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Biomedical subjects

R F Walker

Publications and source records attributed to R F Walker.

At least 55 records · Page 3Linked to original sources
PubMed1988

Anxiety and the dexamethasone suppression test monitored with saliva.

To assess the effect of anxiety on response to the Dexamethasone Suppression Test (DST), cortisol concentrations were determined in patients who had various diagnoses, with anxiety as a secondary characteristic. Saliva was collected before and after venepuncture at 4:05 PM following completion of the Leeds Questionnaire at 3:00 PM. Matrix effects, which caused an initial artefactual decrease in cortisol levels in some saliva samples in patients with high anxiety, could be eliminated by repeated freezing/thawing. There was no significant difference between salivary cortisol concentrations before and after venepuncture, indicating that variability in response to the DST is not a correlate of anxiety and stressful venepuncture. There was no association between anxiety scores and plasma or salivary cortisol values: thus, anxiety is unlikely to be a major contributory cause of nonsuppression of hypercortisolemia in the DST.

Adult↗
PubMed1988

Factors affecting serotonin uptake into human platelets.

Because of complexities in platelet serotonin uptake dynamics, we studied the influence on the time of day and year as well as the subject's age on uptake parameters. While the assay itself was quite reproducible, and the kinetic parameters of 5 HT uptake were stable over a few days, at a given time, within an individual, the variance was quite large when samples from different times of the day or year or from different individuals were compared. An inverse relationship between Vmax (moles/cell number/time) and platelet number was found in data from a group of individuals, suggesting regulation of Vmax not at the level of uptake capacity per cell, but in a manner that somehow takes into consideration the number of platelets in the subject's plasma. Indeed, expressing Vmax in a new way (called "total Vmax"), not based on Vmax "per cell" or "per 10(7) cells" but for the total number of platelets in the volume of PRP used, greatly reduced the scatter in the between-individuals and across-time data. While Vmax (moles/cell number/time) exhibited only a trend toward reduction with age, for example, the decline in total Vmax with subject age was statistically significant. It is suggested that total Vmax (moles/time) may be a more physiologically relevant expression for an uptake function than Vmax (moles/time/cell number).

Adult↗
PubMed1988

Specific uptake of serotonin by murine macrophages.

In view of the reported immunomodulatory properties of the monoaminergic neurotransmitter, serotonin (5HT), this study aimed to assess whether 5HT specifically associates with immunocompetent cells. Although murine splenocytes appear to lack high-affinity membrane binding sites for 5HT, they do possess a specific, active, 5HT uptake system similar in affinity (Km = 40 nM) to that described in platelets. This uptake system appears to be confined to macrophages. Further, macrophages rapidly metabolize 5HT to its 5-hydroxyindole acetic acid metabolite. Specific uptake of serotonin by macrophages may thus constitute an important mechanism whereby this amine is able to regulate immune function.

Animals↗
PubMed1988

Binding of growth hormone-releasing hormones and enkephalin-derived growth hormone-releasing peptides to mu and delta opioid receptors in forebrain of rat.

The purpose of this study was to compare the binding potency to opioid receptors of met-enkephalin-derived, hypophysiotrophic peptides with their reported growth hormone (GH)-releasing strengths in vitro and further, to determine the relative selectivity of each peptide for mu and delta opioid binding sites in the forebrain of the rat. A series of (GH)-releasing pentapeptides and hexapeptides (GHRP's), as well as rat (rGHRH) and human (hGHRH) growth hormone-releasing hormones were tested for preferential binding to specific opioid receptors. The site selectivity of each peptide was determined by its ability to compete for binding with synthetic ligands for mu (Tyr-D-Ala-Gly-MePhe-Gly-ol; DAGO) and delta ([D-Pen2,5]-enkephalin; DPDPE) opioid receptors. The various peptides differed in their selectivities for the two opioid receptors in that most of the GHRP's were mu-selective, while the naturally occurring GHRH's were delta-selective. Amidation of the C-terminal decreased delta selectivity. Besides affecting selectivity for the site, structural changes that enhanced GH-release by enkephalin-derived peptides also decreased their potency to compete for opioid binding sites. For example, dose-response curves for His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (SK&F 110679) inhibition of the binding of DAGO and DPDPE yielded IC50's of 6 and 20 microM, respectively. In contrast, Tyr-D-Trp-Gly-Phe-Met-NH2 (BI360), which is 1 X 10(3) times weaker than SK&F 110679 in releasing GH, had IC50's of 0.1 microM and 0.08 microM for inhibition of the binding of DAGO and DPDPE, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Circadian patterns of serotonin (5-HT) accumulation after pargyline treatment in the rat hypothalamus during development.

