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Biomedical subjects

E MacDonald

Publications and source records attributed to E MacDonald.

At least 55 records · Page 3Linked to original sources
PubMed1995

Effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on tryptophan and glucose homeostasis in the most TCDD-susceptible and the most TCDD-resistant species, guinea pigs and hamsters.

We have previously reported that in rats 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) lethality is associated (although not necessarily causally) with changes in brain serotonin (5-HT) metabolism. In the present study, we have examined whether this holds for other species by comparing the effect of TCDD in the most TCDD-susceptible and the most TCDD-resistant species, guinea pigs and hamsters, respectively. Body weight gain of guinea pigs exposed to TCDD (0.3-2.7 micrograms/kg) diminished dose dependently, while the effect was marginal in hamsters (900-4600 micrograms/kg). Brain 5-hydroxyindoleacetic acid (the main metabolite of brain 5-HT), brain tryptophan (the precursor amino acid of 5-HT), and plasma free and total tryptophan were not affected at any dose in guinea pigs. In contrast, 4 days after exposure, the levels of plasma free and total tryptophan were consistently increased in hamsters. These, as well as brain tryptophan, were still elevated 10 days after exposure. TCDD did not affect plasma glucose level in either species. Liver glycogen was decreased in a dose-dependent manner in TCDD-treated guinea pigs as well as in their pair-fed controls on day 10. There was no change in liver glycogen in hamsters. The activity of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase was only depressed in hamsters by all doses of TCDD. We conclude that changes in tryptophan metabolism or in carbohydrate homeostasis cannot explain the wide interspecies differences in susceptibility to the acute lethality of TCDD, although they may correlate with some aspects of its toxicity in certain species.

Animals↗
PubMed1995

No evidence for a general change in contractile responsiveness of the mesenteric artery with aging.

Rings of human mesenteric artery (1-3 mm diameter) suspended in Krebs solution were contracted (maximal contraction relative to KCl 80 mM = 100%) by the thromboxane mimetic U46619 (190 +/- 10%), noradrenaline (162 +/- 9%), angiotensin II (107 +/- 11%), and 5-hydroxytryptamine (5-HT) (96 +/- 10%). Reducing extracellular Ca2+ strongly inhibited the maximal contraction to angiotensin II and 5-HT and moderately inhibited the maximal contraction to noradrenaline, but had less effect on the maximal contraction to U46619 (contraction in Ca2+ 1.3 microM was reduced to 24 +/- 5, 20 +/- 3, 38 +/- 4 and 52 +/- 4% respectively of the contraction in 2.5 mM Ca2+). Reducing extracellular Ca2+ lowered sensitivity to 5HT, angiotensin II, and U46619, but did not alter sensitivity to noradrenaline. The EC50 and maximal contraction for each of the 4 agonists did not change with patient age at 2.5 mM Ca2+ or in reduced extracellular Ca2+. It is concluded that aging does not affect the responsiveness of mesenteric arterial smooth muscle to physiological vasoconstrictors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

The Nithsdale Schizophrenia Surveys. XIV: Plasma lipid peroxide and serum vitamin E levels in patients with and without tardive dyskinesia, and in normal subjects.

BACKGROUND: Tardive dyskinesia (TD) may be mediated through free radical damage to neurons. Plasma lipid peroxide levels are a measure of radical damage to fats. Vitamin E is a free radical scavenger. METHOD: One hundred and twenty-eight schizophrenic patients were examined for TD using the Abnormal Involuntary Movements Scale. Blood samples were taken to measure plasma lipid peroxide, serum vitamin E and cholesterol, and vitamin E:cholesterol ratios. Twenty-four patients were also examined in October 1993, January 1994, and April 1994. Biochemical results were compared in 81 patients and 79 normal subjects. RESULTS: Patients with and without TD did not differ in median plasma lipid peroxide and serum vitamin E levels, or vitamin E:cholesterol ratios. Correlations between seasonal change scores in TD and biochemical measurements were low. Lipid peroxide levels were higher and vitamin E:cholesterol ratios lower in patients than in normal subjects. Vitamin E levels were lowest in in-patients and in those living in supported accommodation. CONCLUSIONS: The results do not support the hypothesis that TD is mediated through free radical damage to neurons, but suggest increased free radical activity in schizophrenia.

Adult↗
PubMed1995

Distribution and pharmacology of alpha 2-adrenoceptors in the central nervous system.

