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D L Davies

Publications and source records attributed to D L Davies.

At least 37 records · Page 2Linked to original sources
PubMed1995

Comparison of glutamine-enhanced glutamate release from slices and primary cultures of rat brain.

Increased extracellular glutamate has been associated with a wide range of effects including production of neurotoxicity. Glutamine has previously been shown to cause increased release of glutamate from a variety of preparations. Extracellular central nervous system (CNS) glutamine levels are known to increase with neurotoxin exposures, hepatic failure, renal failure, head trauma or stroke. However, the action of glutamine to enhance the release of glutamate under nondepolarizing conditions has not been well studied. Since glutamine-mediated increases in extracellular glutamate are potentially of significance in cellular damage as a result of CNS insult, further examination of this phenomenon is important. Striatal and hippocampal slices or virtually neuron-free primary striatal glial cultures were employed in studies to further elucidate the mechanism(s) of glutamine-enhanced glutamate release. Elevated extracellular glutamine caused increased glutamate release in all three preparations. In hippocampal and striatal slices elevated glutamine caused an enhancement of N-methyl-D-aspartate (NMDA) receptor-mediated [3H]catecholamine release equivalent to that produced by high concentrations (up to 100 microM) of exogenous glutamate. In both striatal slices and primary cultures kynurenate increased glutamate release in the presence of 500 microM glutamine, while kainate either had no effect or decreased glutamate levels in the presence of glutamine. Since several presynaptic modulators of release did not affect the glutamate release produced by glutamine in slices, vesicular release of glutamate from nerve terminals was probably not involved in the effects of the exogenous glutamine. The similarities between striatal slices and primary striatal cultures indicate that enzymatic conversion of glutamine to glutamate within glia may be an important factor in the glutamine-mediated elevation of extracellular glutamate levels.

Analysis of Variance↗
PubMed1995

The SA gene: predisposition to hypertension and renal function in man.

1. The SA gene is expressed in the kidneys and is associated with hypertension in man and experimental animal models. Predisposition to hypertension is associated with renal haemodynamic abnormalities and increased renal SA gene expression. 2. We studied the distribution of the SA gene alleles (A1, A2), defined by the PstI polymorphism, in young adults with contrasting predisposition to hypertension to determine whether genetic variation at the SA gene locus is associated with variations in renal haemodynamics, electrolyte metabolism and the renin-angiotensin system. 3. The frequency of the A2 allele was not significantly different between subjects with high personal and parental blood pressures and subjects with low personal and parental blood pressures. We detected no overall relationship between blood pressures and SA genotype, even after taking sodium intake into account. 4. Glomerular filtration rate, renal blood flow, renal vascular resistance, plasma volume, exchangeable sodium and total body water did not differ according to SA genotypes. Moreover, we detected no significant effect of SA genotype on circulating components of the renin-angiotensin system or atrial natriuretic peptide. 5. In our population, genetic variation at the SA gene locus defined by PstI polymorphism does not influence the renal characteristics that contribute to the development of hypertension.

Adult↗
PubMed1995

Low-level hyperbaric exposure antagonizes locomotor effects of ethanol and n-propanol but not morphine in C57BL mice.

Low-level hyperbaric exposure antagonizes a broad range of behavioral effects of ethanol in a direct, reversible, and competitive manner. This study investigates the selectivity of the antagonism across other drugs. C57BL/6 mice were injected with saline, ethanol, n-propanol, or morphine sulfate, and then were exposed to 1 atmosphere absolute (ATA) air, 1 ATA helium-oxygen gas mixture (heliox), or 12 ATA heliox. Locomotor activity was measured from 10 to 40 min following injection. N-propanol produced a dose-dependent depression of locomotor activity from 1.0 g/kg. Morphine produced a dose-dependent stimulation of locomotor activity at doses of 3.75-12.0 mg/kg. Exposure to 12 ATA heliox significantly antagonized the locomotor depressant effects of 1.0 g/kg n-propanol and 2.5 g/kg ethanol, without significantly affecting blood concentrations of these drugs measured at 40 min postinjection. Exposure to 12 ATA heliox did not significantly antagonize the locomotor-stimulating effects of the two morphine doses tested (3.75 and 7.5 mg/kg). These findings suggest that exposure to 12 ATA heliox antagonizes the behavioral effects of intoxicant-anesthetic drugs like ethanol and n-propanol, which are believed to act via perturbation or allosteric modulation of functional proteins, but does not antagonize the effects of drugs like morphine, which act via more direct mechanisms. This demonstration of selective antagonism adds important support for the hypothesis that low-level hyperbaric exposure is a direct mechanistic ethanol antagonist, with characteristics similar to a competitive pharmacological antagonist.

