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PubMed1978

Identification of systemic phototoxic drugs by human intradermal assay.

An improved method is presented for the detection of systemically administered photosensitizing drugs in humans. Test agents were injected intradermally in physiologic saline and then exposed to broad spectrum radiation from a Xenon solar simulator. Several clinically recognized photosensitizers were identified by this technique. The activating spectrum depended on the test drug. Sulfonamides and vinblastin were activated by sunburning erythemic radiation (UV-B), while tetracyclines, nalidixic acid and phenothiazines by near UV (UV-A), and chlorothiazide by both. It is suggested that intradermal phototesting offers a means of verifying the phototoxic potential of agents suspected clinically of provoking a photosensitivity eruption.

Adult↗
PubMed1974

Effect of bovine parathyroid hormone 1-34 fragment on renal production and excretion of adenosine 3', 5' monophosphate in man.

Biologically active bovine parathyroid hormone (b PTH) 1-34 fragment infused over one hour in normal subjects produced an immediate and sharp increase in the excreted fractions of filtered bicarbonate, sodium and potassium, followed by the return to pre-infusion levels as soon as the administration of b PTH was stopped. There was a gradual but steady increase in the excreted fraction of filtered phosphate but a decrease in the excreted fraction of filtered calcium and magnesium. The excreted fractions of these ions were still abnormal 150 minutes after the completion of PTH infusion. The urinary excretion of 3'5'-cyclic AMP increased immediately about one hundred-fold but returned rapidly to pre-infusion levels. Urinary clearance of cyclic AMP approximated glomerular filtration rate in control periods and was twenty to thirty times greater during b PTH infusion. In subjects overloaded with bicarbonate, b PTH brought about a decrease in bicarbonate T(m) and the same effects on the urinary excretion of other electrolytes. 3'5'-cyclic AMP excretion was clearly higher in control periods and reached higher levels during b PTH infusion when compared to subjects without an alkaline load. 3'5'-cyclic AMP excretion and fractional clearance were also clearly higher in subjects not given b PTH when control periods were compared to periods with bicarbonate infusion or after acetazolamide administration. During distal blockade obtained by simultaneous administration of chlorothiazide and ethacrynic acid, there was a delay in the rise of 3'5'-cyclic AMP excretion after b PTH administration. It can be concluded from these studies that the pattern of excretion of 3'5'-cyclic AMP is similar to that of bicarbonate, sodium and potassium. The increase of 3'5'-cyclic AMP excretion when urinary pH is above 7 suggests a diffusion trapping mechanism for the secretion into the lumen of this nucleotide. Distal diuretics used in distal blockade did not inhibit 3'5'-cyclic AMP production but delayed its secretion into urine.

Adenosine Monophosphate↗
PubMed1976

Drug induced interstitial nephritis, hepatitis and exfoliative dermatitis.

Acute interstitial nephritis associated with hepatitis, exfoliative dermatitis, fever and eosinophilia is uncommon. The syndrome has been described previously in association with phenindione administration, leptospirosis and heavy metal poisoning. Four cases are described, two of which were due to phenindione sensitivity. The other two patients had been exposed to a number of toxins including allopurinol, frusemide, chlorothiazide and methyldopa so that the exact aetiological agent is unclear. Interstitial nephritis should be considered as a cause of acute renal failure in patients with other features of drug hypersensitivity.

Acute Disease↗
PubMed1981

Beta adrenoreceptor-blocking drugs once daily in essential hypertension: a comparison of propranolol, pindolol and atenolol.

Atenolol, Pindolol and Propranolol in single daily doses administered to 18 selected patients with mild essential hypertension achieved adequate control of blood pressure. Chlorothiazide had been initially administered twice a day without full control of blood pressure and this diuretic therapy was continued unaltered throughout the study. Methacholine challenge testing of respiratory function was performed during the placebo phase and with each beta adrenoreceptor-blocking drug. In the 18 non-asthmatic patients, the reduction in FEV1, was significant only for propranolol therapy when compared to placebo. Each beta adrenoreceptor-blocking drug was associated with small, but significant, increases in fasting plasma triglyceride concentrations and suppression of fasting immuno-reactive glucagon concentrations.

