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PubMed1995

Sodium entry mechanisms in distal convoluted tubule cells.

Sodium transport across apical membranes of distal convoluted tubules is thought to be mediated by Na-Cl cotransport and conductive Na entry. Immortalized mouse distal convoluted tubule cells were used to characterize Na entry pathways. Chlorothiazide, an inhibitor of Na-Cl cotransport, and amiloride, which blocks epithelial Na channels, reduced ouabain-suppressible oxygen consumption by 40 and 35%, respectively. In simple buffer solutions, free of bicarbonate, phosphate, or formate, chlorothiazide inhibited Na uptake by 44% and Cl uptake by 48%. Michaelis constants of 21 mM for Na and 14 mM for chloride were calculated. Amiloride inhibited Na uptake by 49% and had no effect on Cl uptake. The calculated Hill coefficient of 1.07 and the equivalence of chlorothiazide-sensitive Na and Cl uptake are consistent with the presence of Na-Cl cotransport. Na-Cl cotransport and amiloride-sensitive Na influx account for 85% of Na entry in distal convoluted tubule cells in the absence of phosphate and formate. The selective Na/H exchange inhibitor ethylisopropyl amiloride had no effect on Na uptake; however, it abolished formate-stimulated Na uptake. The anion exchange blocker 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) inhibited Na uptake. These findings are consistent with parallel Na/H and Cl/formate exchange. Na uptake was inhibited 8% by the selective Na/Ca exchange inhibitor, dimethylbenzamil. An additional 7% of Na entry was phosphate dependent and was abolished by phosphonoformic acid, a competitive inhibitor of Na-Pi cotransport. In summary, the majority of Na entry into distal convoluted tubule cells occurs through Na-Cl cotransport and an amiloride-sensitive pathway (75% in presence of phosphate and formate). An additional 13% may enter by Na/H exchange, with the remainder mediated by Na/Ca exchange and Na-Pi cotransport.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗

PubMed1970

Effects of increased sodium delivery on distal tubular sodium reabsorption with and without volume expansion in man.

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.

Acetazolamide↗

PubMed1982

Tubular mechanism for the spontaneous hypercalciuria in laboratory rat.

Recently it has been observed that Ca excretion in laboratory rats does not follow a Gaussian distribution, with approximately 10% of them excreting Ca at a rate of 2 SD above the group mean. This phenomenon has been described as spontaneous hypercalciuria (SH). Our studies were designed to define its mechanism. 48 Wistar rats were subjected to metabolic studies to identify SH, prospectively defined as Ca excretion 2 SD above the group mean during 7 d of dietary Ca deprivation (</=0.03% by analysis), in the absence of hypercalcemia, PO(4) depletion, or exaggerated natriuresis. Progenies from SH rats were found to have significantly higher urine Ca/creatinine (micrograms per milligram) (male = 38 vs. 23, P < 0.05; female = 79 vs. 60, P < 0.005) with 7/20 males and 9/26 females having values 2 SD above the means of normal. After a 12-h fast and during 10% volume expansion with saline, clearance and micropuncture studies were performed on three groups of acutely parathyroidectomized female rats; (a) normocalciuric (N) progenies from the normal, (b) normocalciuric (NC) progenies from SH, and (c) hypercalciuric (HC) progenies from SH rats. Among these groups, there was no significant difference in body weights, glomerular filtration rate, plasma ultrafiltrable Ca (4.5, 4.6 vs. 4.7 mg/100 g), PO(4), and the fractional excretion (FE) of Na or FE(PO4). FE Ca was significantly higher in HC rats (13.9%) than N (10.1%) and NC (10.7%). Segmental reabsorption of fluid and Na was comparable among the three groups. Fractional delivery (FD) of Ca was, however, significantly increased in the late proximal tubule of HC rats (62 vs. 49 and 46%, P < 0.05). The increased FDCa was no longer apparent in early or late distal tubule (6.9 vs. 6.9 and 7.6%, P = NS). Although FECa exceeded late distal FDCa in all three groups, the increment was significantly greater in HC rats (7.02%) than both N (3.4, P < 0.05) and NC rats (3.05, P < 0.02). The effects of chlorothiazide (27.5 mg/kg/d, i.p. x 7 d) were evaluated in the female offsprings of the SH rats. Before chlorothiazide, average urine Ca/creatinine (253 vs. 77.2) and cyclic AMP (26.6 vs. 13.4 mumol/mg creatinine, P < 0.001) on days 7 and 8 of the Ca-deprived diet were higher than the normal. On days 6 and 7 of chlorothiazide, average cyclic AMP (cAMP) excretion fell to normal range (11.7 vs. 12.7 mumol/mg creatinine) as Ca excretion was reduced to normal (62 vs. 59.4 mug Ca/mg creatinine). WE CONCLUDE: (a) SH, as defined in this study, is an inheritable biochemical marker and renal in origin. (b) The hypercalciuria is independent of parathyroid hormone, changes in plasma Ca and tubular handling of Na. (c) As studied in the PTX and volume expanded conditions of our experiments, decreased Ca reabsorption in superficial proximal convoluted tubule is demonstrable, but the hypercalciuria is probably mediated by diminished Ca transport by the deep nephron. The unlikely possibility of increased secretion by the terminal nephron, however, remains to be excluded. (d) In normal rats, there is internephron heterogeneity in regard to Ca transport during saline loading.

