The influence of zinc and citrate on urease-induced urine crystallisation.

Zinc reduced and citrate promoted the urease-induced pH increase in synthetic urine. Secondary to this, the precipitation of magnesium ammonium phosphate and calcium phosphate was influenced. Independent of this pH-related effect, zinc also increased the precipitation of magnesium ammonium phosphate and decreased the calcium phosphate precipitation. These observations were not totally reproducable in human urine.

Effects of subpicomolar changes in vasopressin on urinary concentration.

The possibility that small amounts of vasopressin (AVP) reduce water excretion without affecting solute excretion was investigated in conscious dogs. AVP was infused intravenously for 120 min at rates of 2 and 5 pg.min-1.kg body wt-1 during water diuresis elicited by a sustained water load of 2% body wt. During control experiments urine osmolality was constantly approximately 60 mosmol/kgH2O; during AVP infusions it increased by factors of 1.36 (P less than 0.01) and 2.12 (P less than 0.01), respectively, concomitant with 39 +/- 6 and 61 +/- 7% reductions in urine flow. Osmolar and free water clearances decreased significantly. Sodium excretion did not change; changes in potassium excretion during AVP were similar to those of the control series, i.e., a gradual decline. During AVP, 5 pg.min-1. kg-1, creatinine and urea clearances decreased (25 +/- 2 and 31 +/- 7%, respectively, both P less than 0.01). With the assumption of metabolic clearance rates of AVP of 15-40 ml.min-1.kg body wt-1, the increase in plasma AVP during the infusion of 2 pg.min-1.kg body wt-1 was 5-13 X 10(-14) M. It is concluded that small increments in plasma AVP may reduce glomerular filtration rate and that with increasing levels of AVP in plasma 1) reduction of free water clearance, 2) reduction in urea clearance, and 3) natriuresis-kaliuresis occur in that order. Apparently AVP cannot reduce water excretion without changing the rate of excretion of solutes.

Atrial natriuretic hormone effect on renal function and aldosterone secretion in sodium depletion.

The effects of atrial natriuretic hormone (ANH) on aldosterone secretion and renal function have been well documented, but the physiological role of ANH is still unknown. To address this issue, eight normal men were infused for 4 h with low-dose (1.1 pmol.kg-1.min-1) human [Ser-Tyr28]ANH after 3 days of low-salt (LS) diet. The same subjects were also studied with placebo infusion on LS and high-salt (HS) diet. ANH infusion caused doubling of urine flow, a fourfold increase in urinary sodium excretion, and a slight increase in potassium excretion. Immunoreactive ANH levels increased from 3.1 +/- 0.5 to 21.0 +/- 1.9 pmol/l during ANH infusion. ANH infusion suppressed plasma renin activity (PRA) to one-third of the basal value, and plasma aldosterone was suppressed from 46.5 +/- 6.5 to 20.9 +/- 2.6 ng/dl. Low-dose ANH infusion caused a marked increase in urine flow and urinary sodium excretion and prominent suppression of PRA and plasma aldosterone in sodium-depleted subjects. These results suggest a physiological significance of ANH in regulation of kidney function and aldosterone secretion.

Renal pharmacodynamic effects of torasemide and furosemide in normal man.

The effects of acute administration of torasemide (1-isopropyl-3-([4-(3-methyl-phenylamino)pyridine]-3-sulfonyl)urea), a new potent loop diuretic, were compared with those of furosemide in 8 healthy male volunteers (aged 22-35 years). The subjects were studied on two separate occasions, at 1-week intervals. After two baseline urine collections of 30 min, either torasemide (20 mg i.v.) or furosemide (40 mg i.v.) was given, followed by further timed urine collections after 15, 40 and 60 min. There were significant increases in urine flow, and in sodium, potassium, chloride and calcium excretion, which were maximal within 15 min after administration of both drugs. These effects were of similar magnitude except for the natriuretic and chloruretic actions which were more pronounced after furosemide than after torasemide (p less than 0.02). The drugs induced no significant changes in effective renal plasma flow or glomerular filtration rate, as measured from the clearances of constantly i.v. infused 123I-orthoiodohippuran and 51Cr-EDTA, respectively. Urinary dopamine, urinary prostaglandin E excretion and plasma renin activity were increased by both drugs. It is concluded that the acute effects of torasemide are comparable to those of furosemide.

Dose-response curve for torasemide in healthy volunteers.