The purpose of this study was to determine if developmental changes in serotonin (5-HT) synthesis occur during maturation of the 5-HT circadian rhythm in the rat hypothalamus of 10- to 35-day-old rats. Pargyline (75 mg/kg, s.c.), a monoamine oxidase (MAO) inhibitor, was administered 30 min prior to decapitation. Hypothalamic 5-HT concentrations after pargyline treatment were measured at six time points over a 24-hr interval in male and female rat pups at 10, 20, 30 and 35 days of age. Daily fluctuations in hypothalamic 5-HT accumulation were detectable as early as 10 days of age in rats of both sexes. Since the influence of MAO on hypothalamic 5-HT concentrations was eliminated by pargyline treatment, the findings suggest that changes in tryptophan hydroxylase activity contribute significantly to daily and age-related patterns of 5-HT accumulation in the rat hypothalamus during development. Circadian rhythms in hypothalamic norepinephrine (NE) and dopamine (DA) also occurred during development; however, sex differences were not detected for these biogenic amines. Since catecholamine catabolism is not exclusively mediated by MAO, our findings are insufficient to conclude whether or not sex differences actually exist in patterns of these monoamines.

Animals↗
PubMed1988

Androstenedione rhythms in saliva in congenital adrenal hyperplasia.

Serial samples of saliva were collected at home by 17 patients being treated for congenital adrenal hyperplasia to determine the circadian rhythm of androstenedione as an index of therapeutic control. Single samples of blood for measurement of plasma testosterone, 170H-progesterone, and androstenedione concentrations were collected from these and a further seven patients for comparison. Plasma androstenedione concentrations showed a close correlation with plasma concentrations of 170H-progesterone and testosterone. There was a strong correlation between the salivary androstenedione profiles and plasma testosterone concentrations in pubertal girls. Concentrations of androstenedione in saliva decreased during the day but remained raised at each sampling time in relation to plasma testosterone concentrations. Salivary androstenedione profiles are shown as nomograms to distinguish the degree of therapeutic control. The concentration of androstenedione, measured in plasma or saliva, is an alternative marker to monitor control of treatment in congenital adrenal hyperplasia. The measurement in saliva is a useful index of androgen production when blood sampling is difficult.

Adolescent↗
PubMed1988

Alpha-adrenergic control of serotonin release from rat pineal glands.

This study was designed to determine if norepinephrine (NE) stimulated release of pineal serotonin (5-HT) is receptor mediated and to identify the receptor(s) most influential in the release process. Efflux of 3H-5-HT from rat pineals in vitro was significantly increased within 5 min after NE was added to perifusion buffer in concentrations ranging from 0.1 to 3 microM. 3H-5-HT was not simply displaced from pinealocytes by NE, since buffer containing 3 microM 5-HT had no effect on 3H-5-HT efflux. Furthermore, NE enhanced 3H-5-HT secretion by a stereospecific process, since d-NE was significantly less effective than l-NE. The alpha 1-adrenoreceptor agonists phenylephrine and cirazoline simulated the effects of NE, significantly increasing 3H-5-HT efflux in single and sequential stimulations. Furthermore, the alpha 1-adrenergic receptor antagonist prazosin reduced NE-stimulated release of 3H-5-HT. In contrast, the alpha 2- and beta-adrenoreceptor agonists naphazoline or clonidine and isoproterenol, respectively, were without effect. In addition, the alpha 2- and the beta-receptor antagonists rauwolscine and timolol, respectively, had no effect on NE-stimulated release of pineal 5-HT. In conclusion, the data show that NE stimulates 5-HT release within minutes from rat pineal glands in vitro. Unlike the pineal mechanism controlling melatonin synthesis, which has a longer latency and requires beta-adrenergic receptor activation, 5-HT release is regulated by activation of alpha 1-receptors. Thus, the pineal may be useful model for studying how separate intracellular processes are controlled by common neural stimuli.

Animals↗
PubMed1987

Serotonin pharmacodynamics in hypothalamic tissues from young and old female rats.

The purpose of this study was to determine the effects of aging on serotonin (5-HT) pharmacodynamics in rostral hypothalamic tissue of female rats. Monoamine oxidase (MAO) activity was greater in old (19 months old) than in young (3 months old) animals. This difference resulted from a higher Vmax for hypothalamic MAO from old rats, whereas Km's were comparable in both age groups. These enzymatic changes were accompanied by altered uptake and release of [3H]5-HT. Although [3H]5-HT uptake was not different at equilibrium between groups, the equilibrium state was achieved more slowly by hypothalamic tissue from old rats. Basal and potassium-stimulated efflux of [3H]5-HT was significantly greater in old rats compared with young ones and these differences remained during multiple depolarizations. The findings of this study suggest that synaptic levels of hypothalamic 5-HT increase with age. Since pharmacological simulation of this condition in young rats produces physiologic dysfunction, the spontaneous changes that occur in hypothalamic 5-HT pharmacodynamics during aging have the potential to promote senescence.