Animals↗

PubMed1975

Antihypertensive activity of a new agent, indapamide: a double-blind study.

In a double-blind trail in 22 patients with mild to moderate essential hypertension, indapamide was compared with chlorathiazide and placebo. Dosage levels were set at 5 mg. indapamide and 500 mg. chlorothiazide daily, for 5 days out of 7, and patients were treated alternately, in random sequence, with each drug for a month over a 3-month period. Blood pressure readings and blood chemistry investigations were carried out before and after each treatment period and a careful history was kept of subjective symptoms and patients' tolerance of therapy. The results show that both active treatments produced drops in systolic and diastolic pressures, but were only statisically significant and different from placebo in the case of indapamide. Indapamide also produce much greater subjective improvement (74%) in patients with functional symptoms compared with chlorothiazide (15%). In an overall assessment, indapamide produced an excellent to good response to treatment in 57% of patients. Comparable responses for chlorotiazide and placebo were 25% and 20% respectivlely. Using patients as their own controls to compare the relative effectiveness of the three periods of treatment, indapamide was shown to be more effective than placebo in 65% of cases and more effective han chlorothiazide in 60%. Although patient tolerance of indapamide was slightly better, both drugs were well accepted and no significant changes from baseline levels were noted in any of the laboratory parameters investigated.

Adult↗

PubMed1998

Peripheral blood mononuclear cells express mutated NCCT mRNA in Gitelman's syndrome: evidence for abnormal thiazide-sensitive NaCl cotransport.

Genetic analysis has demonstrated complete linkage between the human thiazide-sensitive sodium chloride cotransporter gene (NCCT or TSC) and Gitelman's syndrome (GS). Several genomic NCCT mutations have been reported. This study was performed to determine whether peripheral blood mononuclear cells (PBMC) express NCCT mRNA and whether defective PBMC NaCl cotransport could be demonstrated in GS. PBMC were isolated from two brothers with GS, their parents, and healthy control subjects. Northern analysis revealed that NCCT mRNA is expressed in PBMC. The sequence of full-length NCCT cDNA amplified from normal PBMC was identical to human renal NCCT cDNA. Two different mutations were detected in the patients' NCCT cDNA (compound heterozygote). In cDNA derived from the patient's maternal allele, exon 24 was deleted, resulting in a premature stop codon (after amino acid 920). cDNA derived from the patient's paternal allele had an additional 119-bp insertion between exons 3 and 4, generating a premature stop codon (after amino acid 187). The patient's genomic DNA had a previously described 5' splice site mutation in intron 24, GGT --> GTT (maternal allele), and a new 3' splice site mutation in intron 3, CAG --> CAA (paternal allele), which resulted in the activation of a nearby cryptic splice site in intron 3. The latter mutation was not present in 300 normal chromosomes. To determine the functional significance of these findings, chlorothiazide-inhibitable 22Na uptake was measured in PBMC from control subjects, the parents, and the patients with GS in the presence of bumetanide. In control PBMC, chlorothiazide inhibited 22Na uptake by approximately 9%. PBMC from the two patients with GS failed to respond to chlorothiazide. These results demonstrate that PBMC can be used for mutational analysis of NCCT mRNA in patients with GS. Furthermore, functional evidence is provided that the underlying cause of GS is defective NCCT NaCl cotransport.

