Showing papers in "Acta Physiologica Scandinavica in 1971"

Stereotaxic mapping of the monoamine pathways in the rat brain.

Abstract: The ascending monoamine pathways in the rat brain are demonstrated by the pile up of fluorescent material occurring in the axons after various types of lesions. The anatomy of the pathways is outlined in drawings of frontal sections of the brain and the origin and termination of several pathways is determined by studying the anterograde and retrograde degeneration occurring after well localised lesions. It is possible to separate the ascending NA pathways into a dorsal and a ventral bundle of axons. The dorsal bundle innervates the cortex and the hippocampus and the ventral bundle supplies NA nerve terminals to the medulla, the pons, the mesencephalon and the diencephalon. The dorsal bundle is found to originate in the locus coeruleus. Lesions of this nucleus abolish the nerve terminals in all cortical areas and in several other areas of the brain indicating a unique role for the locus coeruleus in influencing the activity of the entire brain. The 5-HT pathways have a distribution similar to the ventral NA pathyway. The course of the nigro-striatal and the meso-limbic DA pathways is presented in detail.

Postsynaptic supersensitivity after 6-hydroxy-dopamine induced degeneration of the nigro-striatal dopamine system.

Abstract: The effect of L-DOPA and the dopamine (DA) receptor stimulating drug apomorphine was studied in rats after unilateral degeneration of the nigrostriatal DA system by intracerebral injection of 6-hydroxydopamine. Both apomorphine and L-DOPA induced a strong rotational behaviour which was registered in a specially designed “rotameter”. The direction of the rotation indicated that the denervated striatum was more sensitive to DA receptor stimulating drugs than the innervated striatum. This supersensitivity probably corresponded to the decentralisation type of supersensitivity in the peripheral nervous system although it developed faster. The action of L-DOPA was inhibited by pretreatment with the DOPA-decarboxylase inhibitor Ro4–4602 which indicated that L-DOPA must be converted to DA in order to stimulate the supersensitive postsynaptic cells. Pretreatment with a single dose of reserpine also induced supersentitivity to apomorphine which reached its maximum on the 3rd day and then decreased on the 4th day. Postsynaptic supersensitivity after degeneration of the nigro-striatal DA system is probably an important reason for the effectiveness of the L-DOPA therapy against Parkinson's disease.

Adipsia and Aphagia after 6-Hydroxydopamine Induced Degeneration of the Nigro-striatal Dopamine System

Abstract: The functional role of the nigro-striatal dopamine (DA) system has been investigated on the basis of a recent detailed mapping of its path and a new method of lesioning the catecholamine systems selectively by intracerebral injection of 6-hydroxydopamine (6-OH-DA). The investigation was especially focused on the symptoms of adipsia, aphagia, hypokinesia and catalepsia after lateral hypothalamic lesions as such lesions may interrupt the ascending DA axons. Electrocoagulations or 6-OH-DA lesions were performed bilaterally at several sites along the DA pathway and the behavioural effects were evaluated in relation to the histochemically detected lesion of the DA pathway. It was concluded that bilateral complete degeneration of the nigro-striatal DA pathway produces severe, long lasting adipsia and aphagia, hypoactivity, difficulties to initiate activity and loss of exploratory behaviour and curiosity. Experiments with DA receptor stimulating and blocking drugs supported the lesion results. Catalepsia and somnolence were attributed to the interruption of other pathways. The results suggest an important role for the nigro-striatal DA system and the striatum in the control of behaviour. A number of symptoms earlier related to the hypothalamus may in fact be due to disturbance of the nigro-striatal DA system.

Striatal dopamine release after amphetamine or nerve degeneration revealed by rotational behaviour.

