Uptake In Slices Research Articles

Inhibition of [ 3H]dopamine and [ 3H]serotonin uptake by cocaine: Comparison between chopped tissue slices and synaptosomes

Cocaine inhibits both [ 3H]dopamine and [ 3H]serotonin uptake in rat striatum and nucleus accumbens. In a chopped tissue slice preparation, the inhibition curve for [ 3H]dopamine uptake is biphasic, suggesting two components of uptake, whereas the curve for [ 3H]serotonin uptake is steep and apparently monophasic. In synaptosomal preparations, both curves are monophasic. Monensin, a sodium ionophore, inhibits uptake but does not change the shape of the cocaine inhibition curve in synaptosomes, suggesting that the biphasic inhibition curves in slices are not likely due to differential sodium gradients across the slices. In tissue slices, only the component which is more sensitive to inhibition by cocaine and related drugs is inhibitable by nicotine. This suggests that the two components of dopamine uptake in tissue slices may be differentially regulated.

Protective Effect of Minaprine against the Abnormal Changes of 2-Deoxyglucose Uptake by Rat Hippocampal Slices Induced by Hypoxia/Hypoglycemia

Effect of minaprine on hypoxia- or hypoxia/hypoglycemia (ischemia)-induced impairment of 2-deoxyglucose (2DG) uptake by rat hippocampal slices was evaluated. Since minaprine was found to possess both a stimulating effect on acetylcholine release and a blocking effect on 5-HT2 receptors, the improving effect of minaprine on impaired 2DG uptake was compared to the findings obtained with oxotremorine, ketanserin and pentobarbital. Hippocampal slices were exposed to 20-min ischemia, and then these slices were returned to oxygenated and glucose-containing buffer for 6 hr. Ischemia reduced 30 mM KCl-induced 2DG uptake by the hippocampus. Pretreatment with minaprine, oxotremorine, pentobarbital and ketanserin attenuated the ischemia-induced decline of 2DG uptake. In addition, minaprine, oxotremorine and pentobarbital relatively recovered the increase of 2DG uptake in the hippocampal slices under hypoxia for 45 min. The present results suggest that minaprine exerts a neuroprotective action against ischemia-induced deficit of energy metabolism in vitro.

Neuroprotective Effect of WEB 1881 FU (Nebracetam) on an Ischemia-Induced Deficit of Glucose Uptake in Rat Hippocampal and Cerebral Cortical Slices and CA1 Field Potential in Hippocampal Slices

Effect of WEB 1881 FU (nebracetam) on hypoxia and ischemia-induced impairment of 2-deoxyglucose (2DG) upatke and CA1 field potentials induced by hypoxia and hypoxia/hypoglycemia (ischemia) in rat brain slices was evaluated and compared to the findings obtained with pentobarbital and idebenone. Hippocampal and cortical slices were exposed to 15–20 min of ischemia, and then these slices were returned to oxygenated and glucose-containing buffer for 6 hr. Ischemia reduced both 30 mM KCL-induced 2DG uptake and CA1 field potentials elicited by the stimulation of Schaffer collaterals in the hippocampus. Pretreatment of nebcetam at 1 mM or pentobarbital at 0.1 mM attenuated a decline of 2DG uptake and CA1 field potentials under the condition of ischemia. In addition, nebracetam and pentobarbital relatively recovered the increases of 2DG uptake in the hippocampus under hypoxia for 45 min. Furthermore, these drugs also attenuated the declinc of 2DG uptake induced by 10 mM glutamate for 20 min. However, treatment with idebenone did not recover the deficit of 2DG uptake and CA1 field potential. The present result suggests that nebracetam and pentobarbital exert neuroprotective actions against not only ischemia but also glutamate toxicity.

Effects of methylguanidine on sodium and organic ion transport.