Three subtypes of the alpha 2-adrenoceptor have been characterized. The drugs currently available which most specifically activate (e.g. dexmedetomidine) or antagonize alpha 2-receptors (e.g. atipamezole, idazoxan) do not show significant differences in their affinities for the subtypes. The drugs which do show some subtype selectivity (oxymetazoline for alpha 2A; prazosin for alpha 2B and alpha 2C) are not useful for in vivo pharmacology due to their relative nonspecificity in binding to other receptors (e.g. alpha 1-adrenoceptors). By examining the distribution of the mRNA coding for the three subtypes, it has been possible to map those regions in the brain which possess cells which synthetize the distinct subtypes. The mRNA coding for alpha 2A receptors is found throughout the brain, especially in locus coeruleus, a region which contains the cell bodies for the ascending and descending noradrenergic neurones. The mRNA for alpha 2B receptors was only found in thalamus. The alpha 2C mRNA had a wider distribution, in basal ganglia its expression was particularly intense. One must hope that the fact that the receptor subtypes are not uniformly distributed throughout the brain means that new subtype selective drugs will not suffer from the same broad diversity of actions of the present alpha 2-agonists and antagonists.

Animals↗
PubMed1995

The effects of D-cycloserine and MK-801 on the performance of rats in two spatial learning and memory tasks.

The present study was undertaken to investigate the effects of modulation of the N-methyl-D-aspartate (NMDA) receptor on learning and memory. Thus, the performance of rats treated with D-cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor complex, and MK-801, a noncompetitive NMDA receptor antagonist, either alone or concurrently were assessed in radial arm maze and water maze tasks. Administration of MK-801 (0.1 mg/kg, i.p.) impaired acquisition in the water maze (increased escape latency and distance) and working memory in the radial arm maze (increased re-entries) in rats. Moreover, in the radial arm maze, MK-801 disrupted locomotion (increased latencies and decreased arm entries per minute) and impaired the acquisition of reference memory (increased number of errors) performance of rats. D-Cycloserine (0.03, 0.3, 1.0, 3.0, 10 mg/kg, i.p.) had no effects on acquisition or memory performance of control or MK-801-treated rats in either of these tasks. However, D-cycloserine (0.03, 0.3, 3.0 mg/kg) reversed the MK-801-induced disruption in locomotion. Furthermore, 3.0 mg/kg D-cycloserine increased behavioral activity and also decreased the time needed to complete the task in control animals. To conclude, our results suggest that the consequences of NMDA receptor modulation on learning and memory processes and sensorimotor functions may be functionally different or have distinct anatomical locations.

Adaptation, Psychological↗
PubMed1994

Characterization of 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced brain serotonin metabolism in the rat.

It has previously been shown that a lethal dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) increases the brain concentrations of serotonin precursor, tryptophan, and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in TCDD-susceptible Long-Evans but not in TCDD-resistant Han/Wistar rats. In the present study, TCDD (50 micrograms/kg; LD100 for Long-Evans and nonlethal for Han/Wistar rats) enhanced de novo biosynthesis of serotonin in the brain of Long-Evans but not Han/Wistar or food-restricted Long-Evans rats 10 days after exposure. Furthermore, TCDD increased the plasma level of free tryptophan in Long-Evans rats alone, which may be causally related to the observed effects of TCDD on brain tryptophan levels. Administration of hemin modified the time course of TCDD-induced anorexia although 10 day cumulative food consumption was not altered. Hemin tended to attenuate TCDD-elicited increases in brain serotonin turnover, whereas a beta-adrenergic blocker, propranolol, did not. In the majority of Long-Evans rats, TCDD inhibited the main tryptophan degrading enzyme in the liver, tryptophan pyrrolase, but the rest exhibited augmented activities; these effects were not altered by hemin. TCDD increased the plasma levels of nonesterified fatty acids in Long-Evans (five-fold) but not in Han/Wistar rats. A slight elevation (two-fold) was also seen in food-restricted Long-Evans rats. It is concluded that TCDD selectively promotes brain serotonin turnover in Long-Evans rats and this acceleration is related to increased plasma levels of free tryptophan. The inhibition of tryptophan catabolism in the liver and elevation of plasma nonesterified fatty acids may contribute to these changes.

Animals↗
PubMed1994

Dose response and time course of alterations in tryptophan metabolism by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the most TCDD-susceptible and the most TCDD-resistant rat strain: relationship with TCDD lethality.

