Showing papers in "The Journal of Physiology in 1955"

Method for the calculation of velocity, rate of flow and viscous drag in arteries when the pressure gradient is known

Abstract: The experiments of McDonald and his co-workers (McDonald, 1952, 1955; Helps & McDonald, 1953) have shown that in the larger arteries of the rabbit and the dog there is a reversal of the flow. Measurements of the pressure gradient (Helps & McDonald, 1953) showed a phase-lag between pressure gradient and flow somewhat analogous with the phase-lag between voltage and current in a conductor carrying alternating current, and the simple mathematical treatment given below has strong similarities with the theory of the distribution of alternating current in a conductor of finite size.

The potassium permeability of a giant nerve fibre

Abstract: The experiments described in the preceding paper (Hodgkin & Keynes, 1955) show that metabolic inhibitors like dinitrophenol and cyanide produce large changes in the relative magnitude of the fluxes of potassium moving inwards and outwards across the membranes of giant axons from Sepia officinalis. For normal fibres recovering from stimulation the influx is 15-30 pmole/cm2 sec, while the efflux is 20-40 pmole/cm2 sec. On poisoning with dinitrophenol, which virtually abolishes the sodium efflux, the potassium influx is reduced to 2-3 pmole/cm2 sec, while the efflux remains the same or is slightly increased. These facts may be explained by supposing that in normal fibres there is, in addition to the passive potassium movements seen by themselves in poisoned fibres, an activeuptake ofpotassium, coupled to the extrusion ofsodium, and amounting to about 20 pmole/cm2 sec. This hypothesis is attractive in that it provides a reasonable explanation ofthe further observation that the sodium efflux drops by some 20 pmole/cm2 sec when external potassium is removed, but it raises one serious difficulty which needs to be resolved. According to the equation derived by Ussing (1949b) for independent passive transport of ions, the influx (Mi) and the efflux (M0) of a monovalent cation such as potassium should be related in the following way:

The effect of the cardiac membrane potential on the rapid availability of the sodium-carrying system

Abstract: There is evidence suggesting that the onset of electrical activity in nerve and muscle depends on a specific permeability increase of the surface membrane which allows sodium ions to enter the fibre at a high rate (for references, see Hodgkin, 1951). Furthermore, it has been shown for the giant axon of the squid (Hodgkin & Huxley, 1952 a) that the amount by which the sodium permeability increases during activity (or depolarization) depends on the value of the potential difference which had been acting on the surface membrane before the depolarization. The present experiments were undertaken in order to look for a similar effect in mammalian Purkinje fibres. By means of a feedback circuit the 'resting' potential could be chosen at will; its effect was observed on certain features of the action potential which are thought to be indicative ofthe sodium permeability, namely the upstroke velocity and the size of the 'overshoot'.

Effects of calcium ions and local anaesthetics on electrical properties of Purkinje fibres

Abstract: Calcium ions and local anaesthetics are said to 'stabilize' excitable membranes. This statement is based on the findings that in the presence of these agents (i) stronger currents are needed to stimulate the tissues, (ii) spontaneous rhythms are slowed or suppressed, (iii) conduction of impulses may be blocked, and (iv) the resting potential remains practically unchanged (for references, see Fleckenstein & Hardt, 1952; Brink, 1954). The present paper describes the action of calcium ions and local anaesthetics on the magnitude of the diastolic membrane potential, the rate of rise and ' overshoot' of the action potential, the threshold potential and the membrane resistance of mammalian Purkinje fibres. A knowledge of such data may contribute to an understanding of the mode of action of these 'stabilizing' agents. METHODS