1-Propanol↗
PubMed1995

In vivo and in vitro studies of the role of HDL in platelet activation in normotensive and hypertensive subjects.

The influence of high density lipoproteins (HDL) on platelet function were examined in vivo and in vitro. Intraplatelet, ionised calcium concentrations ([Ca2+]i) were measured using the fluorescent dye Quin-2. In vitro, platelet responses to AVP were measured in the presence or absence of HDL. Pre-treating platelets from normal volunteers with HDL in vitro lowered the [Ca2+]i response to AVP but did not significantly affect basal values. In vivo, plasma lipoprotein profiles in normotensive (13 men, 17 women) and hypertensive (13 men, 11 women) subjects were compared with basal and AVP-stimulated platelet [Ca2+]i values. Plasma [HDL] were not related to basal or stimulated [Ca2+]i. Plasma cholesterol concentrations were higher in the hypertensive patients largely because low density lipoprotein [LDL] were raised in male hypertensive patients. Plasma [LDL] and total plasma cholesterol correlated negatively with basal [Ca2+]i (but not with AVP-stimulated values) only in this subgroup. In hypertensive patients, AVP-stimulated [Ca2+]i (but not basal values) were lower than normotensive controls. From in vitro studies, it may be concluded that the anti-atherogenic properties of HDL might be mediated by inhibition of platelet reactivity. However, ex vivo a negative influence of LDL on basal (not stimulated) [Ca2+]i appears to be paramount.

Adult↗
PubMed1994

Glial development in primary cultures established from normal and X-irradiated neonatal spinal cord.

The glial population of the lumbosacral spinal cord of the rat can be markedly depleted by exposure to ionizing radiation during the first postnatal week. Identification of specific cell populations which survive the exposure to radiation is difficult in situ; therefore, the present investigation used in vitro approaches to address issues related to specific phenotypes and maturational states of glia in cultures derived from non-irradiated (control) and irradiated (experimental) lumbosacral spinal cords of 3-day-old rats. Cultures were established from the spinal cords 2 to 4 hours following irradiation and were compared to cultures from non-irradiated, littermate controls. By 4 days in vitro (DIV) the numbers of cells in experimental cultures were profoundly reduced when compared to controls, and this reduction persisted through the termination of the study (8 DIV). In addition to reduction in numbers, astrocyte phenotypes were altered in experimental cultures, with greater proportions of the astrocyte population being constituted by the flat angular, large angular, and pancake types and a lesser proportion by stellate cells. The non-astrocytic cell types were dramatically reduced as evidenced by the paucity of oligodendrocytes immunoreactive for galactocerebroside and of small, non-process bearing cells binding the lectin, Griffonia (Bandeiraea) simplicifolia, a marker for microglia. Experimental cultures contained an increased incidence of binucleate astrocytes, an increase not restricted to a particular astrocyte phenotype. This study established the feasibility of utilizing this combined in vivo/in vitro approach in assessment of glial populations in immature spinal cords, and further investigations are in progress using this model.

Animals↗
PubMed1994

Low-level hyperbaric antagonism of ethanol's anticonvulsant property in C57BL/6J mice.