Abstract: Amphetamine induced vigorous rotational behaviour in rats where the nigrostriatal dopamine (DA) system was unilaterally degenerated by an intracerebral injection of 6-hydroxydopamine (6-OH-DA). The rotational behaviour was analysed in a specially designed “rotometer” and found highly reproducable. The intensity of the rotation was proportional to the extent of degeneration in the DA system. The amphetamine site of action was in all probability presynaptic as amphetamine caused a rotation in the opposite direction as compared to the DA receptor stimulating drug apomorphine. Tyrosine hydroxylase inhibition abolished the amphetamine effect, while reserpine potentiated the effect. Evidence was also obtained that the amphetamine induced release of DA was dependent upon nerve impulses. The rotational behaviour reflected the degree of DA receptor stimulation, but changes in the noradrenaline (NA) transmission seemed to modulate the behaviour. Decreased NA transmission after dopamine-β-hydroxylase inhibition increased the rotational behaviour. The unilateral degeneration of the DA system was studied by the changes in posture and movements that occurred during the degeneration. After inhibition of the monoamine oxidase the rats showed a strong rotation beginning on the 23d and ending on the 33d hour after the operation. The rotational behaviour was probably due to degeneration release of DA and equivalent to the degeneration contraction of the nictitating membrane in the peripheral nervous system Amphetamine greatly potentiated the spontaneous degeneration release during this period.

Drug-Induced Changes in the Release of 3H-Monoamines from Field Stimulated Rat Brain Slices

Abstract: Rat cerebral cortex slices preincubated with 3H-noradrenaline (NA) or 3H-5-hydroxy-tryptamine (5-HT) and neostriatal slices preincubated with 3H-dopamine (DA) were stimulated by an electrical field and the overflow of radioactivity determined. The effect of drugs on overflow and release from central NA, DA and 5-HT nerve terminals was studied. Inhibition of monoamine uptake with desipramine, cocaine or chlorimipramine increases the stimulation-induced overflow and the results indicate that at least 35 % of the released monoamines may be taken up again into the monoamine nerve terminals. Activation of NA, DA and 5-HT receptors with clonidine, apomorphine and LSD-25 respectively seems to decrease transmitter release. Blockade of NA and DA receptors with neuroleptic drugs increases the stimulation-induced overflow, probably due to an increased release from the NA and DA nerve terminals. It is known that drugs used in the present investigation have a nerve impulse dependent influence on the rate of synthesis and turnover of monoamines in the central nervous system, which is generally considered to be secondary to changes in nerve impulse frequency via a nervous feed-back mechanism. However, it seems probable from the present results that the turnover changes found in vivo after these drugs may at least partly also be due to a local effect at the central monoamine synapse, possibly via a negative feed-back mechanism.

The Influence of Physical Training and Other Factors on the Subjective Rating of Perceived Exertion

Abstract: The relationship between the subjective rating of perceived exertion (RPE) and different physiological variables during work were investigated in 19 healthy subjects under the following conditions: 1) after heart rate (HR) has been experimentally changed during work by the use of autonomic nervous system blocking agents. 2) during different types of physical work and 3) before and after an 8 week period of physical training, respectively. In most work situations, HR mirrors the physical strain subjectively experienced. However, this good correlation between HR and RPE was altered during the experiments with blocking agents. Therefore, a tachycardia as such is not the primary factor in the setting of HR during exercise — RPE was higher for a given level of oxygen uptake during arm work than during leg work, as well as during bicycling compared to running or swimming. A better correlation was found in these experiments between RPE and blood lactate concentration. After training, and in parallel to the decrease in HR at submaximal work loads, RPE was lower for a given level of oxygen uptake, but was the same when related to the “relative” (per cent of maximum) oxygen uptake.

The distribution of 15-hydroxy prostaglandin dehydrogenase and prostaglandin-delta 13-reductase in tissues of the swine.

Abstract: Prostaglandin dehydrogenase (15-hydroxy prostanoate oxidoreductase, EC 1.1.1 (PGDH) and prostaglandin-Δ13-reductase (prostanoate Δ13-oxidoreductase) were assayed in homogenates of 15 different tissues of the swine. Both enzymes were located mainly in the particle free fraction. The highest activities for PGDH were found in the lung, spleen and kidney, which ranged from 50–82 mU/g of tissue or from 482 to 808 m/g of protein. Lower activities of PGDH were observed in the stomach, testicle, liver and small intestine. The renal cortex contained about three times more PGDH than the medulla. The reductase was most abundant in spleen, kidney, liver, adrenal and small intestine, which ranged between 27–38 mU/g of tissue or 232–390 mU/g of protein. The highest specific activity was however found in adipose tissue which contained 3383 mU/g of protein. The wide distribution of these enzymes as well as other evidence support the concept that they catalyze the initial reactions in the metbolism of the prostaglandins.