Tension receptors in the stomach and the urinary bladder

Abstract: The existence of receptors in the abdominal and pelvic viscera of mammals has long been known from the reflex responses which can be elicited by a variety of experimental procedures (Ranson, 1921; Irving, McSwiney & Suffolk, 1937). Hurst (1911) made an extensive clinical study of the sensibility of the alimentary canal, and concluded that a form of 'muscle-sense' existed in all parts of the alimentary canal, but did not further investigate the receptors. Afferent impulses from gastric and intestinal receptors of the cat have been recorded in the splanchnic nerves and in fine mesenteric nerve strands by Gernandt & Zotterman (1946) and in the cervical vagus by Paintal (1954). Impulses in hypogastric and pelvic afferent fibres from bladder receptors of the cat have been recorded by Evans (1936) and of the dog by Talaat (1937). It has been customary to regard the sense endings as stretch receptors, but no attempt has been made to establish whether the activity is related to muscle tension and, if so, whether the receptors are 'in parallel' or 'in series' with the muscle fibres. The problem has been re-investigated by recording from single afferent fibres in the cervical vagus and the pelvic plexus. Particular attention has been directed to the discharge in single fibres during distension and contraction of the viscera and to the size of the afferent fibres. A preliminary account of this work has been published (Iggo, 1954).

On the localization of acetylcholine receptors.

Abstract: The presence of special chemoreceptor substances at the motor end-plate was recognized when Langley (1907) showed that the junctional region of a muscle is highly sensitive to cerain chemical stimulants. With the use of single fibres, Buchthal & Lindhard (1937) and Kuffler (1943) demonstrated that the stimulating action of acetyl4holine (ACh) is restricted to the synaptic area of the muscle membrane, or at least that the potency of ACh at the end-plate greatly exceeds that at nerve-free regions. More recently, it became possible to use micropipettes for very localized applications of ACh+ ions to single endplates. This method was employed by Nastuk (1951, 1953, 1954) who showed that a pipette of less than 0-5 , tip diameter can be used, either as a continuous point source from which ACh is allowed to diffuse at constant rate towards a nearby end-plate, or, even more effectively, as a momentary source from which ACh+ ions are released electrophoretically, the quantity of the discharge being controlled by the strength and duration of an outward-passing current pulse. This method offers further advantages, for the pipette is small enough to be inserted into the interior of the muscle fibre. Thus, given amounts of ACh can be applied to both sides of the end-plate membrane either in the conventional manner, to the outer surface of the membrane which faces the nerve endings, or to the inner surface which faces the sarcoplasm. Experiments will be described which show that intracellular application of ACh is, relatively or completely, ineffective (see also Castillo & Katz, 1954c). The evidence supports the view that specific chemoreceptors are located on the external surface of the end-plate, that is on the side of the muscle membrane which makes contact with the nerve endings, while the internal surface of that membrane is insensitive to applied ACh.

The blood flow in skin and muscle of the human forearm

Abstract: The venous occlusion plethysmograph measures the total blood flow through all component tissues of a limb segment. It does not give any indication of the relative flow through the skin, muscle and supporting tissues. In the past, observed changes in forearm blood flow have been ascribed, by different workers, to changes in the different component tissues of the limb segment. However, no direct quantitative measurements of the flow in these different tissues have been made in man. Estimates of skin blood flow have been made by Hertzman (1948), using the photo-electric plethysmograph. Behnke & Wilimon (1941) have used the rate of absorption of helium through the skin as an indication of cutaneous blood flow. Hardy & Soderstrom (1938) have, by a study of the skin and deep temperatures, attempted to assess the skin blood flow. The heat elimination of the skin has been measured by Hensel (1952) using a modification of Aschoff's (1944) continuous-flow calorimeter. All these methods can be considered to give an indication of changes in the skin blood flow, but none of them has been correlated with a method which gives a quantitative record of the cutaneous blood flow. The method of physiological skinning of the forearm by iontophoresis with adrenaline developed by Barcroft, Bonnar, Edholm & Effron (1943) has been used to measure skin flow. The forearm blood flow may vary considerably from day to day, even with the subject at rest. Making use of these fluctuations in forearm blood flow, induced by internal and environmental factors, it is possible to estimate the skin and muscle blood flows occurring in the forearm over a substantial range of flows in that segment, and the results are presented in this paper (Cooper, Edholm & Mottram, 1954).

The relation of pulsatile pressure to flow in arteries.