It has previously been shown that an increase in plasma free tryptophan and a consequent increase in brain serotonin (5-HT) metabolism may be associated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) lethality. In the present study we have studied the dose-response and time course relationships of these phenomena in the most TCDD-susceptible Long-Evans (Turku AB [L-E]; LD50 ca. 10 micrograms/kg) and the most TCDD-resistant Han/Wistar (Kuopio [H/W], LD50 > 7200 micrograms/kg) rat strains. Six days after exposure, there was a dose-related increase in brain 5-HT turnover and plasma free tryptophan in both male and female L-E rats. Pair-fed control rats did not exhibit changes in these parameters. The increases emerged in the dose range known to elicit lethality in L-E rats. Furthermore, the increases in plasma free tryptophan correlated well with the changes in body weight caused by TCDD. In contrast, in H/W rats no such increases in brain 5-HT metabolism or plasma free tryptophan were discernible. Similarly, body weight changes were minor in H/W rats despite almost 1000-fold greater doses of TCDD. Large neutral amino acids other than tryptophan were not markedly changed in the plasma of either rat strain. In attempts to identify the mechanism by which TCDD might affect tryptophan binding to albumin, some other physiological factors known to be carried by albumin were determined. Nonesterified fatty acids (NEFA) in the plasma were dose dependently elevated in male and female L-E rats and there was a moderate or good correlation (r = 0.654 for male and r = 0.731 for female rats) between this parameter and plasma free tryptophan. A moderate increase in plasma NEFA was also seen in pair-fed control rats. Bilirubin was dose dependently increased in the plasma of female L-E rats and there was a good correlation between plasma free tryptophan and total (r = 0.779) or conjugated (r = 0.825) bilirubin. The concentration of albumin tended to be suppressed in female L-E rats. The main tryptophan metabolizing enzyme, hepatic tryptophan pyrrolase, was inhibited in female L-E rats but not in male L-E rats or H/W rats of either gender. Moreover, in female L-E rats the time course for changes in plasma free tryptophan and in body weight was remarkably similar, with both effects emerging early (1 or 2 days) after TCDD exposure and showing progressive development thereafter until the last time point of 10 days.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids, Branched-Chain↗
PubMed1994

Effect of pargyline on brain N-tele-methylhistamine in portocaval-shunted rats: relation to amine neurotransmitters.

HPLC determination of histamine, serotonin, dopamine, and noradrenaline in the brain tissue of rats with portocaval anastomoses (PCA) has revealed a selective increase in histamine concentration. In the posterior hypothalamus, the steady-state level of the amine metabolites showed an inverse pattern; N-tele-methylhistamine (t-MeHA), as estimated by gas chromatography-mass spectrometry, was not changed significantly by portocaval shunting, whereas 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid were more than doubled. Interestingly, the net increase in t-MeHA concentration in response to pargyline (80 mg/kg i.p.) was almost the same for PCA and sham-operated rats. This implies that the great enhancement of the histamine level in this area might be a consequence of the persistent stimulation of its synthesis and the unchanged activity of histaminergic neurons. In the rest of the brain, on the other hand, the steady-state level of t-MeHA was higher after PCA (3.8-fold), as were the levels of 5-HIAA and homovanillic acid. Surprisingly, t-MeHA remained unchanged after monoamine oxidase blockade. Of the pargyline-induced alterations in the concentrations of indoles and catechols, the most pronounced were those in the serotonin level; serotonin was elevated more than twofold in hypothalamus and more than 12-fold in the rest of the brain, with a concomitant 80% decrease in 5-HIAA. The dopamine and, to a much smaller extent, noradrenaline levels were also increased, and the levels of homovanillic acid and 3,4-dihydroxyphenylacetic acid fell below the detection limit. The study suggests that at least two different mechanisms operate in the brains of PCA rats to counteract the excessive synthesis of neuromediators, e.g., increased deposition and increased metabolism.

Amines↗
PubMed1994

Intraruminal fluid administration to goats: effects of handling and fluid temperature.

Physiological stress response to intraruminal fluid administration was studied in 5 female goats. The fluid was given through a stomach tube. The water was cold (10 degrees C) or warm (38 degrees C) and in an amount of 7.5-10% of body weight. Plasma concentrations of adrenaline, noradrenaline and cortisol increased significantly after both treatments. Adrenaline and noradrenaline responses were greater and more longlasting after cold water administration, but there was no difference in cortisol response between cold and warm water. Haematocrit and plasma protein concentrations increased also and the effects of cold water lasted longer. Blood pressure showed a sharp rise of short duration and was independent of water temperature. The immediate tachycardiac response was similar with both treatments, but cold water caused an additional peak 15 min later. The cooling did not increase plasma histamine level. The results suggest that stomach intubation and administration of water into the rumen leads to strong activation of hormonal and cardiovascular stress parameters even in goats well adapted to handling. Low temperature of the fluid further heightens the effect. Warming of fluids to near body temperature before their administration is thus recommended.

Animals↗
PubMed1993

Elevated seizure threshold and impaired spatial learning in transgenic mice with putrescine overproduction in the brain.

