Biomedical subjects

R Dawson

Publications and source records attributed to R Dawson.

At least 127 records · Page 7Linked to original sources

PubMed1988

Chronic weight loss in lean and obese rats with a brain-enhanced chemical delivery system for estradiol.

Studies were undertaken to determine the effects on body weight and food intake of a chemical delivery system which preferentially delivers estradiol (E2) to the brain and there serves as a source for the sustained release of the steroid. We injected intravenously various doses of this estradiol-chemical delivery system (E2-CDS), E2-valerate (E2-VAL) or the dimethyl sulfoxide (DMSO) vehicle to young lean male rats and monitored body weight and 24 hr food intake for 39 days postinjection. E2-VAL caused a transient reduction in food intake and body weight gain. By contrast, a single injection of E2-CDS caused a chronic, dose-dependent reduction in the rate of body weight gain. In these lean rats, the duration of reduced body weight gain was not correlated with the observed transient reduction in food intake. In aged, obese male rats, E2-CDS caused a marked and chronic dose-dependent reduction in body weight. In contrast to lean rats, E2-CDS caused a long-term reduction in food intake in obese rats. To evaluate the importance of the E2-CDS-induced reduction in food intake in the observed persistent weight loss in obese rats, E2-CDS was administered to a group of obese rats and a second group which received the DMSO vehicle was pair-fed an equivalent amount of food daily. The resulting weight loss in both groups was equivalent. These results show that the enhanced delivery of E2 to the brain with the E2-CDS causes sustained reduction in the rate of body weight gain in lean rats and persistent weight loss in obese animals.

Animals↗

PubMed1988

Equine Cushing's disease: differential regulation of beta-endorphin processing in tumors of the intermediate pituitary.

Equine Cushing's disease is caused by an adenomatous hyperplasia of the intermediate pituitary which secretes high levels of beta-endorphin, ACTH, and other peptide derivatives of POMC. In the present study we found that plasma and cerebrospinal fluid immunoreactive beta-endorphin (i beta-endorphin) levels were 60- and 120-fold higher than control values in horses with Cushing's disease. There were no significant differences in intermediate lobe i beta-endorphin concentrations, although anterior lobe i beta-endorphin was significantly reduced in Cushing's horses, presumably because high levels of circulating glucocorticoids inhibit POMC biosynthesis in corticotrophs. Although the i beta-endorphin concentration of the tumors was not different from that in normal tissue, the posttranslational processing of beta-endorphin in the two tissues differed significantly. In controls, beta-endorphin-(1-31) was extensively processed to N-acetyl-beta-endorphin-(1-31), -(1-27), and -(1-26) and des-acetyl beta-endorphin-(1-27). N-Acetyl-beta-endorphin-(1-27) was the predominant form, constituting 57% of the total i beta-endorphin, whereas beta-endorphin-(1-31) was quantitatively minor (less than 7% of the total immunoreactivity. In adenomatous pituitaries, the processing of beta-endorphin was restricted, significantly increasing the proportions of beta-endorphin-(1-31) and N-acetyl-beta-endorphin-(1-31) and lowering the amounts of N-acetyl-beta-endorphin-(1-27) and -(1-26). These changes in peptide processing were associated with markedly reduced levels of dopamine, suggesting that the dopaminergic neurons that normally control intermediate lobe secretion no longer innervate the hyperplastic tissue. These findings are consistent with evidence that the dopaminergic innervation of the intermediate pituitary regulates the posttranslational processing and release of beta-endorphin.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1987

Flurothyl seizure thresholds in mice treated neonatally with a single injection of monosodium glutamate (MSG): evaluation of experimental parameters in flurothyl seizure testing.