Abstract: This paper is concerned with the recording of the phasic changes in arterial flow during each cardiac cycle, and the investigation of the pressure oscillations generating this flow. The relation of pressure to flow is 'the central problem in haemodynamics' (Burton, 1952), and has never been satisfactorily resolved for arterial flow, as its oscillatory nature makes the application of Poiseuille's law invalid. The study has been confined here to the femoral artery of the dog. Direct measurements of flow have been made by following the movement of injected bubbles of oxygen recorded by high-speed cinematography (McDonald, 1952 a). Pressure gradients have been measured by simultaneous recording of arterial pressure at two points in the artery and also by electrical differentiation of the output of a capacitance manometer. Flow curves have been calculated from the gradients using equations derived by Womersley (1954), the theory of which is presented in his accompanying paper (Womersley, 1955). General agreement between observed and calculated flow curves has been found and so establishes the validity of the theoretical derivation based on general hydrodynamic principles and also justifies the method of recording flows. Preliminary accounts have been presented to the Physiological Society both of the flow curves (Helps & McDonald, 1953) and of the derivation of flow from the pressure gradients (Helps & McDonald, 1954).

The pulmonary diffusing capacity in normal subjects

Abstract: The measurement of the pulmonary diffusing capacity has recently been the subject of renewed interest, largely stimulated by the development by Lilienthal (Lilienthal, Riley, Proemmel & Franke, 1946) and Riley (Riley, Lilienthal, Proemmel & Franke, 1946; Riley & Cournand, 1951; Riley, Shepard, Cohn, Carroll & Armstrong, 1954) of a new technique for measuring it. In 1910, August & Marie Krogh described the measurement of the diffusing capacity of the lungs during continuous breathing of carbon monoxide, and also during a period of breath holding. They realized that the first of these methods was made unreliable by the difficulty of calculating the alveolar ventilation, from which the mean tension of CO in the alveoli was derived. This is a critical measurement in the calculation of diffusing capacity since this mean tension is the denominator of the fraction which constitutes it. Riley's method circumvents this difficulty since the mean alveolar 02 gradient is calculated without direct dependence on the dead space. However, difficulty is encountered when the tidal volume exceeds about 1 1., since in these circumstances a small error in the measured arterial pCO2 leads to a very considerable change in calculated effective dead space. In a recent paper Riley (Riley et al. 1954) notes this difficulty, and as he finds that the dead space so calculated is often obviously erroneous, he prefers to substitute a more likely value during estimations on exercise, thus in effect 'correcting' the arterial pCO2. It should be noted that this difficulty observed by Riley operates reciprocally so that during exercise with increasing ventilation, the assumed value of the respiratory dead space influences the calculated mean alveolar CO tension to a smaller and smaller extent. It will be shown later that very different values for respiratory dead space may be assumed during exercise, without these

The release of histamine and 5-hydroxytryptamine (serotonin) from platelets by antigen-antibody reactions (in vitro).

Abstract: It has been known for some time that addition of antigen to the heparinized blood of sensitized rabbits in vitro usually results in the appearance of considerable quantities of histamine in the plasma. In his earlier work (1944) Code considered that the histamine came from the white cells, but in a recent review (Code, 1952) he concluded that, in the rabbit, platelets were probably the major source. He also pointed out that a similar release of histamine from blood cells into plasma occurred during clotting, as a result of mechanical trauma, and on addition of proteolytic enzymes or peptone to the blood. McIntire, Roth & Richards (1949), who studied the release of histamine from the cells of the blood of rabbits sensitized to egg white, when incubated in the presence of the antigen, concluded that neither thrombin nor prothrombin were involved, and furthermore found no inhibition even when large amounts of trypsin inhibitor were added. Our interest in this phenomenon arose in, the course of studies on the effect of antigen-antibody reactions on white cells in vitro, during which we observed that purified antigen-antibody systems did not cause histamine release from the washed buffy'layer of rabbit blood unless plasma were also present. Further study showed that free calcium ions were essential, and we also observed that, besides histamine, 5-hydroxytryptamine (serotonin) was released concomitantly. A limited survey of the histamine and 5-hydroxytryptamine content of the platelets and white cells of various species showed striking inter-species variation (Humphrey & Jaques, 1954). In this paper are reported some observations on the mechanism of histamine and 5-hydroxytryptamine release, which are largely concerned with rabbit blood, although other species are considered briefly. A preliminary account has already been published (Humphrey & Jaques, 1953).