Action Potential Generation in Denervated Rat Skeletal Muscle

Abstract: Redfern, P. and S. Thesleff, Action potential generation in denervated rat skeletal muscle. I. Quantitative aspects. Acta physiol. scand. 1971. 81. 557–564. Action potential generation was studied at various periods up to one week after denervation in individual muscle fibres of the extensor digitorum longus muscles of the adult rat. To allow a comparison of action potential generation at various stages of denervation, it was necessary to establish adequate conditions for spike generation. It was found that when fibres were locally polarized to a level of -90 to -100 mV, and the external calcium concentrations was increased to 4 mM, the peak rate of rise and the overshoot of the action potential were maximal. Between 30 and 40 hrs following section of the motor nerve, the mean maximal rate of rise of action potentials, recorded under the aforementioned conditions, was reduced by about one third, and remained at about this reduced level during the subsequent days. Two days after denervation the resting membrane potential was reduced from a mean of 82 mV in innervated muscle to a mean of 68 mV, and remained at about this level for the remaining 5 days studied. The electrical time constant and the input resistance of the muscle fibres gradually increased during the 7 days following denervation, the time constant by about 70 % and the input resistance by about 50 %. With anodal polarization in denervated muscle no significant correlation was found between the resting membrane potential and the maximal peak rate of rise of the spike. It was concluded that denervation produces a genuine reduction in the rate of rise of the action potential in muscle fibre.

Elimination of 125-I-trypsin alpha-macroglobulin complexes from blood by reticuloendothelial cells in dogs.

Abstract: Complexes of 125I-labelled bovine trypsin and the α1- and α2-macroglobulins of the dog were prepared and injected into 3 dogs. The rate of elimination of the radioactivity with a half time of only 8 min fitted a single exponential curve. About 80 % of the radioactivity in the whelps and about 85 % in the adult dog was recovered in the reticuloendothelial cells of the liver, spleen and bone marrow.

Studies on tetrodotoxin resistant action potentials in denervated skeletal muscle.

Abstract: In this study it is shown that action potential generation in rat, mouse and cat muscles is blocked by tetrodotoxin (TTX, 10-6 M) but that the chronically denervated muscles of these species are partially resistant to TTX. In denervated rat muscles the development of the TTX resistant action potential during the first four days of denervation is paralleled by the spread of extrajunctional cholinergic sensitivity. However, the extrajunctional cholinergic receptor and the TTX resistant action potential can be selectively blocked by drugs, indicating that the action potential site and the cholinergic receptor are not identical structures. Denervated muscles are also partially resistant to saxitoxin, although less so than to TTX.

Blood flow in the calf muscle of man during heavy rhythmic exercise.

Abstract: 133Xenon clearance was recorded during maximal vasodilatation in the calf muscles of trained subjects during rest and during heavy rhythmic exercise (contraction about 0.3 sec, relaxation about 0.7 sec) when the subject was tilted from a supine to a “leg down” position. The k-value for the wash-out curve, divided by the mean arterial blood pressure at heart level (MABP), was considered to reflect the relative levels of maximal flow in the two experimental situations. While a shift to “leg down” position during post-exercise hyperemia did not significantly increase flow through the fully dilated muscle vessels, indicating that they were already maximally distended, the same shift during rhythmic exercise raised the average value of k/MABP approximately 60 per cent above control. This observation is in all probability explained by a marked lowering of mean venous pressure by the “muscle pump” in the dependent legs, despite the huge flow during the heavy rhythmic exercise. This would result in a considerable gain in local perfusion pressure and hence in maximal flow capacity.

Increased nerve stimulation induced release of noradrenaline from the rabbit heart after inhibition of prostaglandin synthesis.

Abstract: The effect of inhibition of prostaglandin synthesis on the release of noradrenaline induced by sympathetic nerve stimulation was studied in the isolated perfused rabbit heart. It was found that 5,8,11,14-eicosatetraynoic acid, a compound known to block prostaglandin synthesis in vitro, decreased the outflow of prostaglandins normally induced by nerve stimulation. Simultaneously the outflow of noradrenaline in response to nerve stimulation increased. Since the acetylenic acid did not affect the uptake of exogenous noradrenaline, the increased outflow probably reflects an augmented release of transmitter from the neurons. It has earlier been shown that exogenous prostaglandins inhibit the release of noradrenaline from adrenergic neurons, and that endogenous prostaglandin-like substances are released in response to sympathetic nerve stimulation in amounts sufficient to exert this inhibitory action. Thus a prosta-glandin-mediated negative feed-back control of the release of adrenergic transmitter is known to be feasible. The present observation that inhibition of prostaglandin synthesis enhances the release of noradrenaline, provides the first conclusive evidence for the occurrence of such an endogenous control mechanism.