Administration, Oral↗
PubMed1996

Inhibition of thiazide photohemolysis in vitro by antioxidants and a nitrogen atmosphere.

The diuretics acetazolamide, bemetizide, bendroflumethiazide, benzthiazide, benzylhydrochlorothiazide, bumetanide, butizide, chlorazanile, chlorothiazide, chlortalidone, clopamide, cyclopenthiazide, cyclothiazide, diazoxide, etozoline, furosemide, hydrochlorothiazide, hydroflumethiazide, indapamide, mefruside, metolazone, piretanide, polythiazide, trichlormethiazide, and xipamide were screened in vitro for phototoxic effects by means of a photohemolysis test. In all, 19 out of the 25 test substances revealed phototoxic hemolytic properties after irradiation with either solar stimulating irradiation, UVA and/or visible light. Addition of the antioxidants ascorbic acid, alpha-tocopherole or superoxide dismutase significantly inhibited the phototoxic hemolysis, as well as did investigations carried out in a nitrogen rich atmosphere, findings which indicate the involvement of reactive oxygen species in the phototoxic process.

Antioxidants↗
PubMed1980

Human renal cytoplasmic carbonic anhydrase. Tissue levels and kinetic properties under near physiological conditions.

The cytoplasmic form of human renal carbonic anhydrase, CA-C (carbonate dehydratase, EC 4.2.1.1), purified by affinity chromatography, was characterized kinetically at 37 degrees C in 25 mM N-methyl imidazole buffer, I = 0.15, pH 7.1. using a pH-indicator stopped-flow technique. Under these conditions the rate constants for the uncatalyzed hydration of CO2 and dehydration of H2CO3 were 0.12 . s-1 and 0.60 . s-1, respectively. The kinetic parameters for CA-C were found to be: Hydration reaction, Km = 11.8 mM, V/[E]0 = 10.6 x 10(5) . s-1, dehydration reaction Km = 70 mM, V/[E]0 = 5 x 10(5) . s-1. In the hydration reaction CA-C was non-competitively inhibited by acetazolamide, Ki = 16 nM, sulfanilamide, Ki = 8 micrometer, and chlorothiazide, Ki = 1 micrometer. The levels of immunoassayable CA-C in cortex, medulla and papilla of perfused donor kidneys were 1.3, 1.0 and 0.6 mg enzyme protein/g tissue protein respectively which corresponded well with the levels measured catalytically. The erythrocyte form, HCA-B, was also detected immunochemically (approximately 0.1 mg/g protein) but is thought to be a contaminant. Calculations indicated that the uncatalyzed hydration of CO2 in the tubular cells can support 17 or 0.7% of the rate of urine acidification, dependent on whether the cellular alkaline pH-disequilibrium during acid secretion is 0.1 or 0.01 pH units, respectively. CA-C accelerates the hydration rate 6800-fold which enables the cell to sustain high rates of proton generation, while maintaining near CO2-equilibrium and maximal buffering capacity. Even at an assumed pH-disequilibrium of only 0.01 pH-unit, CA-C is present in 50-fold excess of apparent physiological needs. When the enzyme is inhibited the rate of the uncatalyzed reaction increases, which partly overcomes the effect of inhibition.

Carbonic Anhydrases↗
PubMed1985

Similarities in the release rates of different drugs from polyethylene glycol 6000 solid dispersions.

The dissolution rates (mg min-1) of 10 drugs, solid dispersed by fusion in polyethylene glycol 6000 (PEG 6000) have been examined by rotating disc methodology. The dispersions generally displayed release rates which were linearly dependent upon the drug concentration (% drug) at high polymer content. However the range over which this linearity was encountered varied unduly, e.g. 0-2% for phenylbutazone and 0-15% for paracetamol. The slope of this line (mean value: 0.451 mg min-1 % -1) was statistically the same for nine of the drugs studied, the exception being griseofulvin which did not form a true solid dispersion but was a microcrystalline dispersion of the drug within the PEG. During fusion, chain scission of the PEG 6000 occurred in the presence of several drugs. PEG 6000 was incompatible with disulfiram, frusemide, chlorothiazide and chlorpropamide.

