Acta physiologica Scandinavica. Supplementum

Publications
Ingestion of fat causes a pronounced decrease in lower esophageal sphincter (LES) pressure. This may be due in part to effects of neurotensin (NT), which is released postprandially after the ingestion of fat. The aim of the present investigation was to establish whether the LES pressure decreases at physiological plasma concentrations of NT(1-13). In addition, we have compared the effects and metabolism of NT(1-13) and (Gln4)NT(1-13). The experiments were performed in 3 healthy male volunteers who had fasted for at least 11 hours prior to the study. NT(1-13) or (Gln4)NT(1-13) were infused intravenously at a dose of 12 pmoles X kg-1 X min-1. LES pressure was monitored by a continuous pull-through method with a perfused catheter. The concentrations of chromatographically identified tridecapeptides were determined using NH2 and COOH-terminal directed antisera. Already one min after the start of the infusions the LES pressure had decreased by 43% of the control value. At that time the plasma concentration of the neurotensin tridecapeptide was about 15 pM. NT(1-13) and (Gln4)NT(1-13) had similar half-lives in plasma (2.5 min). NT(1-8) and (Gln4)NT(1-8) were found to be the main metabolites of NT(1-13) and (Gln4)NT(1-13) respectively. The results indicate that the increase in the plasma concentration of NT(1-13) seen after the ingestion of food is sufficient for neurotensin to function as a hormone of the endocrine type. NT(1-13) and (Gln4)NT(1-13) have the same effects on LES pressure in humans and show the same pharmacokinetic characteristics.
 
The 133Xe washout method has been evaluated and found to be a reliable method for the measurement of myometrial as well as ovarian blood flow rates in the rabbit. Monoexponential washout curves for 133Xe have been demonstrated for the whole washout process, both in the uterus and the ovary. Consequently it is possible to calculate the blood flow rate at any time interval during the whole washout process. This 133Xe washout technique has been used for the evaluation of the biological effect of neuropeptides on the local blood flow within the rabbit uterus and ovary. It has been recognized for years that the intrinsic control of a number of functions, including the blood flow regulation, in the genital tract cannot be attributed to cholinergic and/or adrenergic nerves alone. Evidence from 133Xe experiments suggests that the neuropeptides in the female genital tract may play a functional role in these non cholinergic non adrenergic events.
 
Measurement of cutaneous blood flow by the 133Xenon washout method was elaborated by Sejrsen (1971). The method has been applied to evaluate the local regulation of blood flow in normals and in skin diseases. The method can, provided it is used with caution, give quantitative values for cutaneous and subcutaneous blood flow, but has mostly been used to register relative changes in blood flow during various provocation tests. This review details studies with relevance to dermatology performed during two decades.
 
A 133Xe washout technique for measuring the blood flow in the intestinal mucosa is introduced and evaluated. In 11 anaesthetized pigs a laparotomy was performed and the mucosal blood flow rate in the intestine of the pig was determined by a local epimucosal application of 133Xe. In both the colon and the small intestine the 133Xe washout plotted in a semilogarithmic diagram showed a multiexponential configuration. Histological examination and localization studies showed shunting by diffusion of 133Xe in the intestinal mucosa explaining the multiexponential configuration of the washout curve. Therefore the initial slope of the washout was used for measuring blood flow rate. Blood flow rate was simultaneously measured by microsphere entrapment technique. There was an excellent correlation between the blood flow rate determined by the two techniques the correlation coefficient R being 0.89 in the small intestine and 0.996 in the colon.
 
The washout of 133Xenon injected locally in three subcutaneous regions on three volunteers was in a repeated latin square design analyzed regarding flow values and initial clearance. Blood flow showed no dependence on injected volumes (.02-.5 ml), but there was a significant day-day variation and regional and personal differences in subcutaneous blood flow. The initial fast washout was related to the injected volumes due to trauma and dilution of the tissue. From these results precautions are described to increase the validity of the local 133Xenon washout method for measurement of subcutaneous blood flow. In repeated clinical studies it remains important even on the same individuals to record sources of variation apart from the variable to be investigated.
 