This study investigated the ability of hyperbaric exposure to antagonize ethanol's anticonvulsant effect on isoniazid (INH)-induced seizures. Drug-naive, male C57BL/6 mice were injected intraperitoneally with saline, 1.5, 2.0, or 2.5 g/kg ethanol followed immediately by an intramuscular injection of 300 mg/kg of INH. The mice were then exposed to either 1 atmosphere absolute (1 ATA) air, 1 ATA helium-oxygen gas mixture (heliox), or 12 ATA heliox at temperatures that offset the hypothermic effects of helium. Ethanol increased the latency to onset of myoclonus in a dose-dependent manner. Exposure to 12 ATA heliox antagonized ethanol's anticonvulsant effect at 2.0 and 2.5 g/kg, but not at 1.5 g/kg. Ethanol also increased the latency to onset of clonus in a dose-dependent manner beginning at 2.0 g/kg. Exposure to 12 ATA heliox antagonized this anticonvulsant effect. When exposed to 12 ATA heliox, the blood ethanol concentrations at time to onset of myoclonus were significantly higher in mice treated with 2.5 g/kg of ethanol as compared with blood ethanol concentrations of mice exposed to 1 ATA air. These findings extend the acute behavioral effects of ethanol known to be antagonized by hyperbaric exposure and support the hypothesis that low-level hyperbaric exposure blocks or reverses the initial action(s) of ethanol leading to its acute behavioral effects.

Animals↗
PubMed1994

Further studies of the role of hyperthermia in methamphetamine neurotoxicity.

The depletion of striatal dopamine (DA) that can occur after methamphetamine (METH) administration has been linked to METH-induced hyperthermia. The relationship between METH-induced hyperthermia, neurotoxicity (striatal DA depletions) and compounds that protect against METH neurotoxicity was further investigated in this study. Typically, rats exposed to METH die when their body temperatures exceed 41.3 degrees C but such hyperthermic rats can be saved by hypothermic intervention. Subsequently, rats saved by hypothermic intervention have greater depletion of striatal DA at an earlier time of onset (18 hr or less post-METH) than do METH-exposed rats that do not attain such high temperatures. Striatal damage was present 3 days post-METH in these hyperthermic rats, as assessed by silver degeneration of terminals and increases in the astrocytes that express glial fibrillary acidic protein immunoreactivity. By contrast, alterations in the number of [3H]dizoclipine (MK-801) binding sites in cortical or striatal membranes at 1, 3 or 14 days post-METH were not detected. The experiments showed that mean and maximal body temperature correlated well with striatal DA concentrations 3 days post-METH (r = -0.77, n = 58), which suggests a role for hyperthermia in METH neurotoxicity. However, hyperthermia (alone or with haloperidol present) induced by high ambient temperatures did not deplete striatal DA in the absence of METH. Haloperidol, diazepam and MK-801 all reduced METH-induced striatal DA depletion to a degree predicted by their inhibition of hyperthermia and increased ambient temperature abolished their neuroprotection. Although an interleukin-1 receptor antagonist reduced maximal body temperature enough to lower the lethality rate, it did not reduce the temperature sufficiently to block METH neurotoxicity. It was concluded that short- and long-term decreases in striatal DA levels depend on the degree of hyperthermia produced during METH exposure but cannot be produced by hyperthermia alone. In addition, several agents that block DA depletions do so by inhibiting METH-induced hyperthermia. Finally, the results suggested a role for interleukin-1 in the extreme hyperthermia and lethality produced by METH.

Animals↗
PubMed1993

Renal and hormonal effects of chronic inhibition of neutral endopeptidase (EC 3.4.24.11) in normal man.