Monosodium glutamate (MSG) administration to neonatal rodents produces convulsions and results in numerous biochemical and behavioral deficits. These studies were undertaken to determine if neonatal administration of MSG produced permanent alterations in seizure susceptibility, since previous investigations were inconclusive. A flurothyl ether seizure screening technique was used to evaluate seizure susceptibility in adult mice that received neonatal injections of MSG (4 mg/g and 1 mg/g). MSG treatment resulted in significant reductions in whole brain weight but did not alter seizure threshold. A naloxone (5 mg/kg) challenge was also ineffective in altering the seizure thresholds of either control of MSG-treated mice. Flurothyl ether produced hypothermia which was correlated with the duration of flurothyl exposure; however, the relationship of hypothermia to seizure induction was unclear. Flurothyl seizure testing proved to be a rapid and reliable technique with which to evaluate seizure susceptibility.

Animals↗

PubMed1987

Activation of calmodulin by the essential trace element chromium.

Chromium at very low concentrations is an essential trace element--at higher concentrations it is associated with contact dermatitis and other toxicity problems. Its ionic radius is just outside that of other metal cations which have been found to activate calmodulin in vitro. We found that chromium was able to activate calmodulin at two different concentration ranges--over the micromolar range (which would probably never be achieved in man) a small degree of activation was found--but a much greater activation (76% of the maximum possible) was also found at nanomolar concentrations of chromium. In welders, who work with stainless steel and who were not reporting any physical symptoms of chromium toxicity, red cell chromium levels were 28.2 +/- 3.3 nM (n = 22) compared to 7.5 +/- 0.7 nM (n = 11) for normal controls. Thus, the concentration of chromium experienced within the cell can be of the order which will activate calmodulin in vitro. The possibility exists, therefore, that inappropriate activation of calmodulin could be relevant to chromium biology possibly contributing to the symptoms of chromium toxicity.

Animals↗

PubMed1987

Yohimbine-induced alterations of monoamine metabolism in the spontaneously hypertensive rat of the Okamoto strain (SHR). II. The central nervous system (CNS).

Steady state levels of monoamine neurotransmitters were examined in SHR, a genetic model of hypertension and compared to its normotensive control (WKY). SHR and WKY were also challenged with alpha 2-adrenergic antagonists, (yohimbine, YOH, idazoxan) or an alpha 1-antagonist (prazosin) and alterations in CNS monoamine metabolism evaluated. SHR were found to have elevated levels of NE and 5-HT in a number of brain regions involved in cardiovascular control when compared to WKY. DA levels and metabolism were also altered in the SHR. Blockade of alpha 2-adrenoceptors and other direct and indirect actions of YOH exacerbated the abnormalities in central monoaminergic neurotransmission in SHR. Significant decreases in NE content were produced by YOH or idazoxan treatment in both SHR and WKY, presumably the result of the inhibition of alpha 2-adrenoceptor medicated presynaptic control of NE release. YOH treatment abolished the differences in steady state levels of NE between SHR and WKY, however, idazoxan did not. YOH administration resulted in significant increases in DA and 5-HT in a number of brain regions of both SHR and WKY. Idazoxan or prazosin produced few changes in DA and 5-HT metabolism except for increases in DA content in the spinal cord and brainstem of SHR given idazoxan. The YOH-induced increases in DA and 5-HT content of SHR were of a greater magnitude than the WKY in several brain regions. DOPAC levels were significantly elevated by YOH in both WKY and SHR, reflecting the antidopaminergic properties of YOH. 5-HIAA content was significantly reduced by YOH in a number of brain regions in both SHR and WKY, however, this effect was attenuated in several brain regions in SHR. The results of the present study demonstrate the multifarious nature of the alterations in CNS monoamine metabolism in SHR.

Animals↗

PubMed1987

Yohimbine-induced alterations of monoamine metabolism in the spontaneously hypertensive rat. I. The peripheral nervous system.