The safety and diuretic activity of torasemide (1-isopropyl-3- ([4-(3-methyl-phenylamino)pyridine]-3-sulfonyl)urea) were investigated in a phase I single-blind clinical study. After a pretreatment control day on placebo, a single dose of torasemide was administered orally according to an escalating dosage of 2.5, 5, 10 and 20 mg, respectively, in 4 groups of 3 healthy young male volunteers, after an overnight fast and 1 h before breakfast. The peak stimulatory effect on urinary volume was observed within 1 to 2 h and was followed by a gradual decline at the 3rd or 4th h back to or even slightly below the corresponding control values. Thus, the duration of action averaged 3-4 h and only moderate rebound effects were detected. This time-related diuretic activity perfectly fitted with the pharmacokinetics data since torasemide plasma levels peaked at the 1st h after drug administration and thereafter rapidly fell to less than 10% of the maximal plasma concentrations after the 4th h. While 2.5 mg torasemide showed only minor diuretic action, urinary volume and urinary excretion of sodium, chloride and calcium increased linearly with the logarithm of the dose during the first 4 h as well as during the whole 24 h period with 5, 10 and 20 mg torasemide. Conversely, the urinary density and osmolality fell progressively as the dose of torasemide increased. There was a trend towards a moderate decrease in urinary excretion of uric acid which seemed independent of the dose given. Finally, only minimal potassium urinary losses were observed without clear tendency towards an increase with increasing drug doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the subchronic nephrotoxic potential of styrene in Sprague-Dawley rats.

The nephrotoxic potential low non-toxic dose of styrene was studied in male Sprague-Dawley rats. Groups of rats received i.p. injections of styrene in corn oil at doses 0, 2.9, and 5.8 mmol/kg once daily, 5 days/week for 6 consecutive weeks. After collection of urine for 0-24 and 24-48 h following the end of the treatment, the rats were sacrificed. A significant increase in the excreted urinary volume was noticed at 5.8 mmol styrene during 0-24 and 24-48 h, relative to control, whereas urinary concentrations of gamma-glutamyl transpeptidase and glucose were significantly elevated during the 24-48-h period. Urinary activity of N-acetyl-beta-D-glucosaminidase was increased at the higher dose of styrene during 0-24 and 24-48 h. The capacity of renal cortical slices to accumulate p-aminohippurate was significantly reduced 48 h after the exposure to any dose of styrene. Electron microscopic examination of renal cortex 48 h after the exposure to a higher dose revealed the presence of enlarged mitochondria having more electron dense matrix. The data suggest that subchronic exposure to a very low non-toxic dose of styrene may have the potential to elicit nephrotoxicity preferentially in the proximal tubular region of the rat kidney.

The control of hypertension with dibutyryl cyclic AMP.

The effects of the rapid infusion of large doses of dibutyryl cyclic AMP (DBcAMP) were studied to clarify the clinical usefulness of its vasodilating action in 32 middle-aged patients, who underwent various types of surgery and developed systolic hypertension of over 160 mmHg during general anaesthesia. DBcAMP was given i.v. with an infusion pump at a rate of 0.6 mg kg-1 min-1 for 20 min. In all patients just after the infusion, systolic arterial pressure decreased from 174.0 +/- 20.7 to 129.0 +/- 23.9 mmHg, diastolic pressure decreased from 93.1 +/- 13.4 to 64.8 +/- 13.3 mmHg, heart rate increased from 81.2 +/- 15.7 to 91.5 +/- 19.5 beats min-1, and urine volume increased from 69.4 +/- 54.8 to 182.7 +/- 143.5 ml h-1. In three patients, cardiac index increased from 3.44 to 4.24 l min-1 m-2. In seven patients, tachycardia exceeding 120 beats min-1 developed. DBcAMP was also effective in patients with a history of hypertension. The strongest antihypertensive effect was observed in patients anaesthetized with nitrous oxide-oxygen and enflurane. We speculate that DBcAMP is useful to control hypertension and may be particularly indicated in patients with cardiac failure, renal disorders and essential hypertension.

Effect of dietary carbohydrate type and content on the response of male rats to dietary sodium saccharin.

The role of dietary carbohydrate composition and concentration in the response of male rats to sodium saccharin (NaS) was ascertained by comparing the response to 5% dietary NaS in rats given diets containing 65% starch, 50% sucrose together with 15% starch, 65% glucose, or 3% sucrose. NaS induced similar levels of caecal enlargement and increases in urine volume and bladder mass when given with any of the three forms of carbohydrate at 65% in the diet. However with the 3% sucrose diet, NaS caused a lesser caecal enlargement and no increase in urine volume or bladder mass. These findings suggest that NaS not only inhibits saccharide hydrolysis but also inhibits glucose transport. The significance of these findings in relation to NaS-associated bladder tumours is discussed.

Struvite crystal formation by Corynebacterium group D2 in human urine and its prevention by acetohydroxamic acid.