Local activity at a depolarized nerve-muscle junction

Abstract: In this paper experiments are described in which the behaviour of the neuromuscular junction was studied under abnormal conditions. It was hoped to throw further light on the action of acetylcholine (ACh) and on the factors which govern its release from the nerve endings, by examining end-plates which had been subjected to gross changes in the ionic environment. Bath solutions were used whose sodium chloride content had been entirely replaced by sucrose or potassium sulphate. In the latter case the tissue became not only inexcitable but also completely depolarized. It was of interest to find out whether under such abnormal circumstances ACh would still react with the end-plate receptors and produce detectable electric changes in the postsynaptic membrane. This might conceivably be the case, for previous work (Fatt & Katz, 1951; Castillo & Katz, 1954b) suggested that the effect of ACh is independent of, and involves different reactions and different receptors from, the process of electric excitation. Experiments were also made to discover whether the intermittent quantal release of ACh from the motor nerve endings, which occurs spontaneously in the normal preparation and gives rise there to the firing of miniature endplate potentials, continues to operate in depolarized and sodium-deprived tissue. It had been suggested (Fatt & Katz, 1952 a, b) that the release of ACh and the spontaneous activity at the junction depend on the presence of sodium in the surroundings and on the maintenance of excitability of the nerve endings, but the results described below (see also Castillo & Katz, 1954d) call for a revision of this hypothesis.

Potentials recorded from the spinal cord with microelectrodes.

Abstract: The present article is the first of a series of papers designed to describe results obtained by recording the electrical activity of elements in the lumbar region of the spinal cord of cats by means of intracellular micropipettes. Results obtained applying this technique to the study of spinal reflexes have already been reported by Brock, Coombs & Eccles (1952, 1953), Eccles (1952), Eccles, Fatt & Koketsu (1954) and Woodbury & Patton (1952). While in the studies just quoted attention was focused on the abrupt responses elicitable in anaesthetized preparations, an effort was made in this research to analyse the activity of preparations presenting the sustained responses described by Sherrington. Whereas it was usually easy to determine whether the electrode was located in primary sensory fibres, interneurones or motoneurones, it was found difficult to establish whether the potentials were recorded from somata or axons of post-synaptic units, and whether they originated in 'normal' or in damaged units. The results to be described will show the importance of clarifying these problems, and may justify the rather extensive discussion of the techniques employed and of the criteria used for selecting results and for identifying somatic or axonal origin of the recorded potentials.

Study of the photosensitive pigments in the pink and green rods of the frog

Abstract: It is generally accepted that, of the light striking an animal's eye, the fraction useful for vision is that absorbed by the photosensitive pigments in its retinal receptors. Spectral sensitivity and ibsolute sensitivity depend on the absorption curves and optical densities of such pigments within the receptors. The methods which have been most used to measure the absorption curves and densities of visual pigments are those in which the pigments are extracted from the retina and studied in solution. Recently, however, Rushton (1952), Hagins & Rushton (1953a, b) and Weale (1953a, b) have made measurements on retinae in situ. One aim of the present experiments was to design a simple method for measuring densities of photosensitive pigments in individual receptors. The method evolved was applied to the study of frog retinae. Photomicrographs of a retina were made before and after bleaching its photosensitive pigments. From such photographs the following quantities were found: (1) The density change on bleaching of the individual visual purple filled rods for light of wavelength 052,u. (2) The relative areas of the rods and the spaces between them. (3) The average retinal density change on bleaching for wavelength 052,u. (4) The curve of average retinal density change on bleaching against wavelength. Some information was also obtained about the numbers and spectral absorption of the green rods.

A comparative study of the aqueous humour and cerebrospinal fluid in the rabbit

Abstract: The aqueous humour and cerebrospinal fluid (c.s.f.) are specialized tissue fluids with a number of features in common. Just how far the analogy between the two fluids may be carried, however, is by no means clear, and in this work the two fluids, drawn from the same animal, have been compared with a view to establishing points of similarity and difference. The aspects investigated have been the distribution of certain solutes between the fluids and plasma, and kinetic studies of the blood-aqueous and blood-c.s.f. barriers. The interpretation of these kinetic studies required an investigation into the uptake of material by the lens from the aqueous humour, and a study of the kinetics of uptake of material by the brain tissue-the blood-brain barrier.