The effects of alpha 2 adrenoreceptor blockade with YOH on blood pressure, plasma catecholamines and norepinephrine (NE) stores in kidney, adrenal and spleen of spontaneously hypertensive rats of the Okamoto strain (SHR) and Wistar-Kyoto (WKY) control animals were examined. YOH administration resulted in a significant (p less than 0.001) reduction in arterial pressure in both SHR and WKY. Plasma NE and EPI were significantly (p less than 0.05) elevated by YOH treatment in both SHR and WKY, but SHR exhibited a significantly (p less than 0.05) greater percent increase in plasma NE than WKY. YOH produced significant decreases in splenic NE content in both SHR and WKY but reduced renal NE content in the SHR only. SHR had significantly higher basal renal NE and DA content and fewer NE uptake (3H-desmethylimipramine binding) sites (p less than 0.05) than WKY. Treatment of SHR or WKY with either the alpha 2-adrenergic antagonist, idazoxan, or the alpha 1-antagonist, prazosin, failed to significantly alter renal NE levels from those found after saline injection. The enhanced YOH-induced renal NE depletion in SHR suggests an alteration in the presynaptic control of NE release in the genetically hypertensive rat, however, the effects of YOH in the SHR may be mediated by mechanisms unrelated to alpha 2-adrenergic receptors.

Adrenal Glands↗

PubMed1987

Two renal alpha 2-adrenergic receptor sites revealed by p-aminoclonidine binding.

[3H]p-aminoclonidine [3H]PAC, a specific alpha 2-adrenergic agonist, was used to characterize alpha 2-adrenoceptor binding in rat renal membranes. Rosenthal plots demonstrated two binding sites with Kds of approximately 1.7 and 14.2 nM and Bmaxs (maximum binding) of 47.3 and 218.8 fmol/mg protein for the high- and low-affinity sites, respectively. These characteristics were confirmed by estimate of Kd parameters based on association and dissociation experiments. Pseudo-Hill coefficients generated from drug inhibition experiments were all less than unity, suggesting differential binding at two alpha 2-adrenoceptor binding sites. Specific alpha 2-adrenergic agonists exhibited greater binding affinity to both sites than did nonspecific drugs, and all drugs displayed greater affinity for the high- than the low-affinity binding site. Both guanyl nucleotides and sodium chloride inhibited [3H]PAC binding more at the high-affinity than at the low-affinity site. Renal denervation resulted in significant upregulation of receptor density only at the high-affinity sites with no change in receptor affinity at either site, suggesting that a majority of the alpha 2-adrenoceptors in the kidney are postsynaptic. Thus all lines of evidence in this study indicate that two alpha 2-adrenoceptor binding sites exist in the rat kidney.

Animals↗

PubMed1987

Renal catecholamines and alpha 2-adrenergic receptors in salt-related and genetic hypertension.

Increased dietary salt intake alters renal function which often leads to deleterious cardiovascular consequences. Studies were carried out to characterize the effects of high-salt diets on renal catecholamines and alpha 2-adrenergic receptors. These parameters were evaluated in both genetic and acquired forms of hypertension and also in normotensive rats on high-salt diets. Renal catecholamine content was determined by high-performance liquid chromatography with electrochemical detection. Renal alpha 2-adrenergic receptor-binding studies were performed on whole kidney homogenates using 3H-p-aminoclonidine to label both high- (0.5 nM) and low-affinity (5.0 nM) renal alpha 2-adrenergic receptors. Increased salt intake elevated blood pressure, decreased renal norepinephrine stores and resulted in renal alpha 2-adrenergic receptor up-regulation in deoxycorticosterone acetate salt hypertensive rats, Dahl-S rats and COX-SHR. The decreased renal stores of norepinephrine (NE) appeared to reflect increased renal NE utilization. In contrast, SHR (Charles River) had elevated NE stores and alpha 2-adrenergic receptors while on normal salt diets. Short-term (10-14 days) exposure to high-salt diets had modest effects in normotensive rats or COX-SHR, although it was sufficient to increase low affinity renal alpha 2-adrenergic receptor number. Renal dopamine metabolism was also altered by high-salt diets. These studies demonstrated a relationship between renal NE content and renal alpha 2-adrenergic receptors. The implications of this relationship and other salt-related changes in renal catecholamine metabolism were discussed as they pertained to hypertension and renal function.

Animals↗

PubMed1987

Presentation of growth velocities of rural Haitian children using smoothing spline techniques.