1. Acute pharmacological inhibition of the enzyme neutral endopeptidase (EC 3.4.24.11), which cleaves the cardiac hormone atrial natriuretic peptide, raises endogenous levels of the hormone. Short-term administration of inhibitors causes natriuresis and diuresis in normal and hypertensive subjects; we report here the effects of an orally active neutral endopeptidase inhibitor (candoxatril, 200 mg) given twice daily for 10 days to normal salt-replete male subjects (n = 12) in a placebo-controlled cross-over study. 2. Candoxatril administration caused a transient natriuresis on day 1 of treatment, but this was not sustained, and cumulative sodium excretion at the end of the study was not altered by active therapy [1720 +/- 40 versus 1734 +/- 57 (placebo) mmol; means +/- SEM]; exchangeable body sodium content was similarly unchanged. However, urinary cyclic GMP excretion was elevated throughout the active treatment phase when compared with placebo. 3. Although a change in plasma levels of atrial natriuretic peptide could not be demonstrated, platelet atrial natriuretic peptide binding sites were reduced by active treatment [23 +/- 3 versus 39 +/- 4 (placebo) fmol/10(9); P < 0.001]. 4. Basal blood pressure and heart rate were not affected by candoxatril treatment. After 10 days of therapy subjects were given incremental infusions of angiotensin II (2, 4 and 8 ng min-1 kg-1) followed by phenylephrine. Although active therapy had not altered basal plasma concentrations of active renin and angiotensin II, levels of angiotensin II during infusion of the octapeptide were higher during the active phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

A comparison of the potassium and magnesium-sparing properties of amiloride and spironolactone in diuretic-treated normal subjects.

1. The relative potencies of amiloride (5 and 20 mg) and spironolactone (25 and 100 mg) for plasma and erythrocyte electrolytes were investigated in a double-blind, randomised, balanced, crossover study in 12 normal men treated concomitantly with hydrochlorothiazide 100 mg daily for 1 week. 2. Participants satisfied an a priori requirement for a fall in plasma potassium concentration of at least 0.5 mmol l-1 after 7 days of treatment with hydrochlorothiazide alone. 3. After hydrochlorothiazide alone, plasma potassium and sodium concentrations fell (P < 0.001). There were associated reductions in erythrocyte sodium (P < 0.01). Plasma magnesium concentration did not change, although erythrocyte magnesium decreased (P < 0.001). 4. Both amiloride and spironolactone attenuated the thiazide-induced fall in plasma potassium (relative potency, amiloride:spironolactone 10:1, 95% confidence interval 6.3-16.2:1). Amiloride but not spironolactone was associated with a dose-related increase in plasma magnesium; a relative potency estimation was precluded. There was little evidence of influences of amiloride or spironolactone on erythrocyte electrolytes. 5. On a weight basis, amiloride is ten times more potent than spironolactone as a potassium-sparing agent in diuretic-treated subjects but neither agent had major effects on erythrocyte potassium. The drugs may have divergent actions on magnesium handling; hydrochlorothiazide alone had no influence on plasma magnesium.

Adult↗
PubMed1993

Do diuretics cause magnesium deficiency?

1. Controlled trials, of which there are few, do not substantiate claims that diuretics play a role in causing magnesium deficiency. Consequently, the vast majority of patients taking conventional doses of thiazide diuretics (i.e. bendrofluazide 2.5 mg day-1 or equivalent) do not need magnesium supplements. On balance, potassium-sparing diuretics tend to increase serum and intracellular magnesium content; this should not be taken as evidence of prior magnesium deficiency. It remains theoretically possible that large doses of loop diuretics given more than once daily for long periods could induce negative magnesium balance and magnesium deficiency. However, it has been difficult to run appropriately controlled trials in conditions where such therapy is needed (i.e. heart failure) and until more reliable information becomes available no absolute recommendation can be made. 2. Methods for the measurement of intracellular free magnesium levels are now available and are more relevant to the assessment of magnesium deficiency than total intracellular magnesium content; the complex relationship between intracellular free and total magnesium content remains to be defined. Future work involving the effect of diuretics on intracellular free magnesium measurements should make every attempt to avoid the errors of trial design and multiple publication that litter current and past literature.

Animals↗
PubMed1992

The development of the acid deposition and oxidant model (ADOM).