3H-Noradrenaline Release and Mechanical Response in the Field Stimulated Mouse Vas Deferens

Abstract: Isolated mouse vas deferens was preincubated with 3H-noradrenaline (3H-NA) and then mounted in a small glass chamber where it was superfused with buffer and stimulated by an electrical field. Tritium overflow into the buffer and mechanical activity was followed. Almost all the radioactivity taken up and retained in the vas deferens, and about 75 % of the tritium overflow during stimulation was due to 3H-NA. Stimulation for 30 sec at 4–16 Hz caused a biphasic contraction of the vas deferens with an initial rapid twitch and a second tetanus-like phase of contraction. The stimulation-induced tritium overflow during stimulation at 16 Hz for 30 sec was 1.8 % (i.e. 1.8 % of the total tritium content of the vas deferens was overflowing in response to stimulation). The fraction of the tritium content of the vas deferens overflowing per impulse at different frequencies of stimulation was the same at 1–16 Hz and was around 3.5 xlO“5. Upon stimulation for various time periods (10–120 sec) the stimulation-induced overflow was found to be proportional to time. The mechanical response, on the other hand, decreased upon prolonged stimulation. No contractions were elicited in vas deferens from mice pretreated with 6-OH-dopamine. Atropine did not affect the response to stimulation. No contraction and no stimulation-induced overflow was obtained when tetrodotoxin was added to the superfusing buffer. Inhibition of neuronal uptake of NA by desipramine potentiated the contraction caused by stimulation, but the stimulation-induced overflow was almost unchanged. The a-receptor blocking drugs phentolamine and phenoxybenzamine decreased the second phase of contraction and increased the stimulation-induced overflow. Papaverine inhibited the contraction and increased the stimulation-induced overflow. Stimulation of a-receptors by methoxamine potentiated the contraction and decreased the stimulation-induced overflow. From the drug-experiments it is concluded that a decreased effector response is accompanied by an increased 3H-NA release, while an increased effector response is accompanied by a decreased 3H-NA release. The results indicate the existence of a transsynaptic regulatory mechanism for NA release.

Influence of changes in microcirculation on the excitability of the sensory unit in the tooth of the cat.

Abstract: Simultaneous determinations of radioactive iodide disappearance rate (k-value) and sensory nerve impulse frequency from dentinal cavities were performed on canine teeth of anesthetized cats. Changes in k-value reflecting changes in pulpal microcirculation were obtained by direct sympathetic nerve stimulation or by thermal stimulation. Sympathetic nerve stimulation re duced the k-value and induced an initial increase in nerve impulse frequency. During maximal sympathetic nerve stimulation this initial increase was followed by a marked depression in impulse frequency. Application of heat increased k-value as well as impulse frequency, while cold reduced k-value and induced an initial increase in nerve impulse frequency followed by a decrease. Thermal stimulation superimposed during maximal sympathetic stimulation, when k-value was depressed, was inadequate to evoke an appreciable increase in sensory nerve in pulse frequency. It is suggested that the excitability of sensory units in the tooth is strongly modulated by changes in pulpal microcirculation induced by, for example, stimulation of sympathetic vasoconstrictor fibres.

Interindividual Differences in Diurnal Variations in Alertness, Performance, and Adrenaline Excretion

Abstract: Patkai, P. Interindividual differences in diurnal variations in alertness, performance, and adrenaline excretion. Acta physiol. scand. 1971. 81. 35–46. Subjects classified as habitual morning vs. evening workers on the basis of their answers to a questionnaire, were compared with regard to day-time variations in catecholamine excretion and performance. Adrenaline excretion in morning workers was highest in the morning and decreased gradually during the day, while evening workers showed nearly constant excretion values. The performance of morning workers did not vary during the day, while evening workers showed a steady improvement, performing best in the evening. In addition, a significant difference between the two groups was found in the personality dimension of extraversion-introversion, showing that evening workers were more extravert and morning workers more introvert. The constancy of individual diurnal rhythms and their relations to personality traits, are discussed.