The examination of monthly (or quarterly) increments in weight or length is important for assessing the nutritional and health status of children. Growth velocities are widely thought to be more important than actual weight or length measurements per se. However, there are no standards by which clinicians, researchers, or parents can gauge a child's growth. This paper describes a method for computing growth velocities (monthly increments) for physical growth measurements with substantial measurement error and irregular spacing over time. These features are characteristic of data collected in the field where conditions are less than ideal. The technique of smoothing by splines provides a powerful tool to deal with the variability and irregularity of the measurements. The technique consists of approximating the observed data by a smooth curve as a clinician might have drawn on the child's growth chart. Spline functions are particularly appropriate to describe bio-physical processes such as growth, for which no model can be postulated a priori. This paper describes how the technique was used for the analysis of a large data base collected on pre-school aged children in rural Haiti. The sex-specific length and weight velocities derived from the spline-smoothed data are presented as reference data for researchers and others interested in longitudinal growth of children in the Third World.

Body Height↗

PubMed1986

Effect of antibiotics and sedatives on normal neutrophil nicotinamide-adenine dinucleotide phosphate-reduced oxidase activity.

The effects of antibiotics and other commonly used medications on the human polymorphonuclear neutrophil leukocytes' (PMNs) nicotinamide-adenine dinucleotide phosphate-reduced (NADPH) oxidase activity have been investigated in vitro. Five antibiotics (penicillin G sodium, cefamandole nafate, metronidazole hydrochloride, clindamycin phosphate, and tobramycin sulfate, and a triple combination of penicillin G sodium-metronidazole hydrochloride-tobramycin sulfate) and two sedatives (morphine sulfate and diazepam) were incubated with normal human PMNs at therapeutic, infratherapeutic, and supratherapeutic drug levels. The superoxide dismutase-inhibitable, NADPH-dependent reduction of cytochrome C in the PMNs was studied after stimulation with formyl-methionyl-leucine-phenylalanine. Tobramycin sulfate and the triple combination of penicillin G sodium-metronidazole hydrochloride-tobramycin sulfate significantly reduced the NADPH oxidase activity at all dosages studied. Clindamycin phosphate, morphine sulfate, and diazepam also showed significant reduction at therapeutic and supratherapeutic concentrations. Penicillin G sodium, cefamandole nafate, and metronidazole hydrochloride did not cause a decrease in enzyme activity at any levels tested. We conclude that NADPH oxidase activity can be adversely affected by the circulating levels of common antibiotics and sedatives.

Adult↗

PubMed1986

PMN superoxide radical production following a metabolic-endocrine simulation of trauma.

Serious infections following major trauma remain inexplicably high. Metabolic and endocrine changes after injury have been suggested as being responsible for many of the documented defects in the polymorphonucleocyte (PMN). The in vitro bactericidal activity of normal human PMNs has been examined in this laboratory by assaying the activity of the PMN membrane bound enzyme NADPH oxidase and hence O2- production of the PMN in a metabolic/endocrine milieu designed to simulate moderately severe trauma. This was accomplished by incubating the PMN with physiological and trauma serum concentrations of insulin, glucose, cortisol, epinephrine, and glucagon. The results indicate that the O2- production of the PMN is significantly enhanced in this environment. It would appear that exogenous glucose alone was responsible for this enhanced O2- production.

Adult↗

PubMed1986

Developmental and sex-specific effects of low dose neonatal monosodium glutamate administration on mediobasal hypothalamic chemistry.