We have studied the role of putrescine by using transgenic mouse lines overexpressing the human ornithine decarboxylase gene in most of their tissues. The aberrant expression of the transgene is most strikingly manifested in the brain, leading to an increase of up to 20-fold in putrescine content. We report that the transgenic mice with grossly elevated putrescine in all brain regions analysed (cortex, striatum, hippocampus and cerebellum) showed a significantly elevated seizure threshold to chemical and electrical stimuli, and impaired performance in spatial learning and memory tests. The view that putrescine may be primarily responsible for these changes was supported by the fact that the concentrations of the major neurotransmitter amino acids, glutamate and GABA in the brain, were not changed in the transgenic animals, and by the finding that a further increase in brain putrescine, achieved by inhibition of the catabolism of L-ornithine, appeared to provide additional protection against electroshock-induced seizures. These results suggest that the commonly observed increase in ornithine decarboxylase activity and the massive increase in brain putrescine in connection with neuron damage is a neuroprotective measure rather than a cause of the damage.

Animals↗
PubMed1993

Vasodilator action of cromakalim on human mesenteric artery.

Human mesenteric artery rings (1-3 mm diameter obtained from bowel resections), precontracted with KCl 80 mM, were relaxed by cromakalim (IC50 = 0.39 +/- 0.04 microM, maximum inhibition 69 +/- 2%). Cromakalim was more effective at inhibiting KCl 40 mM than KCl 80 mM. Cromakalim also inhibited contraction produced by noradrenaline, and was a more potent inhibitor of the second phase of the noradrenaline contraction than of the first phase.

Aged↗
PubMed1993

Systemic absorption and systemic effects of ocularly administered dexmedetomidine in rabbits.

Dexmedetomidine is a selective alpha 2-adrenoceptor agonist which has previously been shown to reduce the ocular pressure of normotensive rabbits as well as those with pressures artificially elevated by laser irradiation. In this study instillation of an equivalent hypotensive dose (12.5 micrograms) did not cause changes in heart rate, blood pressure, blood glucose or plasma catecholamine content even though dexmedetomidine could be detected in plasma. However, this dose given intravenously (i.v.) was also without effect. Higher ocular doses resulted in equivalent bradycardia and changes in blood glucose levels as when the dose was given i.v. These two parameters proved to be most sensitive indicators of systemic alpha 2-agonism, blood pressure did not change and plasma catecholamine levels were too low to be reliably assayed. It is concluded that when hypotensive doses of dexmedetomidine are instilled into the eye, intraocular concentrations are sufficiently high to exert pharmacological effects. As it is absorbed into the general circulation, it is diluted such that its systemic effects are minimal.

Absorption↗
PubMed1992

The effects of alpha-2 adrenoceptor antagonist, atipamezole, on spatial learning in scopolamine-treated and aged rats.

In order to study whether noradrenergic drugs improve age-related cognitive dysfunctions the present experiments investigated whether atipamezole, a selective and specific alpha-2 antagonist, improves spatial learning impairment due to cholinergic blockade (scopolamine 0.8 mg/kg) or aging in rats. Previously, it has been shown that atipamezole dose-dependently (0.03-3.0 mg/kg) increases the turnover of noradrenaline in rat brain. According to the present results, atipamezole (0.1, 0.3, 0.6 mg/kg) did not affect spatial learning/memory when assessed in a free swim trial of the water maze task in control rats. Furthermore, atipamezole (0.1, 0.6 mg/kg) did not improve learning deficit in scopolamine treated young rats. Higher doses (greater than or equal to 1.0 mg/kg) of atipamezole could not be tested, because they induce floating behaviour in rats. In aged rats, which were screened to be impaired in the initial acquisition of the water maze task, 0.3 mg/kg atipamezole impaired further learning of this task. Because previous studies suggest that age-related learning impairment in the water maze may be, at least partly, due to a cholinergic deficit, the present results suggest that atipamezole which increases the release of noradrenaline in brain does not alleviate this learning deficit.

Adrenergic alpha-Antagonists↗
PubMed1992

Age-associated changes in mesenteric arteries.

Vascular disease increases in incidence with age and is the commonest cause of morbidity and mortality among elderly people. Hypertension is associated with hypertrophy of the arterial media. This study was designed to investigate changes in arterial structure that may occur with age independent of blood pressure. Collapsed sections of human mesenteric arteries (external diameter 2-3 mm) were measured using a semi-automatic image analysis system. There was a nonlinear increase in both the wall/lumen area ratio and the relative intimal area with age. There were no significant relationships between blood pressure and either the wall/lumen ratio or the relative intimal area.

Adult↗