The hemodynamic consequences of regional hypotension in spontaneously hypertensive and normotensive rats.

Abstract: In 3 week old spontaneously hypertensive rats (SHR) and normotensive control rats (NCR) the aorta was ligated distally to the renal arteries, lowering the blood pressure in the hindquarters some 30–50 per cent compared with “ordinary” NCR or SHR. 6–16 weeks later the hindquarters of an ordinary NCR were perfused simultaneously with those of an aorta-ligated NCR or SHR in 20 paired experiments at constant flow with an oxygenated plasma substitute, from maximal dilatation to maximal constriction as induced by graded noradrenaline (NA) doses. Constructed “resistance curves” of the aorta-ligated NCR and SHR hindquarters showed a 40–50 % decreased resistance at maximal dilatation with almost proportional decreases of the steepness of the dose-response curve and of the maximal pressor response, when compared with ordinary NCR, while the threshold sensitivity to NA was the same as in unligated shamoperated NCR. The difference from unligated SHR was still more striking, yielding three separate sets of “resistance curves” each related to the pressure level present in the hindquarters during the months prior to the perfusion. The results indicate an adaptive structural change of the resistance vessels in the chronically hypotensive hindquarters with a media reduction and considerably increased vascular lumina. Thus, the elimination of the pressure load seems capable of completely preventing the development of the adaptive media increase that otherwise seems to occur in SHR. An altered pressure load, decreased or increased, evidently affects the design of the resistance vessels rapidly and this, in turn, will greatly contribute to the hemodynamic differences characterizing hypo- and hypertension as compared to normotension.

Effect of prolonged strenuous exercise on the concentration of triglycerides, phospholipids and glycogen in muscle of man.

Abstract: Muscle tissue from the lateral vastus of the femoral muscle was taken by needle biopsy technique in 7 male subjects before and after strenuous exercise by skiing for about 7 hrs. The mean muscle triglyceride concentration decreased from 17 to 8 μmoles/g wet weight during the exercise. No change was observed in the phospholipid concentration. The mean glycogen concentration in the muscle decreased from 16 to 7 mg/g sswet weight during the exercise. The results indicate that not only muscle glycogen but also muscle triglycerides are of importance for the energy metabolism in man during exercise.

Intracellular Accumulation and Permeability Effects of Some Weak Acids in the Isolated Frog Gastric Mucosa

Abstract: Acetate, propionate and L-lactate (10 meq/l) stimulated hydrogen ion secretion in the isolated frog (Rana temporaria) gastric mucosa. By use of this stimulatory effect it was shown that these acids accumulate in the gastric mucosal cells when present in the undissociated form on the mucosal (secretory) side. From determinations of the impedance locus diagram and the resistance of the mucosa it was shown that undissociated propionic acid (100 meq/l) increased the ionic permeability of the frog gastric mucosa. A similar effect was obtained with acetic acid. It is probable that intracellular accumulation of undissociated weak acids is the mechanism underlying their permeability increasing effects on the gastric mucosa.

Temperature regulation during continuous and intermittent exercise in man.

Abstract: Ekblom, B. C. J. Greenleaf, J. E. Greenleaf and L. Hermansen, Temperature regulation during continuous and intermittent exercise in man. Acta physiol. scand. 1971. 81. 1–10. Body temperature changes and heat dissipation responses were studied in three well-trained men during moderately heavy (60 % of maximal aerobic power) continuous and intermittent exercise at the same average metabolic rate and heat production. The purpose was to determine if hypothetical “work factors” induced specifically by muscular activity influenced body temperature regulation. Compared with continuous work; a) the equilibrium level of rectal temperature (Tre) during intermittent work was elevated 0.35° C which accounted for 21 % of the total Tre increase from resting, and b) the decreased sweating of 32 g/(m2. hr) during intermittent work resulted in a decreased evaporative heat loss of 18.6 kcal/(m2. hr) that could account for the increased intermittent work Tre. These responses appear to be manifestations of reduced thermoregulatory efficiency due, perhaps, to non-linearity in the relationship of body temperature to total work rate or to non-linearity in the contribution of non-thermal inputs at work rates above 100 % of max. VO2. It is also possible that other factors play a part, such as the frequency and duration of the work and rest cycles, rate of limb movement, or circulatory factors related to postural changes.