Aging↗
PubMed1987

Molecular mechanisms controlling norepinephrine-mediated release of serotonin from rat pineal glands.

This study describes various elements of the mechanism controlling norepinephrine (NE)-mediated release of serotonin (5HT) from rat pineal glands. After radiolabelling the endogenous pool of pineal 5HT with 3H-5HT, individual pineal glands were exposed to depolarizing buffers or those containing NE. Although 3H-5HT was not released by 50mM potassium, efflux of the indoleamine was increased by NE. Alpha-adrenergic receptors mediate the effects of NE as indicated by the fact that phenylephrine but not isoproterenol, a beta receptor agonist, also enhanced 3H-5HT release. This hypothesis is supported further by the fact that prazosin and phentolamine (alpha-antagonists) but not sotolal (beta-antagonist), inhibited the stimulatory effects of NE on 5HT release. In order to determine the intracellular second messenger involved in the 5HT release process, pineals were incubated with 8-bromo cAMP or the phorbol ester, PMA. PMA simulated the effects of NE and phenylephrine on 3H-5HT efflux, while cAMP had no effect. Furthermore, calcium-, phospholipid-dependent protein kinase activities in pineal homogenates were responsive to NE. These findings suggest that 5HT secretion from rat pinealocytes occurs rapidly in response to NE signals that act through alpha-adrenergic receptors in concert with phospholipid dependent protein kinase(s). These molecular processes are different from those involved in melatonin metabolism and may represent a general mechanism for regulating 5HT release in the brain.

Animals↗
PubMed1987

Platelet serotonin uptake: methods and strain differences.

The pharmacokinetic properties of platelets make these vascular elements a potential and convenient model for serotoninergic neurons. Because we encountered several difficulties in preliminary platelet serotonin (5HT) uptake assays, we explored the influence of several assay factors on the parameters obtained. We found that a citrate-dextrose anticoagulant stabilized platelet 5HT uptake even at room temperature. More rapid wash rates during the filtration following the assay incubation gave higher apparent uptake affinities. Platelets from an inbred strain of rats exhibited less variability in Vmax than cells from outbred strains studied. These findings, in conjunction with a human twin study also suggesting that variance in platelet 5HT uptake increases with genetic diversification, demonstrate some additional confounding factors in platelet 5HT uptake studies.

Animals↗
PubMed1987

Assessment of adrenocortical activity in term newborn infants using salivary cortisol determinations.

Salivary cortisol concentrations were collected every 2 hours over a 24-hour period in eight healthy 2-day-old term neonates. Two maxima in cortisol output were noted, neither being related to the time of day or time since birth. Salivary cortisol concentrations ranged from 2.5 to 57.4 nmol/L (0.09 to 2.08 micrograms/dL), and throughout the 24 hours showed considerable variation (21% to 42%) not related to the state of arousal. The validity of the method was confirmed by collecting matched plasma and saliva samples from another group of 36 neonates. The correlation between plasma and saliva cortisol was r = 0.83. We suggest that salivary cortisol is a useful, noninvasive method of studying adrenocortical status in the newborn infant.

Adrenal Cortex↗
PubMed1987

Noradrenergic stimulation of serotonin release from rat pineal glands in vitro.

The pharmacodynamics of serotonin (5-hydroxytryptamine; 5-HT) uptake and release were studied in rat pineal glands. Initially, uptake was tested by incubating pineals with several concentrations of [3H]5-HT. The incubation media also contained [14C]mannitol to which cells are impermeable. Since [14C]mannitol accumulates only in extracellular spaces, the radio-labelled sugar was used to determine the differential distribution of [3H]5-HT in pineal compartments. Intracellular accumulation of 3H in pineal glands increased linearly as a function of time for [3H]5-HT concentrations ranging from 1 to 10 mumol/l. The ratio of 3H to 14C also increased for the same time-interval, indicating that the glands accumulated [3H]5-HT preferentially in non-extracellular spaces. [3H]5-HT accumulated in pineal glands which were denervated for more than 7 days before testing, suggesting that uptake is not restricted to adrenergic terminals but also occurs in pinealocytes. In addition to uptake, spontaneous and noradrenaline-stimulated release of [3H]5-HT was tested in perifusion and/or step-transfer systems. Spontaneous release of [3H]5-HT was biphasic consisting of rapid and slower efflux phases. In contrast, release of [14C]mannitol was monophasic, characterized exclusively by rapid efflux. Since [14C]mannitol does not enter cells, the rapid and slower phases of [3H]5-HT efflux may represent release from pineal extracellular and intracellular compartments respectively. The identity of [3H]5-HT in pineal glands and perifusion media was confirmed by thin-layer chromatography. When L-noradrenaline was added to the perifusion media, [3H]5-HT efflux during the slower phase of release was significantly increased above the non-stimulated state.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Determination of ovarian steroid hormone levels in saliva. An overview.