5‐hydroxytryptamine in normal human platelets

Abstract: It has been shown by Humphrey & Jaques (1954) and by Udenfriend & Weissbach (1954) that 5-hydroxytryptamine (HT) in the blood is carried almost entirely by platelets. This suggested that light might be thrown on the physiological function of HT by an inquiry into its concentration and distribution in blood disorders, especially those in which platelet formation and function are abnormal. Some preliminary work showed that there is, in fact, a very marked reduction in both the whole blood and platelet content of this substance in certain diseases. The work reported here, a preliminary account of part of which has already appeared (Hardisty & Stacey, 1955), was carried out in order to establish a reliable method for estimating HT in blood, to determinine standards for normal human subjects and to develop a method for evaluating the ability of platelets to absorb HT.

Velocity profiles of oscillating arterial flow, with some calculations of viscous drag and the Reynolds number

Abstract: Although the velocity distribution of a viscous liquid in steady laminar flow along a straight pipe is well known, much less is known of the flow-pattern when the motion is oscillatory. Such knowledge is essential if correct hydrodynamical principles are to be applied to the circulation of the blood, for not only is arterial flow oscillatory in nature (McDonald, 1955; Womersley, 1955 a) but so also is the flow in the larger veins (Helps & McDonald, 1954). In this paper we present some observations and calculations of the distribution of velocity across an artery (the velocity profile). Arising from this, it is possible to make a plausible estimate of the limit of stability of laminar flow when the motion is oscillatory. A transient breakdown of laminar flow during systole has been observed in the rabbit aorta (McDonald, 1952) even though the maximum Reynolds number was considerably below its critical value for steady motion. We have calculated the maximum rate of shear occurring in oscillatory flow and so have been able to determine the corresponding Reynolds number for a steady flow which would give the same rate of shear. This 'effective Reynolds number' can be made the basis of an estimate of the velocity at which laminar flow will become unstable when the motion is oscillatory.

Hypothalamic control of food intake in cats and monkeys.

Abstract: The role of the central nervous system in regulating food intake was probably suggested first by the discovery that either obesity or emaciation may occur in patients with nervous diseases. For a while these observations were not properly evaluated, because emphasis was laid upon the obesity as such, or the leanness, rather than upon the changed eating habits responsible for the clinical picture. Interest was focused on the hypothalamic region by the experimental studies of many workers (Hetherington, 1941; Hetherington & Ranson, 1940, 1942 a, b; Brobeck, Tepperman & Long, 1943; Kennedy, 1950; Ranson, Fisher & Ingram, 1938) who showed that bilateral lesions in the medial hypothalamus, especially lesions in or ventro-lateral to the ventromedial nucleus, resulted in obesity. The confusion introduced by the notion that pituitary disturbances caused obesity was also clarified by Hetherington (1943), who showed that the hypophysis is in no way directly concerned with the pathogenesis of obesity following injury to the base of brain. Brobeck et al. (1943) demonstrated that this hypothalamic obesity was due to increased food intake (hypothalamic hyperphagia) rather than to disturbances in the fat, carbohydrate or intermediary metabolism. From the time of its discovery this hyperphagia was assumed to be a release phenomenon brought about through the destruction of an inhibitory mechanism.The existence of another mechanism in the lateral hypothalamus of the rat, which controls the 'instinct' or the 'urge' to eat, was demonstrated by Anand & Brobeck (1951 a, b). They showed that bilateral destruction of a well localized area in the lateral hypothalamus, at the same rostro-caudal level as the ventro-medial nucleus, produces complete aphagia and death due to starvation, in spite of the availability of food. It was also observed that of the two mechanisms the lateral one exerts the more basic type of control over food intake and the medial one (inhibitory) produces its effects only when the lateral is intact. The lateral mechanism is designated a 'feeding centre', or even an 'appetite centre', while the medial one is called a 'satiety centre'. Joliffe named the two, together, the 'appestat'. The present study was undertaken to determine, whether similar mechanisms exist in the hypothalamic regions of higher mammals, cats and monkeys, and also whether they are modified by the more highly evolved higher nervous centres.