After 24 h incubation of human urine experimentally inoculated with Corynebacterium group D2, struvite crystals appeared with an increase in pH and ammonium concentration as well as a decrease in the urea concentration. These changes were prevented by the addition of variable concentrations of acetohydroxamic acid. From these results it seems that the prevention of such crystal formation by Corynebacterium group D2 could be due to the inhibition of its urease activity besides acetohydroxamic acid having a significant antimicrobial activity, principally when tested in human urine. These effects were dose-related.

Changes in the urine and scanning electron microscopically observed appearance of the rat bladder following treatment with tumor promoters.

Urine of rats treated with promoters of urinary bladder carcinogenesis was analyzed during weeks 8 to 24 of administration. The sodium salts of several chemicals, including ascorbic acid, erythorbic acid, acid saccharin and o-phenylphenol increased the urinary pH and sodium ion concentration of the urine. In contrast, treatment with sodium hippurate did not cause elevation of urinary pH although it increased the sodium ion concentration in the urine. Butylated hydroxyanisole, butylated hydroxytoluene (BHT), and ethoxyquin did not affect the urinary pH or any electrolytes except for an increase of phosphorus in the urine of rats given BHT or ethoxyquin. Scanning electron microscopic examination showed that epithelial cells of the urinary bladder of rats given promoters of urinary bladder carcinogenesis had pleomorphic microvilli, short, uniform microvilli, and ropy or leafy microridges on their surfaces. Thus, for the class of promoters including the sodium salts of weak to moderate acids, the elevation of urinary pH and the increase of sodium ion concentration accompany the promoting activity, whereas these changes do not occur following administration of the antioxidant class of bladder tumor promoters.

Triamterene-induced crystalluria and cylinduria: clinical and experimental studies.

We examined the occurrence of crystals and casts in the urine of healthy subjects after administration of triamterene and the site of crystal formation in experimental animals. Twenty out of twenty healthy subjects had abundant triamterene crystals and casts in acid urine after receiving a single 100 mg dose. Casts were present in the urine from 2-11 hours after administration of the diuretic. Cast formation occurred in acidic urine and was prevented by alkalinization of the urine with potassium citrate. Animal studies showed that crystallization and cast formation occurred in the medullary and papillary collecting ducts of the rat kidney. These findings provide a possible explanation for the reported nephrotoxicity of triamterene, particularly when given to patients who are receiving non-steroidal anti-inflammatory agents.

The role of the sympathetic nervous system in the regulation of ultradian rhythms in urine excretions.

The effects of alpha and beta adrenoreceptors blockade and surgical kidney denervation on ultradian rhythmicity in urine excretion were investigated in four dogs. Pharmacological treatments and surgical denervation of the kidneys suppressed the ultradian rhythmicity in urine flow but did not completely eliminate the ultradian rhythms in urinary osmolality and in electrolyte concentrations. These findings suggest that the autonomic nervous system plays a major role in the regulation of the ultradian rhythms in water excretion in dogs. The partial persistence of ultradian rhythms in urine osmolality and electrolyte concentrations after autonomic denervation supports the assertion that the ultradian rhythms in solute concentrations are regulated by different mechanisms to those of water excretion, suggesting the possible involvement of a multioscillatory system.

Developmental toxicity of ethylene glycol monopropyl ether in the rat.

In order to determine the potential developmental toxicity of ethylene glycol monopropyl ether (EGPE), pregnant rats were exposed to vapor concentrations of 100, 200, 300, or 400 ppm of the compound for 6 hours per day on days 6-15 of gestation. Maternal effects included a slight reduction in red blood cell count and increased mean corpuscular volume and mean corpuscular hemoglobin at the 200-, 300-, and 400-ppm concentrations. Reticulocyte counts and polychromasia of the red blood cells were increased at all exposure levels, while anisocytosis was increased at 300 and 400 ppm and macrocytosis was increased at 200, 300, and 400 ppm. Hematocrit, hemoglobin concentration, platelet, and total and differential white blood cell counts were comparable to those of the controls. Red urine was seen in the females after the first and second exposures to 200, 300, and 400 ppm of EGPE, but not after subsequent exposures. Absolute and relative spleen weights were increased by 200, 300, and 400 ppm EGPE. Histologic changes were seen in the maternal spleen, liver, and thymus, particularly after exposure to 300 and 400 ppm. Kidneys, bone marrow, and mesenteric lymph nodes were normal. Pregnancy rate, number of corpora lutea, implantation sites and viable fetuses per dam, the incidence of resorptions per litter, and the mean fetal body weights were comparable to those of the controls. Gross external, internal soft tissue, and skeletal examinations of the fetuses revealed that EGPE did not produce teratogenicity or significant embryo/fetotoxicity in the rat at vapor concentrations as high as 400 ppm. Variations in the ossification of certain skeletal elements and the incidence of 14th thoracolumbar rudimentary ribs were increased by exposure to 200, 300, and 400 ppm EGPE.