We studied the acute effect of methylguanidine (MG), a suspected uremic toxin that accumulates in renal failure, on p-aminohippurate (PAH) and tetraethylammonium (TEA) uptake in rabbit kidney slices, on Na+,K+ ATPase activity in the microsomal fraction of rabbit kidneys, and on transepithelial active Na transport across toad skin. MG at concentrations ranging from 0.05 (similar to that reported in uremic patients) to 1.0 mM does not affect the organic anion (PAH) uptake, although it exhibits a concentration-dependent inhibition of organic cation (TEA) uptake. MG at concentrations from 0.05 to 5 mM had no effect on kidney Na+,K+ ATPase activity or on active transepithelial Na transport across toad skins when applied to the outside bathing solution; however, MG (greater than 1 mM) stimulated Na transport when applied to the inside bathing solution. These results are not consistent with the hypothesis that MG is a potential uremic toxin that causes the natriuresis and other toxic effects. However, long-term toxic effects of MG on the kidney were not assessed in the present study.

Effect of infarct size measured from antimyosin single-photon emission computed tomographic scans on left ventricular remodeling

To evaluate the effect of infarct size on left ventricular volumes and geometric remodeling, 26 patients with a first acute Q wave myocardial infarction (anterior in 14, inferior in 12) had the infarct sized from single-photon emission computed tomographic (SPECT) imaging of indium-111 antimyosin. All patients underwent gated blood pool scintigraphy before hospital discharge for determination of ejection fraction and end-diastolic and endsystolic volume indexes. Infarct size was quantitated from indium-111 antimyosin uptake in coronal slices with use of a threshold technique for edge detection. Nineteen of 26 patients had additional simultaneous acquisitions of indium-111 and thallium-201 uptake and the infarct was expressed as a percent of the total left ventricle.Infarct size was larger (59 ± 16 vs. 33 ± 16 g), predischarge ejection fraction lower (35 ± 5% vs. 60 ± 9%) and end-systolic volume index higher (57 ± 13 vs. 36 ± 10 ml/m2) in the group with anterior infarction. Despite these differences, predischarge end-diastolic volume index was not significantly different between the group with anterior (88 ± 17 ml/m2) versus inferior (89 ± 14 ml/m2) infarction. There was a significant inverse correlation between percent infarct size and ejection fraction for patients with dual isotope imaging (r = −0.90) and a significant direct correlation between infarct size and end-systolic volume index (r = 0.79, p < 0.01).Fourteen patients without subsequent myocardial infarction or coronary artery bypass grafting had a repeat gated blood pool study late (26 ± 15 months) after infarction. Patients with an anterior infarction had a significant increase in end-diastolic volume index (+10 ± 11 ml/m2), which was also significantly different from the change in end-diastolic volume index in the group with inferior infarction (−5 ± 5.2 ml/m2).These data suggest that infarct size and location have a profound effect on left ventricular function and chamber size. Anterior infarcts, because they are larger, cause more severe left ventricular dysfunction and higher end-systolic volume early. The consequent increases in end-systolic wall stress may be the driving mechanism for late left ventricular chamber enlargement. This method for measuring infarct size has potential usefulness for selecting patients who will benefit from pharmacologic intervention to prevent late left ventricular dilation.

Osmoregulatory betaine uptake by rat renal medullary slices.

Betaine is an osmolyte present in high concentrations in renal medullary cells. Betaine and other organic osmolytes, such as glycerophosphorylcholine, myo-inositol, and sorbitol, have been shown to increase in concentration during antidiuresis when the inner medullary extracellular osmolality rises. Its concentration may increase in renal cells either by betaine uptake or by choline metabolism to betaine. These studies measured the uptake of (14C)betaine into cortical, outer medullary and inner medullary slices from rat kidney. The tissue-to-medium ratio of (14C) betaine increased with increasing osmolality up to 450 mosmol/kg in outer medullary and inner medullary slices, but not in cortical slices. Betaine uptake increased when the osmolality was raised with NaCl or mannitol, but not with urea. When LiCl was substituted for NaCl in a medium of 300 mosmol/kg, there was significant inhibition of betaine uptake, although the tissue-to-medium ratios remained greater then unity. Thus, increases in osmolality stimulate betaine uptake in rat renal medullary slices and this uptake occurs by both sodium-dependent and sodium-independent betaine transport.