Neonatal administration of monosodium glutamate (MSG) to rodents results in severe damage to the arcuate nucleus of the hypothalamus (AN). MSG-induced AN damage produces profound alterations in hypothalamic neurotransmitters and anterior pituitary function. Reproductive function is also severely compromised in both male and female MSG-treated rats. The present study investigated the developmental sequelae of MSG-induced alterations in hypothalamic monoamine metabolism as well as other aspects of MSG toxicity. Female rats given 4 mg/g of MSG on postnatal days 2 and 4 did not exhibit any significant alterations in hypothalamic monoamine metabolism on postnatal days 21 or 30, however, postpubertal MSG-treated females had significantly reduced levels of mediobasal hypothalamic (MBH) dopamine and DOPAC. In contrast, male MSG-treated rats had slight reductions in hypothalamic and MBH dopamine levels but these reductions were not statistically significant. Male MSG-treated rats did exhibit significant reductions in hypothalamic DOPAC on postnatal day 30 and MBH homovanillic acid (HVA) levels on day 100. Acetylcholine levels were also measured in the MBH and pituitary of adult male MSG-treated rats and found to be unaltered. The developmental profile of hypothalamic monoamines and their metabolites and MSG-induced alterations in dopamine and DOPAC levels in the MBH of female rats are discussed in relation to the neurochemical mechanisms involved in triggering puberty.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

Hypothalamic monoamine metabolism in mice: evaluation of drug challenges and neurotoxic insult.

Hypothalamic monoamine metabolism was evaluated in male and female mice that were administered monosodium glutamate (MSG, 4 mg/g) on postnatal day 4. Hypothalamic dopamine (DA) content was reduced approximately by 22% across all experiments and pituitary DA content was also significantly decreased. Despite reductions in hypothalamic DA levels, MSG-treated mice did not exhibit significant reductions in the levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Hypothalamic monoamine and metabolite profiles in MSG-treated and control mice were examined after the administration of pargyline (PAR), alpha-methyl-p-tyrosine (MPT) or reserpine (RES). DA turnover as indexed by PAR and MPT techniques were not as conclusive as the metabolite measures in suggesting an accelerated DA utilization. MSG-treated mice were more resistant to the DA-depleting actions of reserpine than were the controls. No alterations were found in hypothalamic norepinephrine metabolism in MSG-treated mice, however, after drug challenges, alterations were found in serotonin metabolism. These results indicate the extent and nature of the changes that occur in hypothalamic monoamine metabolism after neonatal MSG treatment. The DA neurons that survive MSG treatment appear to exhibit neurochemical characteristics dissimilar to those of tuberoinfundibular DA neurons. Additionally, the neuropharmacological actions of MPT, PAR and RES are discussed as they relate to hypothalamine monoamine metabolism in the mouse.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

Genetic and salt-related alterations in monoamine neurotransmitters in Dahl salt-sensitive and salt-resistant rats.

Monoamine and metabolite levels were determined in brain regions and in the kidney, heart and adrenals taken from Dahl salt-sensitive (DS) and salt-resistant (DR) rats on either normal (NS) or high (HS) (8.5% NaCl) salt diets. The HS diet significantly (p less than 0.01) elevated blood pressure only in DS rats. DS-HS rats had a significantly (p less than 0.001) greater increase in renal weight and a significantly (p less than 0.001) greater reductions in renal norepinephrine (NE) content and concentration than the DR-HS rats. Cardiac NE content and concentration were also lower (p less than 0.001) in DS rats when compared to DR rats. Adrenal catecholamines were also altered in DS rats. There were genetic differences in brain regional levels of NE, dopamine (DA) and serotonin (5-HT) between DR and DS rats. NE levels were significantly (p less than 0.03) higher in DS compared to DR rats in the pons and hypothalamus. DA levels were significantly (p less than 0.01) greater in the striatum of DS compared to DR rats as were 5-HT levels in the striatum and cortex. HS diets had no effect on brain monoamine or metabolite levels in either DS or DR rats except to elevate cortical 5-hydroxyindoleacetic acid levels. The cardiovascular implications of these genetic and salt-related changes in peripheral and central nervous system monoamines were discussed.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1985

The calmodulin content of normal and leukaemic lymphocytes.

Normal human peripheral blood mononuclear cells (PBMC) and leukaemic cell lines (three of human and one of gibbon origin) were found to contain similar levels of calmodulin (CaM) when expressed relative to the total cell protein. Two of the cell lines examined further were found to contain much higher amounts of CaM per cell (up to 5-fold) than PBMC but this was readily explained by their much greater cell size. Variations in CaM levels were noted during culture of both PBMC and leukaemic cells which were apparently independent of the percentage of cells undergoing active division in these cultures. These results do not support the contention that transformed cells contain a higher proportion of CaM than normal cells.