Vasoconstrictor fibre discharge to skeletal muscle, kidney, intestine and skin at varying levels of arterial baroreceptor activity in the cat.

Abstract: Estimations of the average discharge rates in vasoconstrictor fibres to skeletal muscle, kidney, intestine and skin at varying levels of arterial baroreceptor activity were made by comparing quantitatively the reflexly induced vascular responses with those obtained with stimulations of the regional vasoconstrictor fibres at known frequencies. The results indicate that withdrawal of baroreceptor restraint was normally followed by a considerably lower firing rate in renal vasoconstrictor fibres than in e.g. skeletal muscle vasoconstrictor fibres. A complete elimination of the inhibitory influence induced vasoconstrictor fibre discharge rates up to 8 imp/s in skeletal muscle but only at most 4 imp/s in the kidney. Intestinal vasomotor fibres were found to be activated to approximately the same extent as those to skeletal muscle. The vasomotor fibres to the cutaneous arterio-venous anastomoses were evidently not activated when the baroreceptors were unloaded. The reason for this non-uniform activation of the different sets of vasoconstrictor fibres seems to be different levels of spontaneous activity in the respective “neuron pools” in the bulbar vasomotor centre. The renal vascular responses to baroreceptor unloading became augmented when the excitatory level in the vasomotor centre was enhanced, as e.g. when the animal became acidotic.

The time course of the active state in relation to sarcomere length and movement studied in single skeletal muscle fibres of the frog.

Abstract: The rising and falling phases of the active state were analyzed, by means of quick-release technique, during a series of 4 incompletely fused isometric twitches in single semitendinosus muscle fibres of the frog. The analysis was carried out at different sarcomere lengths within the range 1.7–2.8 μ. The rate of rise of the active state was independent of the sarcomere length. A reduction in fibre length was associated with an earlier onset of the decay of the active state leading to a decrease in duration of the activity at the shorter length. The duration of the active state at 1.9 μ sarcomere spacing was 69 (range: 51–40) per cent of the duration existing at 2.6 μ sarcomere length as determined in 7 different fibres. Movement (active shortening) per se, apart from the change in sarcomere length, affected the kinetics of the active state. An interval of free shortening interposed during an isometric contraction reduced the fibre's capacity to produce tension for the rest of the contraction period without changing the total duration of the mechanical activity substantially. The movement produced a relatively small effect as long as the active state was maximum; the depressant effect became greater and greater, however, the later the movement occurred during the decay phase of the active state. The nature of the length and movement dependence of the active state is discussed in the light of the calcium-activator mechanism of the excitation-contraction coupling.

The effects of "immunosympathectomy" on blood pressure and vascular "reactivity" in normal and spontaneously hypertensive rats.

Abstract: Newborn litters of spontaneously hypertensive rats (SHR) and normotensive control rats (NCR) were identically treated with sympathetic nerve growth factor antiserum (Wellcome) which markedly interferes with adrenergic cardiovascular control (Zaimis 1967). Blood pressure, measured intermittently during 8 months, was in treated SHR (SHRis) about 25 % higher than in NCRis, their respective pressures being about 40 % and 25 % lower than those of sham-treated SHR and NCR.–The hindquarters of one SHRis, or NCRis, were then perfused at constant flow in parallel with those of ordinary NCR. Starting from maximal vasodilatation, resistance increases were induced by graded noradrenaline (NA) infusions, from “threshold” to maximal pressor responses. Compared to NCRis, SHRis showed an increased resistance at maximal dilatation, an increased slope of the NA dose-response curve and an increased maximal pressor response, while their NA “thresholds” did not differ significantly. Thus, the structurally determined hemodynamic differences between ordinary SHR and NCR (Folkow et al. 1970 b) characterize also SHRis and NCRis, though to a reduced extent. Even when comparing SHRis with ordinary- NCR, which exhibited similar “resting” pressures, these differences partly remain, suggesting that the SHR resistance vessels might, for genetic reasons, be more prone to adapt structurally to pressure loads than those of NCR.