The importance of 133Xenon absorption into rubber detector caps during cutaneous and subcutaneous blood flow measurement was investigated in 46 experiments involving 38 persons. 133Xenon was administered atraumatically. Cutaneous and subcutaneous washout rates were registered by portable Cadmium Telluride detectors without rubber caps, with rubber caps, and with rubber caps with Mylar membranes interposed between the rubber and the tissue investigated. No difference in rate constants obtained by means of various detector types was detected. The accumulation of 133Xenon in the rubber caps was found to take place within the first few minutes after the detectors had been brought into position. The 133Xenon then diffused back into the tissue exhibiting a great variation regarding rate constants. The 133Xenon diffused form rubber into air and perfused tissue tracing a monoexponential course; and again the rate constants would vary considerably. No correlation was found between elimination rates obtained with detectors with and without 133Xenon polluted caps, and no way of correcting for the 133Xenon content in the rubber caps was found. Relative changes in rate constants could still be recognized, but absolute values were not obtainable.
 
Fifty-five men and 28 women were tested at age 16 and retested at age 27. Muscle biopsies were taken from m. vastus lateralis to analyse fibre types, fibre areas and enzyme contents. A cycle ergometer test to was used to estimate the maximal oxygen uptake. Physical performance was assessed in an endurance test, where the subjects had to run as far as possible in 9 min on a 400-m track, and in three strength tests designed to test maximal dynamic strength (Sargent jump) and maximal static strength (handgrip test, two-hand lift). The subjects answered a questionnaire concerning physical activity during their leisure time and an activity index was calculated from the answers. The relative proportion of type I fibres (type I%) tended to increase with age in women and decreased in men. At age 27, the type I% was higher in women than in men. Multiple regression analysis indicated that sex per se could explain some of the interindividual variation in the type I% at age 27 and in the changes with age in the type I%, but also factors as physical activity (increase in type I%) and smoking (decrease in type I%) probably contributed to the variation. VO2max (ml.kg-1.min-1) increased with age in women and was unchanged in men so that there was no significant sex difference in VO2max at age 27. Running performance remained unchanged from age 16 to age 27 in both sexes and men performed better than women at both ages. Running performance was directly related to the type I% for both women and men at age 27, a relationship which existed also for men at age 16, but not for women at that age. It seems that the age related changes in relationship between running performance and type I% may be related to the altered choice of physical activity from speed and strength to more endurance demanding activities and the increased VO2max in the women. This may allow an adaptation of the skeletal muscle towards type I fibres in the active ones. The sex differences in strength increased from age 16 to age 27. The relationship between strength and the type II% in the women changed with age from a positive correlation (Sargent jump only, partiell correlation after body dimensions were considered) to negative correlations for all the strength tests, i.e. the more type I fibres the stronger. A positive correlation between strength and activity index was revealed in the women at both ages.(ABSTRACT TRUNCATED AT 400 WORDS)
 