Chemistry, Pharmaceutical↗
PubMed1984

Relationship between peritubular membrane potential and net fluid reabsorption in the distal renal tubule of Amphiuma.

Amphiuma kidneys were isolated and perfused with modified Ringer solution and peritubular and transepithelial membrane potentials (p.d.s) in distal tubules measured with micro-electrodes during rapid changes of luminal electrolyte concentrations. Peritubular membrane potential and net fluid reabsorption (split-oil-droplet method) were also measured with and without application of various drugs known to alter transport. Raising the luminal sodium concentration from 10 to 100 mM reversibly increased the peritubular p.d. The magnitude of the peritubular p.d. was a saturable function of luminal sodium concentration. In the presence of chloride in the lumen the peritubular hyperpolarization following increased luminal sodium could be inhibited by luminal amiloride (10(-4)M). Sodium-induced hyperpolarization of the peritubular p.d. could be completely inhibited by 10(-5)M-ouabain. Adding amiloride (10(-4)M) to the luminal fluid rapidly and reversibly depolarized the peritubular p.d. and inhibited fluid reabsorption. Addition of amphotericin B (20 micrograms/ml) to the luminal perfusion solution had no effect on peritubular p.d. at 100 mM-luminal NaCl but at 10 mM-NaCl, peritubular p.d. hyperpolarized. Fluid reabsorption was stimulated (with 100 mM-NaCl in the lumen). Addition of amphotericin when the tubule was perfused on both sides with solutions containing a constant potassium concentration of 78 mM and a variable sodium concentration ranging from 7.8 to 34.5 mM revealed strong dependence of the peritubular hyperpolarization on the sodium concentration. Luminal furosemide (10(-4)M) and chlorothiazide (10(-4)M) and peritubular ethacrynic acid (10(-4)M) all reduced fluid reabsorption but hyperpolarized the peritubular p.d. The data suggest the presence of an electrogenic sodium transport process in the peritubular membrane that directly contributes to the generation of the peritubular potential. In addition, chloride transport has an important role in determining this potential.

Absorption↗
PubMed2003

Interactions of human organic anion transporters with diuretics.

The tubular secretion of diuretics in the proximal tubule has been shown to be critical for the action of drugs. To elucidate the molecular mechanisms for the tubular excretion of diuretics, we have elucidated the interactions of human organic anion transporters (hOATs) with diuretics using cells stably expressing hOATs. Diuretics tested were thiazides, including chlorothiazide, cyclothiazide, hydrochlorothiazide, and trichlormethiazide; loop diuretics, including bumetanide, ethacrynic acid, and furosemide; and carbonic anhydrase inhibitors, including acetazolamide and methazolamide. These diuretics inhibited organic anion uptake mediated by hOAT1, hOAT2, hOAT3, and hOAT4 in a competitive manner. hOAT1 exhibited the highest affinity interactions for thiazides, whereas hOAT3 did those for loop diuretics. hOAT1, hOAT3, and hOAT4 but not hOAT2, mediated the uptake of bumetanide. hOAT3 and hOAT4, but not hOAT1 mediated the efflux of bumetanide. hOAT1 and hOAT3, but not hOAT2 and hOAT4 mediated the uptake of furosemide. In conclusion, it was suggested that hOAT1 may play an important role in the basolateral uptake of thiazides, and hOAT3 in the uptake of loop diuretics. In addition, it was also suggested that bumetanide taken up by hOAT3 and/or hOAT1 is excreted into the urine by hOAT4.

Animals↗
PubMed1981

Nesidioblastosis of the pancreas: definition of the syndrome and the management of the severe neonatal hyperinsulinaemic hypoglycaemia.