Adult↗

PubMed1982

Long-acting and short-acting diuretics in mild essential hypertension.

A randomised, placebo-controlled, double-blind crossover study was conducted in 14 patients with mild essential hypertension comparing different regimens of administration of the "short-acting" diuretic, chlorothiazide and the "long-acting" diuretic, chlorthalidone. There were 6 randomised treatment phases each of 5 weeks duration. For blood pressure recorded both at the Clinic and at home the most prominent effects were seen with standing blood pressure, for which significant reductions of mean blood pressure compared to the placebo phase were observed with chlorthalidone 25 mg once daily (-5 +/- 1 (SE) mm Hg - p less than 0.05), chlorthalidone 50 mg once daily (-7 +/- 1 mm Hg - p less than 0.01) and chlorothiazide 500 mg twice daily (-4 +/- 1 mm Hg - p less than 0.05). Blood pressure reductions with chlorothiazide 500 mg once daily and 1000 mg once daily were not significant. About half of the patients completing the trial could be described as "non-responders". The observed biochemical changes (reduced plasma potassium and chloride concentrations and increased plasma bicarbonate and urate concentrations) were most marked in the phases with the most prominent blood pressure effects. The result support the suggestion that a sustained diuretic effect is desirable when diuretics are used in the treatment of hypertension. This can be obtained by selection of the appropriate dosage regimen for a particular diuretic, such as once daily administration for "long-acting" and twice daily for "short-acting" thiazide-type diuretics.

Adult↗

PubMed2000

Localization of diuretic effects along the loop of Henle: an in vivo microperfusion study in rats.

In order to clarify the effects on sodium reabsorption in the loop of Henle of methazolamide (a carbonic anhydrase inhibitor), chlorothiazide and the loop diuretics frusemide and bumetanide, superficial loops were perfused in vivo in anaesthetized rats and the individual diuretics were included in the perfusate. Differentiation between effects in the pars recta and in the thick ascending limb of Henle (TALH) was achieved by comparing responses to the diuretics when using a standard perfusate, designed to mimic native late proximal tubular fluid, and a low-sodium perfusate, designed to block net sodium reabsorption in the pars recta. With the standard perfusate, methazolamide caused decreases in sodium reabsorption (J(Na)) and water reabsorption (J(V)); with the low-sodium perfusate, a modest effect on J(Na) persisted, suggesting that carbonic anhydrase inhibition reduces sodium reabsorption in both the pars recta and the TALH. The effects of chlorothiazide were very similar to those of methazolamide with both the standard and low-sodium perfusates, suggesting that chlorothiazide also inhibits sodium reabsorption in the pars recta and TALH, perhaps through inhibition of carbonic anhydrase. With the standard perfusate, both frusemide and bumetanide produced the expected large decreases in J(Na), but J(V) was also lowered. With the low-sodium perfusate, the inhibitory effects of the loop diuretics, particularly those of frusemide, were substantially reduced, while net potassium secretion was found. These observations indicate that a significant component of the effect of frusemide (and possibly of bumetanide) on overall sodium reabsorption is located in the pars recta, and that loop diuretics induce potassium secretion in the TALH.

Absorption↗

PubMed1994

The effects of diuretics on posttraumatic joint stiffness and limb swelling in a rabbit periarticular fracture model.