The effect of localized cooling on conduction in cat nerves

Abstract: It is an old observation that cold blocks nervous conduction and that nerve fibres subserving different modalities differ in their susceptibilities. Commonly it is believed that susceptibility to cold block is related to the diameter of the individual nerve fibre. The evidence for this belief is, however, fragmentary and conflicting. Comparing C fibres with A fibres, Lundberg (1952) found that the former were most resistant to cold block, but in Sinclair & Hinshaw's (1951) experiments the fibres most resistant to cold were not C fibres but certain fibres of the A group. A similar divergence of results is also apparent in experiments to assess the differential susceptibilities of different sized fibres within the large (myelinated) fibre group itself. In some experiments the largest of these fibres have proved the most sensitive to cold block (Torrance & Whitteridge, 1947; Whitteridge, 1948), while in others (Lundberg, 1952; Dodt, 1953) they have proved least sensitive. The work reported here describes the effects of localized cooling on several nerves in the cat.

The inhibitory suppression of reflex discharges from motoneurones.

Abstract: In a preceding paper (Coombs, Eccles & Fatt, 1955b) an account was given of the ionic events (increases in membrane permeability and the consequent ionic fluxes) that account for the potential changes which are produced in motoneurones by inhibitory impulses, i.e. the inhibitory post-synaptic potential (i.p.s.p.). The present paper provides evidence on two further questions that arise in an inquiry into central inhibitory action: What is the time course of the postulated change in membrane permeability? How does this membrane change together with the consequent ionic fluxes cause the inhibitory suppression of reflex discharges from motoneurones? The intensity-time course of this inhibitory suppression has been thoroughly studied with direct inhibitory action on monosynaptic reflex discharges (Lloyd, 1946; Laporte & Lloyd, 1952; Bradley, Easton & Eccles, 1953). Actually the intensity of inhibition is indirectly measured by the depression of the size of a testing monosynaptic reflex discharge which is applied at various times during the direct inhibitory action of a single afferent volley. The time course of the intensity so measured may be called an inhibitory curve. It will be shown below that it is possible to explain in detail the inhibitory curve that is produced with direct inhibitory action on a population of motoneurones.

The cause of the vasodilatation accompanying activity in the submandibular salivary gland.

Abstract: Claude Bernard (1858) showed that stimulation of the chorda tympani led to vasodilatation in the submandibular salivary gland, and Heidenhain (1872) found that this effect was not abolished by doses of atropine that prevented salivary secretion. On the basis of these observations, a special set of vasodilator nerve fibres in the chorda was postulated which was supposed to be stimulated concomitantly with the secretory fibres when the gland was activated. When the humoral theory of neuro-effector transmission had been established, it became difficult to account for the failure of atropine to block the vasodilatation; for the secretory nerve fibres which were blocked were certainly cholinergic and the vasodilator nerve fibres had been thought to be in the same category. Dale & Gaddum (1930) attempted to account for this discrepancy by supposing that the acetylcholine was released from vasodilator nerve endings in such great 'intimacy with the receptor mechanism that atropine cannot prevent its access thereto'. Barcroft (1914) had, on the other hand, discarded the notion of special vasodilator nerve fibres and had shown that the metabolic activity of the atropinized salivary gland was still increased when the chorda was stimulated, even though no secretion was obtained. He thus accounted for the vasodilatation as the outcome of metabolic activity in the gland, much the same as had already been suggested for the origin of the vasodilatation in active muscle. Gaskell (1916), who accepted this explanation, quoted some experiments by Severini (1878) who had found histological changes in the secretory cells after chorda stimulation of the atropinized gland. In addition to these two possible explanations of the origin of the vasodilatation in the active gland, it could be suggested that there are vasodilator fibres in the chorda tympani whose postganglionic connexions are non-cholinergic;