Actions of phosphomonoesters on CA1 hippocampal neurons as revealed by a combined electrophysiological and nuclear magnetic resonance study

Phosphomonoesters (PMEs), precursors of membrane phospholipids, are found in high levels in the developing brain and Alzheimer's disease brain. The present study details the neurophysiological and metabolic effects of acute PME elevation on the Fisher 344 rat in vitro hippocampal slice. Two abundant PMEs, phosphoethanolamine (PE) and L-phosphoserine (PS), reliably altered properties of synaptic transmission at the Schaffer collateral/commissural-CA1 cell synapse. Specifically, PE reversibly depressed the amplitude of population EPSPs at millimolar concentrations but had no effect at micromolar concentrations. PS had biphasic effects on population EPSPs, inducing first a reduction followed by an enhancement of response amplitude. In contrast to PE, the effects of PS were not reversible; population EPSPs were augmented during the wash of PS, and the CA3 region generated evoked (but not spontaneous) epileptiform discharges. 31P nuclear magnetic resonance spectroscopy revealed enhanced slice uptake of PS compared to PE. There was no significant effect of PE on slice high-energy phosphates but incubation with PS significantly lowered slice phosphocreatine (PCr) and ATP concentrations. These observations indicate that the slice uptake of PS could be energy requiring and the enhanced response amplitude observed at 5 mM PS also could produce a drain on high-energy phosphates. Possible modes of PME action on hippocampal physiology are discussed.

Development of sugar-induced blood pressure elevation after uninephrectomy in a resistant rat strain.

Certain rat strains acutely increase blood pressure (BP) when given diets high in NaCl. Prior results showed that "salt-sensitive" rat strains, at least the ones studied, also increase BP in response to sugar loading. To examine this relationship further and learn more about the pathogenesis of sucrose-induced BP elevations, we examined the effects of unilateral nephrectomy (uninephrectomy) on sucrose-induced BP changes. The rationale is based upon the findings that renal mass removal sensitizes BP response to salt loading. Over 15 weeks, augmented sugar (sucrose) consumption by Long-Evans (LE) rats did not increase BP markedly compared to rats consuming a diet relatively low in sugar unless uninephrectomy was performed. The differences in BP caused by the high sugar diet in a uninephrectomized rat could not be explained adequately by alterations in catecholamine excretion, plasma renin activity, excesses in blood volume, or the other parameters examined. However, salt-induced hypertension has been attributed to the presence of circulating substances affecting ion transport. Among the dietary groups, there was a significant correlation between the ability of plasma to depress PAH and TEA renal slice uptake and the difference in BP. This is consistent with the presence of a circulating factor affecting cell transport that has its greatest activity in the high sugar-uninephrectomy group of LE rats. We conclude that reducing renal mass potentiates sugar-induced BP elevation similar to salt-induced BP elevation in a normally resistant rat strain, and the rise of BP may be caused by a circulating factor.

Endogenous inotropic substance from heart tissue has digitalis-like properties

In the past few years, we developed an extraction procedure which we successfully used to isolate a crude fraction containing digitalis-like substance (DLS) from porcine left ventricular tissue. In this study, the crude fraction was found to cross-react with digoxin antibodies and showed immunoreactivity of 4.25 ± 0.6 ng digoxin equivalent /ml. On further purification of the crude fraction using silica gel G column chromatography, a fraction C was obtained, which was highly positive inotropic on canine trabeculae and it dose-dependently inhibited ouabain sensitive 86Rb + uptake in rat heart slices. A 50% inhibition of uptake was obtained by 25 ul of fraction C. Fraction C also inhibited canine kidney Na +, K +-ATPase (Sigma, U.S.A.) dose-dependently and a 50% inhibition of this enzyme required 17 ul of fraction C. Ashing of the fraction C at 500°C resulted in loss of inotropic and enzyme inhibitory activities, indicating an organic nature of the unknown digitalis-like substance.

