results indicate that dietary protein restriction does not influence the course of renal injury in untreated SHR. However, the combination of antihypertensive drug therapy with protein restriction in SHR delays and may arrest progression of glomerulosclerosis and proteinuria.

Animals↗
PubMed1996

Adrenal steroids stimulate thiazide-sensitive NaCl transport by rat renal distal tubules.

The current experiments were designed to test the hypothesis that adrenal steroids increase thiazide-sensitive Na and Cl transport by the mammalian renal distal convoluted tubule (DCT). Male Sprague-Dawley rats were adrenalectomized and received steroid hormones by osmotic pumps. Six groups of animals were studied as follows: group I, no hormones; group II, replacement levels of dexamethasone only; group III, replacement levels of aldosterone only; group IV, replacement levels of both hormones; group V; replacement levels of aldosterone and high levels of dexamethasone; and group VI, replacement levels of dexamethasone and high levels of aldosterone. Circulating levels of both hormones were found to be in the high physiological range when infused at the high rate. In vivo microperfusion of distal tubules was performed to determine rates of Na and Cl transport. Chlorothiazide was used to assess the magnitude of electroneutral Na-Cl cotransport. Both aldosterone and dexamethasone stimulated thiazide-sensitive Na and Cl transport by the distal tubule by more than fivefold. [3H]metolazone binding was measured to assess the number of thiazide-sensitive Na-Cl cotransporters in renal cortex. Each steroid also increased the number of [3H]metolazone binding sites in kidney cortex more than threefold. The results are consistent with the presence of both mineralocorticoid and glucocorticoid receptors in the mammalian DCT. Physiological changes in circulating levels of adrenal steroids may affect renal NaCl excretion in part by regulating the rate of electroneutral Na-Cl absorption by the DCT.

Adrenalectomy↗
PubMed1997

Acid-base changes alter Mg2+ uptake in mouse distal convoluted tubule cells.

Metabolic alkalosis leads to renal magnesium conservation, whereas metabolic acidosis is associated with urinary magnesium wasting. Micropuncture studies suggest that these actions affect magnesium transport in the distal tubule. The cellular mechanisms of acid-base changes were investigated in an immortalized mouse distal convoluted tubule (MDCT) cell line. Intracellular free Mg2+ concentration ([Mg2+]i) was determined by microfluorescence using the Mg(2+)-responsive dye, mag-fura 2. Mg2+ transport was assessed as a function of change in [Mg2+]i with time following placement of Mg(2+)-depleted cells into a buffer containing 1.5 mM magnesium. The uptake rate of Mg2+, d([Mg2+]i)/dt, into Mg(2+)-depleted cells determined with a buffer solution of pH 7.4 was 178 +/- 21 nM/s. Mg2+ uptake at pH 8.0 was markedly increased 278 +/- 35 nM/s, whereas transport at pH 6.0 was significantly reduced to 121 +/- 15 nM/s. Mg2+ uptake at pH 7.4 was not stimulated with 20 or 40 mM bicarbonate, nor were the differences in Mg2+ uptake with pH associated with changes in membrane voltage. Mg2+ uptake was stimulated with membrane hyperpolarization at pH 6.0 but not at pH 8.0. Chlorothiazide (10(-4) M), which stimulates Mg2+ uptake by hyperpolarizing the membrane voltage, increased uptake at pH 6.0, 59 +/- 14%, but decreased it at alkaline pH of 8.0, -55 +/- 3%. Accordingly, MDCT cells become refractory to the stimulating effects of hyperpolarization at alkaline pH values. These studies show that protons may directly affect Mg2+ transport in MDCT cells.

Acid-Base Equilibrium↗
PubMedDate not supplied

Blood pressure lowering diminishes age-related changes in the rat aortic intima.

These studies were undertaken to determine whether age-related changes in the aortic intima can be inhibited by prolonged blood pressure lowering. Normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were treated with a combination of chlorothiazide, reserpine, and hydralazine beginning at 20 weeks of age and continuing until 62 weeks. Aortic morphology was assessed at the termination of the study by light and electron microscopy. Average systolic blood pressures during the final 6 months of therapy were: for untreated WKY, 147 +/- 5 mm Hg (mean +/- SE); for treated WKY, 110 +/- 2; for untreated SHR, 206 +/- 3; and for treated SHR, 104 +/- 4. Intimal and medial abnormalities were maximal in untreated SHR, while untreated WKY showed moderate changes consistent with their age. In contrast, both treatment groups exhibited relatively minimal alterations despite their advanced age. The occurrence of intimal lesions in individual animals correlated with the average level of blood pressure during therapy. These data suggest that blood pressure reduction, even in normotensive animals, may reduce the effects of aging on the arterial wall.

Aging↗