This paper describes the development and testing of the Acid Deposition and Oxidant Model (ADOM), a nine-year project funded by a consortium consisting of Environment Ontario, Environment Canada, the German Umweltbundesamt, and the Electric Power Research Institute. The project consisted of three major phases: a design phase, an implementation phase, and an evaluation phase. In the design phase, the system being modeled was divided into its components-transport, gas phase chemistry, aqueous phase chemistry, dry deposition and cloud processes. The formulation of the modules for each of these processes was guided by the requirement that the modules reflect the state of the art, and at the same time be consistent with the available numerical resources. In the implementation phase, submodels were constructed, and then subjected to several tests, which included mathematical consistency checks, sensitivity studies, and evaluation against field and laboratory data. The modules were then assembled and interfaced with the input data sets. The codes for the modules as well as the overall model were vectorized to take advantage of the capabilities of supercomputers such as the CRAY. The North American and West German versions of the model are being tested against data collected in North America and in Europe. This paper describes the evaluation of ADOM with data associated with a regional ozone episode in Ontario in June 1983, and measurements made during an experiment to study the scavenging characteristics of spring storms in the central and northeastern United States in April 1981.

Journal Article↗
PubMed1992

Candoxatril, a neutral endopeptidase inhibitor: efficacy and tolerability in essential hypertension.

OBJECTIVE: To examine the efficacy and tolerability of the neutral endopeptidase inhibitor, candoxatril (UK 79,300) as monotherapy in essential hypertension. DESIGN: Double-blind, placebo-controlled, parallel-group study of 28 days' duration. SETTING: Three hospital outpatient departments participating in the Glasgow Blood Pressure Clinic (Glasgow, UK). PATIENTS: Forty patients with essential hypertension with diastolic blood pressure 95-114 mmHg after a 2-4 week placebo run-in period. INTERVENTIONS: Twenty-eight days' treatment with candoxatril 200 mg twice daily or matching placebo capsules. MAIN OUTCOME MEASURES: Changes in supine and erect blood pressure, and volunteered side effects during double-blind treatment. RESULTS: When measured at the end of the dose interval, the fall in supine blood pressure following candoxatril was not significantly greater than that after placebo. Compared with placebo, a significant effect for candoxatril was seen only for systolic blood pressure in the erect posture; the fall in erect diastolic blood pressure attributable to candoxatril was insignificant. Median plasma atrial natriuretic peptide concentration increased in candoxatril-treated patients and decreased in the placebo group. No stimulation of the renin-aldosterone axis was seen. There was a non-significant trend towards greater urinary excretion of cyclic guanosine monophosphate after candoxatril. Mean plasma concentration of candoxatril at (UK 73,967--the active metabolite of candoxatril) reached a peak of 1010 +/- 437 ng/ml after acute dosing, and 1328 +/- 405 ng/ml after chronic dosing; time to maximum concentration was 2 h in each case. Candoxatril was well-tolerated; numbers of adverse events did not differ between active treatment and placebo. CONCLUSIONS: Although atrial natriuretic peptide levels were significantly increased, candoxatril 200 mg twice daily for 28 days did not produce a clinically relevant fall in blood pressure. Our results cast some doubt upon the role of neutral endopeptidase inhibition in the treatment of unselected hypertensive patients.

Antihypertensive Agents↗
PubMed1991

Long-term ethanol-exposure markedly changes the cellular composition of cerebral glial cultures.

The vulnerability of morphologically distinct glial subpopulations to ethanol toxicity was surveyed in tissue culture. Secondary cultures of rat glia were examined at intervals during 56 days of ethanol treatment for changes in growth and cellular characteristics. Beginning at 6 days in vitro (DIV), the experimental cultures were treated with either 0.2% or 0.5% (w/v) ethanol in the medium; control cultures received ethanol-free medium. Relative to control cultures, the ethanol-treated cultures exhibited a consistent and dose-dependent suppression in cell number. The development of these cultures was documented with sequential phase-contrast photomicrography. Prior to treatment day 5 (11 DIV), the preponderance of cells were epithelioid in configuration; the astrocytic character of these cells was verified by the immunocytochemical localization of glial fibrillary acidic protein. In control cultures, a subpopulation of process-bearing cells was acquired gradually during the first 3 weeks in culture. The majority of these process-bearing cells were considered to be oligodendrocytes due to their position above the astrocytic carpet and by the immunocytochemical localization of galactocerebroside. Exposure to 0.5% ethanol markedly suppressed the acquisition of process-bearing cells. This ethanol-related suppression of process-bearing cells was apparent in the photomicrographic records of culture development and was confirmed by differential cell counts after 50 days of treatment. These results suggest a possible differential sensitivity of oligodendrocytes of their precursors to ethanol toxicity at elevated (0.5% w/v) concentrations.