Effect of 1,3-di-n-butyl-7-(2-oxopropyl)-xanthine (denbufylline) on metabolism and function of cerebral cholinergic neurons.

Effect of denbufylline, a low Km phosphodiesterase inhibitor, on cerebral cholinergic neurons was investigated using male Wistar rats. Single administrations of denbufylline (3, 10 and 30 mg/kg, p.o.) decreased cerebral cortical, hippocampal and striatal acetylcholine (ACh) contents in a dose-dependent manner. However, denbufylline (30 mg/kg, p.o.) had no effect on the activities of ACh synthesizing and degrading enzymes in these brain areas. In vitro addition of denbufylline (10(-8)-10(-4) M) produced no significant change in [3H]choline uptake in striatal slices, while denbufylline (10(-4) M) increased high (20 mM) potassium-evoked endogenous ACh release from striatal slices. Denbufylline (30 mg/kg, p.o.) increased cyclic AMP (cAMP) contents in the cerebral cortex, hippocampus and striatum. In vitro addition of dibutyryl cAMP (5 x 10(-3) M) also accentuated the high (20 mM) potassium-evoked endogenous ACh release from striatal slices. These results suggest that denbufylline may induce the facilitation of ACh turnover by enhancing endogenous ACh release via the increase of cAMP content in the brain.

Effect of l,3-Di-n-Butyl-7-(2-Oxopropyl)-Xanthine (Denbufylline) on Metabolism and Function of Cerebral Cholinergic Neurons

Effect of denbufylline, a low Km phosphodiesterase inhibitor, on cerebral cholinergic neurons was investigated using male Wistar rats. Single administrations of denbufylline (3, 10 and 30 mg/kg, p.o.) decreased cerebral cortical, hippocampal and striatal acetylcholine (ACh) contents in a dose-dependent manner. However, denbufylline (30 mg/kg, p.o.) had no effect on the activities of ACh synthesizing and degrading enzymes in these brain areas. In vitro addition of denbufylline (10-8-10-4 M) produced no significant change in [3H]choline uptake in striatal slices, while denbufylline (10-4 M) increased high (20 mM) potassium-evoked endogenous ACh release from striatal slices. Denbufylline (30 mg/kg. p.o.) increased cyclic AMP (cAMP) contents in the cerebral cortex, hippocampus and striatum. In vitro addition of dibutyryl cAMP (5 × 10-3 M) also accentuated the high (20 mM) potassium-evoked endogenous ACh release from striatal slices. These results suggest that denbufylline may induce the facilitation of ACh turnover by enhancing endogenous ACh release via the increase of cAMP content in the brain.

An evaluation of the redox cycling potencies of paraquat and nitrofurantoin in microsomal and lung slice systems

The redox cycling abilities of the pulmonary toxins paraquat and nitrofurantoin have been compared with those of the potent redox cyclers, diquat and menadione in lung and liver microsomes by using the oxidation of NADPH and consumption of oxygen. The relative potencies of these compounds to undergo redox cycling were in the order: diquat ∼- menadione ⪢ paraquat ∼- nitrofurantoin. This was partly attributed to the much lower affinity ( K m ) of lung and liver microsomes for paraquat and nitrofurantoin than for diquat and menadione. The potential to redox cycle was assessed in an intact cellular system by determining the oxygen consumption of rat lung slices in the presence (10 −6, 10 −5 and 10 −4 M) or absence of each of the four substrates. At concentrations of paraquat (10 −5 M) known to be accumulated by lung slices, a small but significant stimulation of lung slice oxygen uptake was observed. Nitrofurantoin (10 −4–10 −6 m) did not affect lung slice oxygen uptake in lung slices, an observation consistent with its being a poor redox cycling compound, which is not actively accumulated into lung cells. This data has important implications in assessing the risk of exposure to paraquat. Low levels of paraquat would not be expected to cause lung damage because insufficient compound is present in the lung to exert its toxicity by redox cycling (due to the high ( K m ) observed).