Three newborn infants are reported who developed severe non-ketotic hypoglycaemia (blood glucose less than 1.1 mmol/l; 19.8 mg/100 ml) within 6 hours of birth. All had inappropriately raised plasma insulin concentrations for the level of glycaemia, and required high rates of glucose infusion (less than 15 mg glucose/kg per minute) to prevent symptoms of hypoglycaemia. Medical treatment (hydrocortisone, diazoxide, chlorothiazide, phenytoin, propranolol, and depot glucagon) was ineffective in preventing hypoglycaemia and all 3 infants were subjected to partial and then total pancreatectomy. The pathological features of nesidioblastosis are reported from quantitative immunohistochemical studies on the pancreata. These results together with those from metabolic and endocrine studies performed on the 3 infants during the investigation of the cause of the hypoglycaemia and during the preoperative and postoperative period are presented in detail in order to define a practical approach to the management of this difficult clinical problem in the neonate.

Diazoxide↗
PubMed1975

Anion effects on cation movements during correction of potassium depletion.

The differential effects of KCl vs. KHCO3 for intravenous K+ repletion were evaluated in a series of nephrectomized dogs previously depleted of 20% of total-body K by a 2-wk regimen consisting of K-free diet plus DOCA plus chlorothiazide. Twenty-four percent of K losses (5% of original TBK) were replaced by a 2-h infusion of either CKl or KHCO3. Blood pH was maintained at normal levels by controlling the rate of respiration. Skeletal muscle biopsies were taken before and 2 h after repletion, and blood samples were taken at intervals throughout. The following differences resulting from KHCO3 compared to KCl repletion were found: a) a greater cellular K uptake, a lower rate of increase, and a lower steady-state extracellular K+ concentration; b) a less increase in intracellular K+ concentration and a less decrease in intracellular Na+ concentration. These differences, which were independent of extracellular pH or kidney function, are thought to be secondary to unequal distribution of Cl- and HCO3-ions.

Animals↗
PubMed1980

Natriuretic effect of oxytocin on saline-expanded neonatal dogs.

The natriuretic effect of oxytocin was studied in 40 anesthetized newborn dogs 2-33 days of age. After saline expansion, puppies excreted only 2.86% of the filtered sodium (adult dogs undergoing similar volume expansion excrete about 65-8% of the filtered sodium). After oxytocin was infused in these saline-expanded puppies at 8 mU x kg-1 x h-1, fractional sodium excretion increased to 7.51%. Oxytocin had no natriuretic effect in nonexpanded puppies. In nonexpanded animals, when distal nephron function was blocked by a combination of ethacrynic acid, chlorothiazide, and amiloride, fractional sodium excretion averaged 31%. In contrast, distal nephron blockade in saline-expanded animals resulted in fractional sodium excretion of 55%. When oxytocin was infused in either saline-expanded or nonexpanded puppies undergoing distal nephron blockade, there was no increase in sodium excretion. These results support the following conclusions. In the newborn dog 1) the attenuated natriuretic response to saline expansion is related to increased reabsorption of sodium in the distal nephron; 2) an adult type of natriuretic response to saline expansion can be induced in puppies by infusion of oxytocin; and 3) oxytocin inhibits sodium reabsorption in the distal nephron.

Animals↗
PubMed1993

Effects of formate and oxalate on chloride absorption in rat distal tubule.