Evaluation of the dose response and in utero exposure to saccharin in the rat.

A two-generation bioassay on sodium saccharin (NaS), involving 2500 second-generation male rats, was designed to determine the dose response for urinary bladder tumours in male rats and to evaluate other changes possibly related to the occurrence of the tumours. Six treatment groups (125-700 rats/group) were fed dietary levels of NaS ranging from 1.0 to 7.5%. To evaluate the role of in utero exposure, two additional groups were exposed to NaS either only during gestation via dams fed diet containing 5.0% NaS or for a single generation beginning at birth. In the latter group, the nursing dams were placed on an NaS diet immediately after giving birth and their offspring were weaned onto diets containing 5.0% NaS. A third additional group, included to evaluate the specificity of NaS and the role of excess sodium in the occurrence of urinary bladder tumours, was fed diet containing sodium hippurate (NaH) for two generations--5.0% NaH to the first generation and to the second until 8 wk old, and subsequently 3.0% because of unexpected toxicity. A clear dose response for urinary bladder tumours was observed in the second-generation NaS-treated male rats. The steep slope of the dose-response curve indicated a rapid decline in tumour incidence with decreasing dose. The 1.0% dietary level (fed to 700 rats) was considered to be a no-effect level for bladder tumours. The only other treatment-related pathological changes were an increase in urinary bladder weight in rats fed greater than or equal to 3.0% and an increase in mineralization of the kidneys with greater than or equal to 1.0%. Several physiological effects were seen in the NaS-treated groups showing an increase in bladder tumours (i.e. those fed greater than or equal to 3.0%). Some changes, e.g. depressed growth and increased water consumption, were indicative of a general disturbance of these rats, but analysis of body-weight, food-consumption, compound-consumption and water-consumption data revealed no correlations within any dose group between these quantitative data and the occurrence of bladder tumours. Other changes indicative of the compromised situations of the rats fed high dietary levels of NaS were anaemia in weanling rats fed 5.0 or 7.5% and a reduction in litter size at dietary levels greater than or equal to 3.0%. Changes in urine volume and urine osmolality were highly correlated with the occurrence of the urinary bladder tumours.(ABSTRACT TRUNCATED AT 400 WORDS)

Some changes in gastro-intestinal metabolism and in the urine and bladders of rats in response to sodium saccharin ingestion.

In rats fed sodium saccharin in the diet changes in urine composition, increased bladder-tissue mass and, in males only, an accumulation of minerals in the bladder tissue have been observed. In this report evidence is presented that indicates that these changes are a consequence of the effects of sodium saccharin in the gastro-intestinal tract and are not due to systemic sodium saccharin. Sodium saccharin has been shown to inhibit gastro-intestinal enzymes that digest carbohydrates and proteins and to increase caecal absorption of mineral ions. The significance of these findings to saccharin-associated bladder tumorigenesis is discussed.

Interactions of analgesics with other drugs.

Antipyretic analgesics, such as salicylates, acetaminophen, and pyrazolones, are often given concomitantly with a variety of other drugs. Drug interactions that occur at the receptors are known as pharmacodynamic interactions; alterations in absorption (bioavailability), distribution (plasma protein-binding), and elimination (renal excretion, hepatic metabolism) are termed pharmacokinetic interactions. For example, antacids and food both delay the absorption of analgesics. Highly protein-bound drugs (such as phenylbutazone, phenytoin, or warfarin) can compete with the common binding sites of salicylates. Hepatic elimination of salicylates can be influenced by drugs such as beta-blockers and cimetidine. Clinically important interactions involving salicylates, acetaminophen, and other antipyretic analgesics are discussed.

Short-term toxicity of 2,6-dimethylhept-5-en-1-al in rats.

Groups of 15 male and 15 female rats were fed for at least 90 days on diets that provided 2,6-dimethylhept-5-en-1-al (DMH) at average intakes of 0 (control), 9, 37 and 150 mg/kg body weight/day. Steps were taken to limit loss of DMH during diet mixing, storage and feeding. No effects attributable to treatment were encountered in body weight, food intake, water intake, haematology (at wk 6 and 13) or the gross and microscopic pathological examinations. At the highest dose level there was a slight reduction in renal concentrating ability at wk 6 in males and wk 14 in females, together with a small increase in relative kidney weight and liver weight in females. The serum-glucose concentrations of both sexes on the highest dose were elevated compared with the controls. It was concluded that the intermediate dose, providing an intake of 37 mg/kg/day, was the no-untoward-effect level.