N-(3,5-Dichlorophenyl)succinimide nephrotoxicity in streptozotocin-induced diabetic rats

N-(3,5-Dichlorophenyl)succinimide (NDPS) is an experimental fungicide which induces renal toxicity. The following study examined the nephrotoxicity induced by NDPS in streptozotocin (STZ) diabetic rats. Male Fischer 344 (F344) rats were injected with 35 mg/kg STZ (i.p.) or citrate buffer. Fourteen days after STZ or citrate buffer injection, the rats (4–6 rats/group) were injected with (0.4 or 1.0 mmol/kg) NDPS or vehicle (sesame oil, 2.5 ml/kg). Kidney weight, blood urea nitrogen (BUN) levels, morphology and renal cortical slice uptake of organic ions was quantitated 48 h after NDPS administration. A 0.4 mmol/kg dose of NDPS induced diuresis, increased kidney weight and a moderate elevation in BUN levels in the normoglycemic group. The 1.0 mmol/kg dose of NDPS produced diuresis, proteinuria, increased kidney weight and a marked increase in BUN levels in the normoglycemic group. The renal cortical slice uptake of p-aminohippurate (PAH) and tetraethylammonium (TEA) was also decreased 48 h after NDPS injection in the normoglycemic group. No alterations in kidney weight, BUN levels, morphology or renal cortical slice uptake of organic ion was observed in the diabetic animals treateed with (0.4 or 1.0 mmol/kg) NDPS. The results of this study indicate that the renal toxicity of NDPS was reduced in the diabetic rat.

Calcium Is the First Messenger for the Action of Thyroid Hormone at the Level of the Plasma Membrane: First Evidence for an Acute Effect of Thyroid Hormone on Calcium Uptake in the Heart*

The thyroid hormone T3 produced a very rapid and transient increase in 45calcium uptake by freshly isolated rat heart slices, which was seen already 15 sec after the addition of the hormone, reached a maximum at 30 sec, and then progressively declined and returned to control values after 10 min. This effect of T3 was independent of extracellular calcium, concentration related (evident at a physiological concentration of 10 pM, reached maximum of about 75% above control at 1 nM, and was smaller at greater concentrations), and thyroid hormone specific, as judged from the order of potency of several thyroid hormone analogs: L-T3 greater than L-T4 greater than or equal to D-T3 greater than 3'-isopropyl-3,5-L-diiodothyronine greater than D-T4 greater than 3,5-L-diiodothyronine greater than r-L-T3 greater than D,L-thyronine. The inorganic calcium channel blockers La3+, Cd2+, and Mn2+ inhibited, in a concentration-related fashion, basal and T3-induced increases in 45Ca uptake in the cardiac slices. The organic calcium channel blockers verapamil, nifedipine, and diltiazem were without effect, indicating that in the quiescent cardiac slice the effect of T3 on 45Ca uptake is independent of sarcolemmal depolarization. Additional studies demonstrated that the stimulatory effect of T3 on 2-deoxyglucose uptake by the cardiac slices required extracellular calcium and was inhibited by the calcium channel blockers La3+, Cd2+, and Mn2+. The present study provides conclusive evidence for two central issues: that calcium is the first messenger for the prompt, plasma membrane-mediated action of thyroid hormone to increase cellular sugar uptake, and that thyroid hormone produces an acute increase in calcium uptake by the heart, an effect that is demonstrable at physiological concentrations and is thyroid hormone specific and, therefore, points to a physiological relevance for this action.