The qualitative and quantitative aspects of beta-endorphin-related peptides present in the human pituitary gland were investigated using autopsy pituitaries as starting material. Beta-endorphin-related peptides were isolated from two batches of autopsy pituitaries (40 and 51 glands) by acid acetone extraction, acetone precipitation, gel filtration (Sephadex G-75 or Bio Gel P 4/P 10), cation exchange chromatography (SP-Sephadex C-25) and different types of reversed phase high performance liquid chromatography (RP-HPLC). Purification was monitored using beta-endorphin radioimmunoassay, which is specific to the 6-17 sequence of beta-endorphin. Methods suitable for microscale structural analyses of the isolated peptides were developed. Amino acid analysis was performed using quantitative precolumn dansylation and RP-HPLC separation of the dansyl amino-acids. Amino-terminal sequences were determined using semi-microscale manual Edman degradation. An RP-HPLC system was set up for sensitive and unambiguous identification of the released phenylthiohydantoin amino acids. The immunoreactive peptide with the highest apparent molecular weight was identified as human beta-lipotropin on the basis of its amino acid composition. The results of amino-terminal sequence analysis, amino acid compositions of the HPLC-isolated tryptic peptides and carboxy-terminal residue analysis were fully compatible with the previously suggested structure of human beta-lipotropin. About 20% of isolated pituitary beta-lipotropin appeared to be in deamidated form. No proteolytically degraded forms of beta-lipotropin were detected. The yield of pure beta-lipotropin was 6.7-7 nmol/gland. A peptide with properties similar to human beta-endorphin was isolated with a yield of 1.5-5 nmol/gland. Amino acid composition, amino-terminal sequence, carboxy-terminal residue and immunochemical properties were identical to those of human beta-endorphin as suggested previously. About 25% of beta-endorphin appeared to be in methionine sulphoxide form as isolated. Several minor components of immunoreactivity with molecular weight similar to beta-endorphin were detected but none of these were obtained pure even after three RP-HPLC purification steps. Further purification was impossible due to the scarcity of the starting material. A previously unidentified beta-endorphin-related peptide with an apparent molecular weight of about 2000 daltons was isolated from the autopsy pituitaries. Amino acid composition, amino-terminal residue, carboxy-terminal sequence and immunochemical properties showed the peptide to be beta-endorphin 1-18. The yield of isolated peptide was 0.4 nmol/gland. This peptide has not been pr
 
This paper examines the evidence for and against the various rival theories for the explanation of pain in angina pectoris. It is shown that the counterarguments used during the 1920s against the coronary theory had not been answered a decade later when the coronary theory was generally accepted by the research and clinical community.
 
Research over the last two decades has indicated that changes in cardiovascular disease mortality rates have been influenced by those in national economic indicators as well as by measures of consumption of tobacco, animal fats and alcohol. These findings predominantly involved the United States, United Kingdom and Scandinavian countries. The economic indicators included real per capita income and social welfare expenditures (beneficial relationships to mortality rates), and unemployment rates and business failure rates (detrimental relationships to mortality). James Henry's formulations have emphasized that many different illnesses respond to emotional stresses in different psychophysiological patterns depending on the specific constellations of emotions aroused. On the assumption that the impact of national economic changes on cardiovascular mortality reflects emotional stresses, losses, frustrations and deprivations, similar tests were undertaken using Western German heart disease mortality rate data over 1951-1989. Time-series regression analysis showed that, holding constant the effects of tobacco, animal fats and alcohol, increased income and social welfare expenditures are related to heart disease mortality rate declines, whereas increased unemployment and business failure rates are related to heart disease mortality rate increases over more than a decade.
 
A survey was carried out on the reduction of animal use in the projects funded by the CFN between 1979 and 1987. 63 projects had received funds. 37 projects were reported in time for the symposium, and the results were presented there; surveys on another 11 projects were received later. The projects funded covered different areas, basic research, testing, evaluation studies, biological production, vaccine testing, education, improved animal experimental techniques, therapy and problems with in vitro toxicology. They were all in line with the objective of the CFN, which is to reduce animal experimentation in Sweden. A definite reduction in animal use is reported in some studies and predicted to take place as a result of others, either relatively soon or in a longer perspective. The survey has a bias, since the scientists themselves were asked to report on their projects and evaluate the effects of the reduction in the use of animals. However, the answers give rise to new interesting questions about future possibilities of animal reduction in a variety of areas and this points at one of the main conclusions, namely the need for further investigation into areas of interest. In order to work out a realistic strategy for reduction of animal use, a coordinating body is needed to investigate areas of promise, where animals either can be reduced or experimental techniques refined, and develop strategies for addressing target areas. The CFN should play such an offensive role.
 