Periarticular long bone fractures usually result in soft-tissue swelling because of edema and hemorrhage, as well as progressive, often permanent joint stiffness. The authors evaluated the effects of chlorothiazide, a commonly used diuretic, and acetazolamide, a weaker diuretic with a different mechanism of action, on joint stiffness and swelling using an established rabbit hindlimb model. Bilateral distal tibial fractures were produced in 30 adolescent New Zealand white rabbits. Twelve rabbits served as age-matched controls and received no treatment, 11 were treated with chlorothiazide, and seven were treated with acetazolamide, each for five days at doses adjusted for body weight but equivalent to human dosing. Eleven limbs were excluded from study because of fracture angulation in excess of 10 degrees. The mean stiffness ratios, comparing preoperative stiffness with stiffness at the end of the three-week study period, for diuretic-treated rabbits were significantly less than those in the control rabbits; there was no difference between the two treated groups. The total swelling and time to peak swelling did not differ among the three groups; however, peak swelling was least in the chlorothiazide group, the strong diuretic, when compared with the control and acetazolamide groups. The marked effect of diuretics on joint stiffness and their minimal effect on limb swelling were unexpected results and, taken in conjunction with previous treatment modalities tested in this model, indicate a complex, still poorly understood sequence of events leading to joint stiffness after periarticular injury.

Acetazolamide↗

PubMed1996

Selective effect of thiazides on the human osteoblast-like cell line MG-63.

Thiazide diuretics have been shown to decrease bone-loss rate and to improve bone mineral density in patients using this medication. However, the exact role of thiazides on bone cells is still debated. In the present work, we studied whether thiazides could affect the normal features of osteoblasts using the human model cell line MG-63. Hydrochlorothiazide (HCTZ) did not affect cell growth nor DNA synthesis in these cells, yet slightly increased alkaline phosphatase activity in these cells at pharmacologically relevant concentrations. Under similar conditions, HCTZ dose-dependently inhibited 1,25(OH)2D3-induced osteocalcin secretion by these cells (maximal effect, -40 to 50%, P < 0.005). However, HCTZ did not inhibit the basal production of osteocalcin in MG-63 cells (without 1,25(OH)2D3 induction), which was very low to undectable. Two different thiazide derivatives, chlorothiazide and cyclothiazide, and two structurally related sulfonamides with selective inhibition of carbonic anhydrase (Acetazolamide) or hyperglycemic effects (Diazoxide) were also tested. Chlorothiazide (1000 microM) inhibited osteocalcin secretion (-42 +/- 12.7%) at doses 10-fold higher than HCTZ (100 microM) while cyclothiazide was effective at doses of 1 microM (-27 +/- 3.6%), and hence 100-fold lower than HCTZ, compatible with the relative natriuretic effect in vivo of these compounds. Acetazolamide (10 microM) poorly affected osteocalcin secretion at doses 100-fold higher than those needed in vivo to inhibit carbonic anhydrase. Likewise, Diazoxide (100 microM) poorly affected osteocalcin secretion at doses known to promote its biological effect. Higher doses of acetazolamide and diazoxide induced cell death. Neither Acetazolamide nor Diazoxide affected alkaline phosphatase, whereas chlorothiazide had a weak positive effect on this enzymatic activity. The production of macrophage colony-stimulating factor (M-CSF) was stimulated in the presence of 1,25(OH)2D3 (50 nM), TNF-alpha (2 ng/ml) or both in MG-63 cells. HCTZ (25 microM, 24 hr of preincubation) did not modify basal M-CSF production and did not reduce the response to 1,25(OH)2D3 alone. In contrast, HCTZ inhibited the response to TNF-alpha alone (P < 0.05), and also reduced the response to a combination of 1,25(OH)2D3 and TNF-alpha (P < 0.01). In conclusion, these results indicate that thiazide diuretics show a selective inhibition of osteocalcin secretion and M-CSF production by MG-63 cells unlike structurally related drugs. Therefore, these features may explain, in part, the positive effect of thiazides on bone mineral density.