Potentiation of the cell specific toxicity of paraquat by 1,3-BIS(2-chloroethyl)-1-nitrosourea (BCNU): Implications for the heterogeneous distribution of glutathione (GSH) in rat lung

In order to study oxidative stress in the lung, we have developed a rat lung slice model with compromised oxidative defences. Lung slices with markedly inhibited glutathione reductase activity (∼80% inhibition) were prepared by incubating slices, with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) (100 μM) in an amino acid-rich medium for 45 min at 37°. These lung slices had similar levels of GSH and ATP and polyamine uptake (a marker of alveolar epithelial type I and II cell function) to control rat lung slices. We have utilized these BCNU pretreated slices to study the effects of the herbicide, paraquat, in comparison to those of 2,3-dimethoxy-1,4-naphthoquinone, a potent redox cycler. Paraquat (10–100 μM) caused only minimal changes in the levels of GSH or ATP in control or compromised slices. In contrast, 2,3-dimethoxy-1,4-naphthoquinone caused a decrease in GSH in control slices but a markedly enhanced decrease in both GSH and ATP in compromised slices. Both compounds had only limited effects on putrescine and spermidine uptake in control slices. However, they caused a marked inhibition in compromised slices. Paraquat had little effect on 5-hydroxytryptamine uptake (a marker of endothelial cell function) in either control or compromised slices whereas the quinone inhibited uptake in the compromised slices. Thus, the lack of effect of paraquat on GSH and ATP does not support the involvement of oxidative stress in its toxicity. In contrast, using polyamine uptake, as a functional marker of alveolar epithelial cell damage, suggests a role for redox cycling. As paraquat is known to be accumulated primarily in alveolar type I and II cells (a small fraction of the lung cell population), our data suggest that only a small proportion of pulmonary GSH and ATP is present in alveolar epithelial type I and II cells but that much larger amounts may be present in endothelial cells. These studies highlight the problem of gross tissue measurements in heterogeneous tissues such as the lung.

Influence of streptozotocin (STZ)-induced diabetes, dextrose diuresis and aceton on cisplatin nephrotoxicity in Fischer 344 (F344) rats

The following studies examined the impact of the diabetic state on cisplatin nephrotoxicity. This study also investigated the potential mechanisms for diabetes mediated reduction of cisplatin toxicity. A diabetic state was induced in male Fischer 344 (F344) rats after intraperitoneal (i.p.) injection of 27–35 mg/kg STZ. Cisplatin (5 mg/kg, i.p.) nephrotoxicity was examined in normoglycemic and diabetic rats after 48 and 96 h. Cisplatin was nephrotoxic within 96 h to normoglycemic animals as indicated by an increased kidney weight, marked elevations in serum BUN levels as well as significant P < 0.05) decrease in renal cortical slice accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA). Cisplatin failed to depress renal cortical slice accumulation of PAH and TEA in the diabetic rats. Cisplatin was also less effective in increasing BUN levels or kidney weight in diabetic rats. Further studies investigated the impact of glycosuric diuresis and ketone bodies on cisplatin nephrotoxicity. Dextrose diuresis of normoglycemic rats failed to reduce the effect of cisplatin on BUN levels, kidney weight and renal cortical slice uptake of PAH and TEA. Acetone pretreatment of normoglycemic rats also did not reduce cisplatin nephrotoxicity. These results indicate: (1) cisplatin nephtotoxicity is attenuated in the experimental diabetic state, (2) diabetes does not reduced cisplatin nephrotoxicity through glycosuric diuresis and (3) ketone body accumulation does not modulate cisplatin nephrotoxicity.

Insulin like activity in (-) epicatechin.

Water extract of the bark of plant of Pterocarpus marsupium Roxb is used as an antidiabetic drug in indigenous medicine in India. (-) Epicatechin, its active principle, has been found to be insulinogenic. The present in vitro study reports some insulin like activities of (-) epicatechin. Like insulin, (-) epicatechin stimulates oxygen uptake in fat cells and tissue slices of various organs, increases glycogen content of rat diaphragm in dose-dependent manner with corresponding increase in U14-C glucose uptake, and inhibits theophylline induced lipolysis in isolated fat pads in dose-dependent manner. Experiments on competitive binding of 125I-insulin and (-) epicatechin to liver cell plasma membrane indicate that insulin does not share binding site with (-) epicatechin. (-) Epicatechin at a concentration of up to 1 mM does not effect the release of glucagon from the islets in vitro. Thus, (-) epicatechin has insulinogenic as well as insulin like properties.