We have evaluated the immediate (0-30 min) circulatory effects of an i.v. bolus of a new compound, MPV 295, an imidazole derivative (1 to 120 micrograms/kg of b.w.) on anaesthetized (morphine, pentobarbital), normotensive, artificially ventilated beagle dogs using catheterization technique. MPV 295 firstly raised and then decreased aortic pressures at dose 30 micrograms/kg. Systolic pressure decreased also at doses 15 and 60 micrograms/kg. Heart rate and cardiac output decreased but the change in cardiac output was significant only at dose 30 micrograms/kg. Peripheral vascular resistance increased. Pulmonary arterial systolic pressure decreased at dose 15 micrograms/kg but did not respond significantly to other doses. In conclusion, MPV 295 exerted an initial sympathomimetic action which was followed by hypotensive effect with the former being peripheral and the latter central in origin. It showed a narrow dosage range for the hypotensive action and, like clonidine, appeared to be an alpha 2-agonist in qualification experiments.
 
The levels of beta-endorphin and adrenocorticotropic hormone (ACTH) were measured by radioimmunoassays in rat plasma, pituitary, hypothalamus and pineal at different times of the day. Significant diurnal variations in the levels of immunoreactive beta-endorphin were detected in the plasma and hypothalamus. Immunoreactive ACTH levels varied significantly during the darklight cycle in the posterior lobe of the pituitary, and in the hypothalamus, but not in the plasma. The hormone levels were high during the dark, except in the posterior pituitary, where the highest levels were detected during the light period. Gel chromatography showed that both beta-endorphin and ACTH immunoreactivities in plasma and tissues consist of multiple components.
 
Experiments are surveyed, suggesting that rats (WKY and SHR) have a very wide 'safety range' concerning salt intake with respect to cardiovascular homeostasis. Further, they are able to maintain their 'resting' volume and circulatory equilibria remarkably well over a 240-fold range of intakes, at least when young. The major longterm functional consequences of low and high intake were noted concerning sympathetic nervous control, chronic low Na intake leading to reduction of the transmitter release per impulse, and vice versa at high intakes. Otherwise blood volume, exchangeable sodium, cardiac and vascular muscle functions remained largely unchanged during rest, but the altered capacity of sympathetic control made the low Na rats dangerously vulnerable to e.g. fluid losses. In these respects SHR were, if anything, worse off than WKY. If allowed to choose their Na intake, the rats put themselves at an intake 30-50 times above that on which they can barely manage, and SHR on an even higher level than WKY. Some comparisons to man's situation are made, adjusting for differences in body size and metabolic rate. Such data suggest that human Na intakes in western societies are in fact similar to those instinctively chosen by e.g. sheep or rats, when on free access to salt. Some aspects of the assumed relationships between Na intake and primary hypertension, are also discussed. At least in the SHR variant of primary hypertension high salt intake is evidently of fairly subordinate pathogenetic importance, as seems to be the case also in the great majority of human subjects, to judge from recent epidemiological studies.
 
We have used a combination of site-directed mutagenesis and spectroscopic techniques to investigate electron-transfer reactions between hemes a and a3 in cytochrome c oxidase. A state of the enzyme was prepared in which heme a/CuA are oxidized and heme a3/CuB are reduced with CO bound to heme a3, which stabilizes the reduced state of the binuclear center. In addition, in this state the pKs of protonatable groups in the vicinity of the binuclear center, interacting electrostatically with heme a3, are larger than with oxidized heme a3. Upon flash photolysis of CO from the two-electron reduced enzyme electrons at heme a3 equilibrate rapidly with heme a. In the R. sphaeroides enzyme the electron-transfer rates from heme a to a3 and from heme a3 to a were, deconvoluted and were found to be approximately 1.5.10(5) s-1 and approximately 1.4.10(5) s-1, respectively. After this rapid electron equilibration between hemes a and a3, protons are released from groups interacting electrostatically with heme a3, which is associated with additional electron transfer from heme a3 to heme a. The proton-coupled electron transfer displays a pH dependent extent and rate. In addition, it displays a deuterium-isotope effect of a factor of about three. The reaction sequence is compatible with the three-dimensional cytochrome c oxidase structure, which shows that more protonatable groups are found around heme a3 than around heme a and supports the involvement of the binuclear center in proton pumping. Proton uptake/release upon reduction/oxidation of heme a3 takes place through a proton pathway including residues Thr(I-359) and Lys(I-362) (K-pathway), but not through the pathway including residues Asp(I-132) and Glu(I-286) (D-pathway). During reaction of the reduced enzyme with O2, both substrate and pumped protons are taken up through the D-pathway.
 