Alkaline Phosphatase↗

PubMed1981

Renal tubular handling of zinc in the dog.

Clearance and stop-flow techniques, performed on anesthetized dogs, were used to obtain evidence for renal tubular reabsorption or secretion of 65Zn (administered intravenously with varying amounts of carrier ZnCl2). Ultrafilterability of plasma 65Zn was determined in vitro with Amicon CF-50A filter cones. Clearances were obtained under six conditions: antidiuresis, mannitol diuresis alone and following the infusion of chlorothiazide, citrate, cysteine, histidine. The percentage of ultrafilterability averaged, respectively, 1.15, 1.38, 0.91, 1.53, 19.90, and 11.61, while fractional zinc excretion averaged 0.046, 0.10, 0.31, 0.43, 0.78, and 0.12, respectively. Control stop-flow patterns invariably showed net Zn reabsorption in the distal nephron. Stop-flow patterns after chlorothiazide revealed significant net secretion in the far distal area in all animals. Patterns after either citrate or histidine infusion revealed significant net reabsorption in the proximal nephron. Those after cysteine were similar to the control patterns. Thus, both clearance and stop-flow experiments revealed net reabsorption as the major tubular mechanism of zinc handling, tubular secretion occurring only during chlorothiazide administration.

Animals↗

PubMed2005

Efforts to control the errant products of a targeted in vivo generator.

Alpha-particle immunotherapy by targeted alpha-emitters or alpha-emitting isotope generators is a novel form of extraordinarily potent cancer therapy. A major impediment to the clinical use of targeted actinium-225 (225Ac) in vivo generators may be the radiotoxicity of the systemically released daughter radionuclides. The daughters, especially bismuth-213 (213Bi), tend to accumulate in the kidneys. We tested the efficacy of various pharmacologic agents and the effect of tumor burden in altering the pharmacokinetics of the 225Ac daughters to modify their renal uptake. Pharmacologic treatments in animals were started before i.v. administration of the HuM195-225Ac generator. 225Ac, francium-221 (221Fr), and 213Bi biodistributions were calculated in each animal at different time points after 225Ac generator injection. Oral metal chelation with 2,3-dimercapto-1-propanesulfonic acid (DMPS) or meso-2,3-dimercaptosuccinic acid (DMSA) caused a significant reduction (P < 0.0001) in the renal 213Bi uptake; however, DMPS was more effective than DMSA (P < 0.001). The results with DMPS were also confirmed in a monkey model. The renal 213Bi and 221Fr activities were significantly reduced by furosemide and chlorothiazide treatment (P < 0.0001). The effect on renal 213Bi activity was further enhanced by the combination of DMPS with either chlorothiazide or furosemide (P < 0.0001). Competitive antagonism by bismuth subnitrate moderately reduced the renal uptake of 213Bi. The presence of a higher target-tumor burden significantly prevented the renal 213Bi accumulation (P = 0.003), which was further reduced by DMPS treatment (P < 0.0001). Metal chelation, diuresis with furosemide or chlorothiazide, and competitive metal blockade may be used as adjuvant therapies to modify the renal accumulation of 225Ac daughters.

Actinium↗

PubMed1988

Influence of chronic diuretic therapy on serum, lymphocyte and erythrocyte potassium, magnesium and calcium concentrations.

Serum, lymphocyte and erythrocyte potassium, magnesium and calcium concentrations were measured in 31 patients with congestive cardiac failure and 14 patients with mild noncomplicated hypertension, who had been receiving either furosemide or chlorothiazide (with or without potassium supplementation) or a combination of hydrochlorothiazide and amiloride for more than 6 months. Lymphocyte potassium concentrations (pmol/100 cells +/- SE) were as follows: controls 18.1 +/- 1.5, furosemide 14.1 +/- 0.9 (p less than 0.001), furosemide + potassium 12.3 +/- 0.7 (p less than 0.001), chlorothiazide 13.1 +/- 1.0 (p less than 0.001) and hydrochlorothiazide + amiloride 18.6 +/- 0.7 (p = NS). There was a statistically significant relationship between the number of months the patients had been on diuretics and their lymphocyte potassium concentrations. Serum electrolytes, apart from the group receiving chlorothiazide who showed a significant fall in serum K, were unchanged.