Assessment of ovarian activity based on saliva samples has proven particularly useful in studies of women in well-developed countries and is potentially of even greater value in women of lower socioeconomic status in Third World countries. Assay techniques suitable for measuring low concentrations of steroids in saliva have become available only recently, so data derived from salivary sampling regimens are far less extensive than those based on plasma or urinary sampling procedures. Collecting saliva is an attractive alternative to the more conventional procedures because of the ease of frequent collection and freedom from religious and social constraints. Simple, direct assays for salivary progesterone have been established, but those for estradiol require considerably more research before becoming useful in routine practice. Predicting ovulation with data derived from saliva sampling awaits the development of more suitable assays for salivary estradiol.

Estradiol↗
PubMed1986

Changes in adrenal and testicular activity monitored by salivary sampling in males throughout marathon runs.

Measurement of cortisol and testosterone in saliva samples provided by marathon runners at 6.4 km (4-mile) intervals has been used for monitoring acute changes in adrenal and testicular activity, and the changes compared with mean values in timed samples on five rest days. The collection of mixed whole saliva was well accepted; the missed sample rate in the 8 runners in the Cardiff marathon was less than 10%. On rest days, salivary cortisol and testosterone were within the normal male range and showed a circadian rhythm; mean values at 08.00 h (23.5 nmol L-1; 258 pmol L-1, p less than 0.001, p less than 0.001 respectively) were higher than at 22.00 h (2.8 nmol L-1; 130 pmol L-1). In samples collected at 09.00 h, immediately prior to the Cardiff marathon, cortisol (25.1 nmol L-1) and testosterone (304 pmol L-1) were higher than the mean values (14.9 nmol L-1; 209 pmol L-1) on non-run days. Concentrations of both steroids increased during the marathon; testosterone peaked (442 pmol L-1) at 21 miles, whereas cortisol continued to increase, being maximal (87.9 nmol L-1) at 30 min after completion of the run. Four of the runners in the Cardiff marathon also participated in the Bristol marathon and the changing patterns in salivary hormones were strictly comparable. Salivary sampling would appear to be of value in monitoring acute and rhythmic changes in endocrine function in marathon runners. The temporal relationship between changes in salivary cortisol and testosterone are consistent with direct inhibition of testicular secretion by high cortisol concentrations.

Adrenal Glands↗
PubMed1986

Temporal effects of norepinephrine on pineal serotonin in vitro.

The purpose of this study was to examine the temporal effects of norepinephrine (NE) stimulation on pineal serotonin (5HT) in vitro. Rat pineal glands were individually incubated in nutrient media for 6 h. After a 2-h preincubation, the glands were exposed to tryptophan (TRYP) or TRYP + norepinephrine (10(-4)M each) for 4 additional h. Media and pineals were then analyzed for 5HT and 5HIAA content. Initial exposure to TRYP increased 5HT levels in the media. Norepinephrine increased media 5HT concentrations further and also caused 5HIAA levels to rise significantly. These findings suggest that 5HT secretion and/or oxidation is an early response to stimulation of the pineal gland by NE. Following prolonged NE exposure, media 5HT declined to control values while 5HIAA remained high. Similarly, intrapineal levels of 5HT fell after prolonged stimulation with NE. Thus, pineal responses to initial and continued stimulation with NE are differentiable as early and late effects upon 5HT. Early effects may include secretion and/or oxidation of 5HT followed later by utilization of 5HT in N-acetylation pathways such as that leading to melatonin synthesis. The finding that 5HT is secreted in response to NE suggests that the indoleamine may be a hormone of the pineal gland. Based upon its known influence on physiologic rhythms, daily secretion of 5HT from the pineal may be an important part of the gland's time-keeping function.

Animals↗
PubMed1986

Age factors potentiating drug toxicity in the reproductive axis.

Traditionally, drug toxicity in the reproductive system has been a concern only as it affects fertility and fecundity in young individuals. The purpose of this report is to address the potential problem of synergy between drug actions and abnormal secretion of reproductive hormones that together produce disease in older individuals. Thus, reproductive toxicity has different, but no less serious implications in aging individuals. During aging, the coordinated function of elements within the reproductive neuroendocrine axis degrades. This change promotes atypical secretion of hormones producing abnormal responses in target organs and thus creates a condition with pathogenic potential. Certain drugs may contribute to reproductive toxicity in aging individuals either by accelerating the process of dysregulation and/or by synergizing with hormones to stimulate pathologic changes in target tissues. The geriatric population of the world is increasing, and since it consumes a proportionately larger percentage of drugs than younger groups, this novel form of reproductive toxicity may represent a problem in drug safety that warrants serious consideration.

Aging↗