Calmodulin↗

PubMed1985

Neonatal monosodium glutamate administration alters noradrenergic measures in the brainstem of the mouse.

Mice treated neonatally with MSG (4 mg/g) were compared to saline-injected controls on a number of neurochemical parameters of brainstem noradrenergic activity. MSG treatment resulted in an attenuation of brainstem norepinephrine (NE) decline after alpha-methyl-p-tyrosine administration. Neonatal MSG administration did not result in alterations in the steady state levels of brainstem NE or MOPEG. The synthesis of NE was slightly increased in the pons-medulla of MSG-treated mice as indexed by pargyline-induced NE accumulation. NE release, however, appeared diminished as reflected by a significant (p less than 0.05) decrease in the ratio of normetanephrine to NE found in the pons-medulla of MSG-treated mice given pargyline. The results suggest that MSG-induced damage to the arcuate nucleus produces selective alterations in brainstem NE systems. These alterations may reflect the toxic action of MSG on the opiomelanocortin neurons of the arcuate nucleus or other descending systems that are damaged by MSG. The loss of the descending opiomelanocortin input to the brainstem could result in these types of neurochemical consequences since the pharmacologic action of opiate drugs results in a selective enhancement of brainstem NE turnover in rodents.

Animals↗

PubMed1985

Tuberohypophyseal and tuberoinfundibular dopamine systems exhibit differential sensitivity to neonatal monosodium glutamate treatment.

The arcuate nucleus (AN) is the presumed origin of the dopaminergic innervation of posterior lobe of the pituitary. Posterior lobe dopamine levels were determined in rats that had been neonatally treated with monosodium glutamate (MSG) to lesion the AN. MSG-induced AN damage was confirmed neurochemically, histologically and immunocytochemically. MSG treatment resulted in a substantial loss of AN neurons and approximately a 50% loss of dopamine uptake capacity (Vmax) in the mediobasal hypothalamus. Posterior pituitary dopamine levels were not significantly altered by MSG-induced AN damage. These results suggest that MSG treatment spares the tuberohypophyseal dopamine system and that the AN may not be the sole origin of the dopaminergic innervation of the posterior pituitary.

Animals↗

PubMed1985

Enhanced depressor effect of muscimol in the DOCA/NaCl hypertensive rat: evidence for altered GABAergic activity in brain.

To elucidate the role of the central gamma-aminobutyric acid (GABA) system in the maintenance of deoxycorticosterone (DOCA)NaCl hypertension, the responses of mean arterial pressure (MAP), plasma norepinephrine (NE), and epinephrine (EP) to intracerebroventricular (ICV) administration of muscimol, a GABA agonist, and the responses of MAP to bicuculline, a GABA antagonist, and to clonidine, an alpha 2-adrenoceptor agonist known to lower blood pressure by inhibiting sympathetic tone, were examined in conscious, unrestrained 4 week DOCA/NaCl hypertensive rats and age-matched uninephrectomized control rats. Muscimol (50-1000 ng/300 g, ICV) caused dose-dependent decreases in MAP which were greater in DOCA/NaCl rats than in controls. Basal plasma NE and EP were significantly higher in DOCA/NaCl rats than in controls. Muscimol (1000 ng/300 g, ICV) induced decreases in plasma EP which were greater in DOCA/NaCl rats than in controls without changing NE levels in either group. Bicuculline (3 micrograms/300 g, ICV) caused increases in MAP which were the same in both groups. The depressor response to clonidine (5 micrograms/300 g) was greater in DOCA/NaCl rats than in controls. These results suggest that the activity of the central GABAergic system is altered in the rat with established DOCA/NaCl hypertension and that the alteration in central GABAergic function may be related to the increased sympathoadrenal activity and the maintenance of hypertension in this model.

Animals↗