Nephrotoxicity of para-substituted thiobenzamide derivatives in the rat

Histological examination, plasma urea nitrogen levels (BUN), and renal cortical slice uptake of p-aminohippurate (PAH) or tetraethylammonium (TEA) were used to assess the nephrotoxicity of thiobenzamide and its para-substituted derivatives in Sprague—Dawley rats. Intraperitoneal injection of p-methylthiobenzamide (PMTB) to rats resulted in dose-dependent nephrotoxicity as judged by increased BUN levels, decreased TEA uptake and histologic examination of the kidney. Para-methoxythiobenzamide and PMTB were more potent nephrotoxins than thiobenzamide, which was itself minimally nephrotoxic. Para-methylthiobenzamide- S-oxide (PMTBSO) was more nephrotoxic than PMTB. Rats were pretreated with 1-methyl-1-phenylbenzoylthiourea (MPBTU), a non-toxic arylthiourea which inhibits the metabolism and toxicity of thiocarbonyl compounds. The nephrotoxicity and hepatotoxicity of PMTB was reduced by treatment with MPBTU 30 min prior to PMTB. Pretreatment with MPBTU protected against the renal toxicity of PMTBSO. The results indicate that electron donating para-substituted thiobenzamides produce dose-dependent renal injury, dependent upon oxidative biotransformation.

Astrocytic swelling in traumatic-hypoxic brain injury

Swelling of brain slices is shown to occur in response to elevated potassium levels or glutamate, which is accompanied by astrocytic swelling. Cl-/HCO3- anion exchange inhibitors, such as SITS (4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid) or furosemide, but not the specific cotransport inhibitor bumetanide, inhibit swelling or increased ion uptake in rat brain slices caused by elevated potassium although there were marked species differences in sensitivity. A novel anion exchange inhibitor, L-644,711, inhibits swelling and increased ion uptake caused by glutamate in rat and cat brain slices, as well as inhibiting [3H]glutamate uptake in primary rat astrocyte cultures. Possible mechanisms of action of the inhibitors are discussed. L-644,711 was also found to be effective in promoting recovery from a trauma plus hypoxia head injury model in cats. Marked perivascular astrocytic swelling is associated with this head injury model, and L-644,711 also inhibited such astroglial swelling as determined ultrastructurally. The significance of these findings in relation to possible connections between astrocytic swelling and brain pathology is discussed.

Cephaloridine nephrotoxicity in streptozotocin induced diabetic fischer 344 (F344) rats

The purpose of this study was to determine if cephaloridine nephrotoxicity is attenuated in streptozotocin (STZ)-induced diabetic rats. Fischer 344 (F344) rats (205–250 g) were given a single injection (i.p.) of STZ (27–35 mg/kg) or citrate buffer. The nephrotoxicity of (750 mg/kg) cephaloridine (i.p.) was then compared with normoglycemic and 14-day diabetic rats. Increased blood urea nitrogen (BUN) levels as well as diminished renal cortical slice accumulation of tetraethylammonium (TEA) and lactate-stimulated p-aminohippurate (PAH) were measured ( P < 0.05) in normoglycemic rats 48 h after cephaloridine administration. Cephaloridine failed to alter BUN levels and organic ion accumulation in diabetic rats. Diabetes did not totally protect against cephaloridine toxicity since kidney weights were elevated in normoglycemic and diabetic rats 48 h after administration of 750 mg/kg cephaloridine. A series of experiments also measured BUN levels, kidney weight and renal cortical slice uptake of PAH and TEA 24, 48 and 72 h after (1500 mg/kg) cephaloridine administration. Cephaloridine increased ( P < 0.05) kidney wt and decreased PAH and TEA uptake ( P < 0.05) in the normoglycemic group at 24–72 h. No change in kidney wt, PAH or TEA uptake was observed in the diabetic rats. These data indicate diabetes reduces cephaloridine nephrotoxicity.