We previously demonstrated that formate and oxalate stimulate Cl-transport in the rat proximal tubule in accord with a model involving NaCl uptake across the luminal membrane via Cl-/organic anion exchange in parallel with Na+/H+ exchange and organic acid recycling. The purpose of the present study was to test whether similar mechanisms contribute to Cl- transport in the rat distal tubule. In distal tubules microperfused in situ with an isotonic solution, addition of 0.5 mM formate to the luminal perfusate increased Cl- (JCl) and fluid (Jv) absorption by 77 and 93%, respectively. Addition of 5 microM oxalate increased JCl and Jv by 52 and 108%, respectively. In distal tubules perfused with a hypotonic solution, formate stimulated JCl and Jv by 85 and 98%, respectively, and oxalate stimulated JCl and Jv by 80 and 115%, respectively. Addition of 0.5 mM acetate caused no significant change in JCl and Jv. The stimulation of JCl and Jv by formate was largely abolished by addition of 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (100 microM) or ethylisopropyl-amiloride (10 microM) to the luminal perfusate. Chlorothiazide (0.5 mM) inhibited baseline JCl and Jv but caused no inhibition of the increments in Jv and JCl induced by formate. Formate stimulation of JCl and Jv was confined to early segments of the distal tubule. We conclude that formate and oxalate markedly enhance JCl and Jv in the early distal tubule by a thiazide-insensitive mechanism involving NaCl entry across the apical membrane by Cl-/organic anion exchange in parallel with Na+/H+ exchange.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1984

Ventilatory response to chronic metabolic acidosis and alkalosis in the dog.

Systematic data are not available with regard to the anticipated appropriate responses of arterial PCO2 to primary alterations in plasma bicarbonate concentration. In the present study, we attempted to rigorously characterize the ventilatory response to chronic metabolic acid-base disturbances of graded severity in the dog. Animals with metabolic acidosis produced by prolonged HCl feeding and metabolic alkalosis of three different modes of generation, i.e., diuretics (ethacrynic acid or chlorothiazide), gastric drainage, and administration of deoxycorticosterone acetate (alone or in conjunction with oral sodium bicarbonate), were examined. The results indicate the existence of a significant and highly predictable ventilatory response to chronic metabolic acid-base disturbances. Moreover, the magnitude of the ventilatory response appears to be uniform throughout a wide spectrum of chronic metabolic acid-base disorders extending from severe metabolic acidosis to severe metabolic alkalosis; on average, arterial PCO2 is expected to change by 0.74 Torr for a 1-meq/l chronic change in plasma bicarbonate concentration of metabolic origin. Furthermore, the data suggest that the ventilatory response to chronic metabolic alkalosis is independent of the particular mode of generation.

Acidosis↗
PubMed2001

Magnesium transport in the renal distal convoluted tubule.

The distal tubule reabsorbs approximately 10% of the filtered Mg(2+), but this is 70-80% of that delivered from the loop of Henle. Because there is little Mg(2+) reabsorption beyond the distal tubule, this segment plays an important role in determining the final urinary excretion. The distal convoluted segment (DCT) is characterized by a negative luminal voltage and high intercellular resistance so that Mg(2+) reabsorption is transcellular and active. This review discusses recent evidence for selective and sensitive control of Mg(2+) transport in the DCT and emphasizes the importance of this control in normal and abnormal renal Mg(2+) conservation. Normally, Mg(2+) absorption is load dependent in the distal tubule, whether delivery is altered by increasing luminal Mg(2+) concentration or increasing the flow rate into the DCT. With the use of microfluorescent studies with an established mouse distal convoluted tubule (MDCT) cell line, it was shown that Mg(2+) uptake was concentration and voltage dependent. Peptide hormones such as parathyroid hormone, calcitonin, glucagon, and arginine vasopressin enhance Mg(2+) absorption in the distal tubule and stimulate Mg(2+) uptake into MDCT cells. Prostaglandin E(2) and isoproterenol increase Mg(2+) entry into MDCT cells. The current evidence indicates that cAMP-dependent protein kinase A, phospholipase C, and protein kinase C signaling pathways are involved in these responses. Steroid hormones have significant effects on distal Mg(2+) transport. Aldosterone does not alter basal Mg(2+) uptake but potentiates hormone-stimulated Mg(2+) entry in MDCT cells by increasing hormone-mediated cAMP formation. 1,25-Dihydroxyvitamin D(3), on the other hand, stimulates basal Mg(2+) uptake. Elevation of plasma Mg(2+) or Ca(2+) inhibits hormone-stimulated cAMP accumulation and Mg(2+) uptake in MDCT cells through activation of extracellular Ca(2+)/Mg(2+)-sensing mechanisms. Mg(2+) restriction selectively increases Mg(2+) uptake with no effect on Ca(2+) absorption. This intrinsic cellular adaptation provides the sensitive and selective control of distal Mg(2+) transport. The distally acting diuretics amiloride and chlorothiazide stimulate Mg(2+) uptake in MDCT cells acting through changes in membrane voltage. A number of familial and acquired disorders have been described that emphasize the diversity of cellular controls affecting renal Mg(2+) balance. Although it is clear that many influences affect Mg(2+) transport within the DCT, the transport processes have not been identified.