The activation of different neuroendocrine subsystems depends on the individual perception and coping with the challenging situation, the formulation of these relations by J.P. Henry represents a most useful concept also for the assessment of welfare consequences of particular caging variables. We investigated effects of cage enrichment on behaviour and neuroendocrine activations of male laboratory mice. Mice in enriched cages behaved more aggressive, lacked stable dominance hierarchies and exhibited neuroendocrine alterations depending on their individual social position. Subdominant passive mice were characterized by an augmented adrenal capacity to synthesize epinephrine despite low activities of the tyrosine hydroxylase. Dominant mice showed elevated circulating corticosterone concentrations despite high tyrosine hydroxylase-activities. Findings showed a dissociation of neurosympathetic and adrenomedullary components in subdominant passive mice and a simultaneous activation of sympathetic adrenomedullary and hypothalamo-adrenocortical components in dominant mice. Within the conceptual framework of the Henry model this would suggest different deteriorations of welfare in dominant and subdominant passive mice. In the situation of intensified aggression in the enriched cages the increased epinephrine synthesis in subdominant mice reflect their more frequent receipt of attacks and the elevated corticosterone secretion in dominant mice reflect their hindered ability to control the dominant position.
 
An international collaborative project, initiated by the DLR-NASA Life Sciences Working Group, led to the performance of a head-down tilt bedrest (HDT) study at the DLR Institute for Aerospace Medicine. Scientific and operational questions were addressed in preparation for the D-2 Spacelab mission. Principal areas of interest were cardiovascular regulation and fluid/electrolyte metabolism. The results are detailed in a series of 13 reports to which the present paper serves as an introduction.
 
In the present communication the attention is on the existence of small neurons in the olfactory bulb which contain tyrosine hydroxylase (TH) and DOPA-decarboxylase (DDC) but not dopamine-β-hydroxylase (DBH). This strongly suggests that the olfactory bulb in rats contains dopamine neurons.
 
Some models for the decision-making processes in animal behaviour are discussed, together with their merits and drawbacks. Abnormal behaviour is defined as an untypical reaction to a particular combination of motivational factors and stimuli. Much abnormal behaviour can be regarded as stress-coping responses. Three categories of abnormalities are discussed: stereotyped motor patterns, abnormal aggression and cannibalism. It is concluded that animals with high frequencies of abnormal behaviour should be regarded as not healthy and the experimental results treated in accordance with this. Methods of preventing abnormal behaviour consist of the recognition of the species-specific ethological demands and the incorporation of these demands into the housing systems of the animals.
 
The influence of skinfold thickness on the local subcutaneous blood flow (SBF) and absorption rate of subcutaneously injected and infused soluble insulin was investigated in insulin-dependent diabetic patients. The local 133Xenon washout technique was used for measuring SBF and the disappearance of 125I labelled insulin for measuring insulin absorption. A Harpenden skinfold caliper was used for measuring skinfold thickness. A large variation in skinfold thickness (range 6-40 mm, N = 50) was demonstrated. The SBF was curvilinear related to the skinfold thickness with decreasing SBF for increasing skinfold thickness (N = 50). A similar relationship was found between the SBF and the absorption rate of subcutaneously injected (N = 10) and infused (N = 7) insulin. The large variation in skinfold thickness and thus insulin absorption may partly explain the well-known large inter-individual variation in insulin absorption, and the different absorption rates from areas with different skinfold thickness should be taken into account when treating with insulin.
 