Adult↗

PubMed1975

Effect of diuretics on oxidative phosphorylation of dog kidney mitochondria.

An effect of diuretics on cellular metabolism has been shown. In order to examine further the direct effect of diuretics on renal mitochondria, their effect on isolated cortical (C) and outer medullary (OM) mitochondrial respiration was examined. Oxygen consumption rate (QO2) was measured in a Gilson oxygraph utilizing either glutamate-malate or succinate as substrate. QO2, expressed in nanoatoms of O2 per milligram of protein per minute, was always higher in C than OM: 140.7 +/- 2.8 VS. 121.2 +/- 2.4 (P less than 0.001) with glutamate-malate and 181.1 +/- 6.3 vs. 129.7 +/- 5.2 (P less than 0.001) with succinate. A dose-response curve was constructed for each of the following: sodium ethacrynate, furosemide, chlorothiazide, acetazolamide and chlormerodrin. All diuretics inhibited C and OM equally. The 50% inhibitory molar concentration for EA was 6.2 times 10(-4); for furosemide 1.5 times 10(-3); for chlorothiazide 8.1 times 10(-3); for acetazolamide 10.8 times 10(-3); and for chlomerodrin 3.1 times 10(-5). Neither cysteine nor dithiothreitol inhibited the effect of EA. The effect of chlormerodrin was abolished by cysteine. These results demonstrate that while a difference exists between C and OM mitochondria during control studies, each of the diuretics examined exerted an equal inhibitory effect on mitochondrial respiration from both C and OM. Mercurials are the most potent inhibitors and presumably exert their effect by reacting with sulfhydryl groups. They are followed in potency by ethacrynic acid, furosemide, chlorothiazide and acetazolamide.

Animals↗

PubMed1985

Diuretic effects on renal brush border membrane transport and metabolism.

Previous studies have indicated that the thiazide diuretics exert effects on proximal electrolyte transport. To determine whether the locus of these effects is at the brush border membrane (BBM) and if renal metabolism is affected, adult female Sprague-Dawley rats were acutely treated with either 1 mg/kg metolazone, 20 mg/kg chlorothiazide followed by a 20 mg/kg/hr maintenance infusion, 10 mg/kg acetazolamide followed by a 10 mg/kg/hr maintenance infusion, or the vehicles only. Administration of these agents resulted in an approximately tenfold increase in sodium excretion. Neither urinary phosphate nor inulin excretion changed significantly in any group. Sodium dependent BBM vesicle phosphate transport was examined at 0.15, 0.5, and 1 and 120 minute incubation periods in the diuretic treated groups and their respective control groups. Decreased uptake was seen in all pre-equilibrium time points in rats treated with metolazone: 0.15 minutes: 221 +/- 24 pmoles/mg protein (pmol/mg prot) in control rats versus (vs) 185 +/- 23 pmoles/mg prot in metolazone-treated animals (P less than .05) ; 0.5 minutes: 463 +/- 54 vs 369 +/- 49 pmol/mg prot (P less than .005); 1 minute: 549 +/- 74 vs 460 +/- 61 pmol/mg prot (P less than .05); no significant difference in phosphate transport was noted at the two hour equilibrium time point. No significant differences in sodium dependent phosphate transport existed between chlorothiazide or acetazolamide treated rats and control animals. Substrate-stimulated renal gluconeogenesis did not differ between metolazone treated and control animals. We therefore conclude that metolazone inhibits phosphate transport through an effect on the BBM and does not affect renal gluconeogenesis in the rat.

Acetazolamide↗

PubMed1978

Lymphatic network of kidney. II. Effect of diuretics on intrarenal renin release.