Acid-Base Equilibrium↗
PubMed1994

Pharmacological classification and renal actions of diuretics.

Diuretics may be classified according to their chemical structure, their mechanism and site of action within the nephron, and their diuretic potency. Those agents with primary action in the proximal nephron include the carbonic anhydrase inhibitors, e.g. acetazolamide, a sulfonamide derivative. Other drugs containing the sulfonamido grouping, e.g. furosemide, chlorothiazide and metolazone, also have secondary effects on the proximal nephron. Those drugs which have their major pharmacologic activity within the ascending limb of the loop of Henle, inhibiting the sodium/potassium/2 chloride electroneutral transport system, include the sulfonamide agents furosemide, bumetanide, piretanide and torasemide, and the phenoxyacetic acid derivative, ethacrynic acid. In the early portion of the distal convoluted tubule, sodium chloride reabsorption is impaired by the thiazide group, indapamide and metolazone, as their primary site of action. In the late reaches of the distal convolution and in the collecting duct, agents that inhibit the exchange of sodium for that of hydrogen and potassium have their major sites of activity. These agents, spironolactone, amiloride and triamterene, differ not only chemically but in their mechanisms of action. Diuretics may also be grouped according to potency. The loop of Henle agents are the most powerful, causing the excretion of 20-25% of filtered sodium load. The thiazide group and metolazone are moderately potent, resulting in the excretion of 5-8% of filtered sodium, and the 'potassium-sparing' drugs are only mildly potent, causing the excretion of only 2-3% of filtered sodium.

Diuretics↗
PubMed1988

Variant of Bartter's syndrome with a distal tubular rather than loop of Henle defect.

A 19-year-old normotensive patient had all of the clinical features of Bartter's syndrome: hypokalemia, elevated renin and aldosterone levels and increased excretion of prostaglandin E. In contrast to the patients described by Bartter, the patient had a normal capacity to form solute-free water, suggesting intact loop of Henle function. Baseline potassium and chloride excretion rates were higher than those observed in 5 normal subjects, but the response to intravenous chlorothiazide, a drug which acts in the early distal convolute tubule, was abnormal. While chloride excretion rose by only 61% in this patient, it increased sixfold in the normal subjects. Sodium excretion quadrupled in the controls but less than doubled in this patients. Roughly equivalent increments in potassium excretion occurred in normals and controls, suggesting that the patient's distal potassium-secretory mechanism was intact. Review of the literature indicates that whether the site of the abnormal renal tubular potassium (chloride) leak is the proximal tubule, the loop of Henle or the distal convoluted tubule, patients may achieve features indistinguishable from those previously reported as characteristic for Bartter's syndrome. If loop of Henle malfunction is required to diagnose classical Bartter's syndrome, then our patient (and several reported elsewhere) has a variant form.

Adult↗
PubMed1980

Renal handling of calcium.

More than 95% of the filtered calcium is reabsorbed. In the proximal convoluted tubule calcium absorption is passive. The pars recta transports calcium actively but little is known about its regulation. Transport of calcium in the thick ascending limb is both active and passive, and function of medullary and cortical segments is heterogeneous. Parathyroid hormone (PTH) stimulates calcium transport in the cortical segment. Calcium absorption in the distal convoluted tubule is active, and both chlorothiazide and PTH enhance it. Function of the granular portion of the collecting tubule resenbles the distal convoluted tubule. The light portion does not transport calcium.

Animals↗