Scanning electron micrograph of typical coprodeal epithelium from hens on a low-salt diet (2a), and on a high-satt diet (2b). Notice weil developed microvilli in a and the few and short microvilli in b. Magn. 2.700 X. 
The coprodeum of the hen is provided with a folded tunica mucosa with an epithelium showing large variation in Na absorption and inducible Cl secretion. The major, but probably not the only, mediator of these adaptations is aldosterone which not only opens an apical Na channel but causes induction of microvilli in the apical membrane. This leads at least to a 5-fold enlargement of the apical area which may be the reason for the delayed changes in apparent aldosterone sensitivity and inducible Cl secretion. This reaction has an unusually slow response time - 5 days for full adaptation - in contrast to the opening/closing of apical Na channels which react within a few hours and are fully switched over within 24 h. Aldosterone may thus exert a larger role in growth and differentiation than envisioned so far (Skadhauge 1987).
 
There have not been any studies on the effect of chronic physical stress on the activity of sympathetic nerves in various organs, and of the secretory activity of the adrenal medulla, when the animal was at rest and undisturbed. The main aims of the present thesis were therefore to study the following questions: Does the sympatho-adrenal system adapt to a chronic increase in its activity? If so - how is this adaptation expressed? How does adaptation to chronic exercise compare with acclimation to cold? What is the role of cardiac sympathetic nerves in the relative bradycardia of the athletic heart? What is the role of the cardiac sympathetic nerves in the development of exercise-induced cardiac hypertrophy? Daily physical exercise induces adaptive changes in both central and peripheral noradrenergic neurons in the rat. The stores of noradrenaline are increased in brain, heart and adrenal gland, and at least transiently in the spleen as well. There are changes in (nervous) activity in both central and peripheral noradrenergic neurons, but whereas the activity is increased in the brain, the activity of peripheral sympathetic neurons is decreased in both heart and spleen and probably in the vasculature as well. It is suggested that the decrease in activity in peripheral sympathetic neurons is secondary to an increase in inhibitory activity by central noradrenergic neurons. This central effect may in turn be at least partially a reflex adustment to the increased sensitivity to the vasoconstrictor actions of noradrenaline that occurred in the trained rats. The bradycardia of the 'athlete's heart' may be largely or entirely due to the decrease in cardiac sympathetic nervous activity caused by training. Physical training appears to induce 'cross tolerance' to cold stress, while cold-acclimation does not lead to 'cross tolerance' to acute exercise. The adaptive cardiac hypertrophy produced by chronic exercise is not caused by a direct effect of the increased workload on the cardiac muscle cell, but is instead mediated by release of noradrenaline from cardiac sympathetic nerves. Furthermore, increased activity of cardiac sympathetic nerves may be the final common pathway in all forms of compensatory cardiac hypertrophy.
 
This paper presents the findings from a series of studies that examine the influence of repeated days of exercise in the heat and dietary K+ and Na+ on heat acclimation. Data are presented to examine the effects of heavy sweating on potential risk of K+ depletion. Studies of leg blood flow, substrate exchange (a-v differences) and muscle glycogen use during exercise have been used to describe the influence of a heat acclimation regimen (8-days exercise in the heat) on peripheral metabolism.
 
Isoproterenol is a potent lipolytic agent. It has also been shown to induce accumulation of lipid droplets in the myocardium in vivo. The isolated working rat heart model was applied to evaluate the effect in vitro. Twenty-four rats were randomly separated into four experimental groups of six rats, all receiving Krebs-Hensleit buffer with 11mM glucose. The control group had no supplement, the other groups received either 10(-5) M isoproterenol, 1.2 mM palmitate, or a combination of the two. Tissue levels of triglycerides and phospholipids, and the fractional volume of lipid droplets were determined at the end of the 30 min perfusion in the working heart mode. Ventricular function was monitored continuously and showed a marked increase in the isoproterenol treated groups. The level of tissue phospholipids remained unchanged in all groups. Whereas tissue triglycerides were significantly increased in the group receiving only palmitate as compared to the other groups. A corresponding increase was, however, not found to be significant for lipid droplet quantitation. The results are discussed in terms of possible mechanisms for isoproterenol-induced accumulation of neutral lipids in the myocardium.
 
Top-cited authors
Kjell Fuxe
  • Karolinska Institutet
Urban Ungerstedt
Annica Dahlström
  • University of Gothenburg
Ulf Stenevi
  • University of Gothenburg
Olle Lindvall
  • Lund University