Animals↗
PubMed1991

Fibroblast growth factor-induced increased survival of cholinergic mesopontine neurons in culture.

Basic fibroblast growth factor (bFGF) was found to increase the survival of immunocytochemically-identified cholinergic mesopontine neurons in dissociated cell cultures of embryonic rat midbrain. In contrast, cultures exposed to, (a) bFGF and an antibody to bFGF, (b) antibody to bFGF alone, or (c) untreated, contained approximately half the number of cholinergic neurons compared to bFGF-treated cultures.

Animals↗
PubMed1991

Delayed growth and maturation of astrocytic cultures following exposure to ethanol: electron microscopic observations.

This investigation examined the effects of ethanol on the morphologic features of cultured rat astrocytes using a treatment paradigm that provided consistent exposure to ethanol at concentrations of 0.2%, 0.5%, or 1.0% (w/v). Cultures were assessed between 4 and 8 days in vitro during the logarithmic phase of growth; differences in culture growth, cell profile area and ultrastructural configuration were found. A dose-dependent inhibition of culture growth was observed after 48 and 96 h of ethanol exposure. In control cultures, the consequences of culture growth included the progressive crowding of cells, a concomitant reduction in the cell profile area, and increased cell-cell contact. On culture day 8, electron microscopic examination of control cultures demonstrated a complex stratified cellular layer, the junction of cells by puncta adhaerentia and the acquisition of intermediate filament bundles. In contrast, the impaired growth in ethanol-exposed cultures was associated with the retention of an extensive cell profile area suggesting restrained morphologic development. At the electron microscopic level, ethanol-exposed cultures showed a dose-dependent attenuation in both the depth and complexity of the cell layer. These findings indicated that the growth kinetics and morphologic development of astrocytic cultures are vulnerable to ethanol exposure at moderate and high levels. These findings were attributed to both ethanol cytotoxicity and a deprivation of cellular interaction resulting from the restricted population size.

Animals↗
PubMed1991

Renal, cardiovascular and hormonal characteristics of young adults with autosomal dominant polycystic kidney disease.

We studied young adults with autosomal dominant polycystic kidney disease (ADPKD) to determine the characteristics that precede renal impairment. Nineteen affected (A) and 20 unaffected (U) offspring from families with ADPKD showed no significant differences in basal glomerular filtration rate (A: mean 97, SD 19; U: 100, SD 23 ml/min/1.73 m2) or renal functional reserve, but effective renal plasma flow was significantly lower in affected offspring (A: 532, SD 86; U: 605, SD 118 ml/min/1.73 m2, P less than 0.01). Plasma renin activity [A: median 26 (95% CI: 15 to 37); U: 14 (11 to 27) microU/ml, P less than 0.05, one-tailed test] and aldosterone [A: 2.5 (2.0 to 3.0), U: 1.0 (1.5 to 2.0) micrograms/100 ml, P less than 0.04, one-tailed test] were increased in affected offspring despite the higher systolic blood pressure (A: mean 123, SD 5; U: 115, SD 3 mm Hg, P less than 0.02) and significant expansion of total exchangeable sodium (A: 40.8, SD 2.3; U: 38.0, SD 3.5 mmol/kg, P less than 0.01). The ouabain-sensitive component of red cell sodium efflux was less in affected offspring (A: 0.258; SD 0.040; U: 0.288, SD 0.042 hr-1, P less than 0.04) and in both groups was correlated inversely with total exchangeable sodium. Echocardiography revealed no difference in left ventricular mass index nor prevalence of mitral valve prolapse. Potential cyst growth factors such as the glucocorticoids and somatomedin C were similar in both affected and unaffected groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