The individual effects of chlorothiazide, furosemide, and mannitol on renin activity in renal lymph have been studied in dogs. Elevation of renin activity in lymph is noted following infusion with either chlorothiazide or furosemide, while a reduction of renin activity in renal lymph is noted after mannitol infusion. The importance of elevated sodium levels in the proximal end of the distal tubule and its effects on renin release in kidney interstitium is stressed. More work is advocated to elucidate fully the role of renin when released intrarenally.

Angiotensin I↗

PubMed1981

High urine flow rate increase prostaglandin E excretion in the conscious dog.

Although previous studies from this and other laboratories have shown that urinary prostaglandin E excretion (UPGEV) can very independent of urine flow rate, recent studies during water diuresis in the conscious dog have suggested that high urine flow rate per se may increase UPGEV. To examine the effect of urine flow rate on UPGEV we administered either mannitol, chlorothiazide or Ringer's solution to mongrel dogs and measured UPGEV. During anesthesia neither mannitol or chlorothiazide increased UPGEV. There was, however, a consistent increase with all three agents in awake animals. This increase in UPGEV was independent of alterations in glomerular filtration rate. There was a consistent increase in urinary sodium excretion and decrease in urinary osmolality with all three agents. The changes in PGE, however, were similar to those found during water diuresis when no increase in sodium excretion was found. It is not presently clear whether these findings reflect a true increase in renal PGE synthesis due to some changes in flow or pressure within the renal medulla or rather represent unchanged PGE synthesis by renal tubular cells, the high tubule fluid flow rate causing increased entry into the tubular lumen in contrast to the renal interstitium.

Anesthesia↗

PubMed1995

Prolonged therapy by the combination of furosemide and thiazides in refractory heart failure and other fluid retaining conditions.

The efficacy and side effects of the combination therapy of thiazide and furosemide administered to patients with refractory heart failure, for a prolonged period of time, were assessed. Thirty-two patients were hospitalized during the years 1985-1991. Left heart failure (left ventricular ejection fraction (LVEF = 22.4% +/- 6.6%) was present in 26 patients, right heart failure in 3 patients, chronic renal failure, cirrhosis and bilateral pleural effusion were present each in one patient. Chlorothiazide 0.5 g daily was added to conventional therapy. Patients were monitored closely during hospitalization and later as outpatients. During hospitalization, addition of chlorothiazide caused a reduction of 4.8 +/- 4.0 kg in patients' weight, serum potassium decreased from 4.4 +/- 0.6 to 4.0 +/- 0.5 mmol/l (P < 0.005) and serum sodium from 139.0 +/- 4.7 to 136.8 +/- 5.5 mmol/l (P < 0.05). The duration of the combined therapy was 17.2 +/- 19.1 months. Thirteen patients had short treatment (1.6 +/- 0.8 months) and 19 patients had prolonged treatment (26.5 +/- 19.0 months). No specific characteristics distinguished patients in both groups. Thiazides were discontinued in 19 patients, 10 of which had side effects. In only 5 of the 19 patients treated for the prolonged period had thiazides to be discontinued because of side effects. Addition of thiazides to furosemide is efficacious in severe heart failure. The combination should be started during hospitalization. Many patients can be maintained on this combination for a prolonged period of time on an ambulatory basis.

Aged↗

PubMed1994

First-derivative UV spectrophotometric and high-performance liquid chromatographic analysis of some thiazide diuretics in the presence of their photodecomposition products.

Ethanolic solutions of three thiazide diuretics, chlorothiazide, hydrochlorothiazide and trichlormethiazide, were irradiated with a high-pressure mercury lamp. The products were isolated and their first-derivative UV spectra in ethanol were recorded and compared to those of the parent compounds. The determination of the parent compounds in the presence of the decomposition products was carried out at wavelengths near 220 nm using the zero-crossing technique. Three reversed-phase HPLC methods were also developed for the analysis of the parent compounds. In parallel analyses of the reaction mixtures a good correlation was achieved between these two methods in the determination of hydrochlorothiazide and trichlormethiazide while there was greater variation in the results of chlorothiazide.

Chlorothiazide↗