Showing papers in "The Journal of Physiology in 1983"

Excitatory amino acids in synaptic transmission in the Schaffer collateral-commissural pathway of the rat hippocampus.

Abstract: 1. The effects of excitatory amino acids and some antagonists applied by ionophoresis to stratum radiatum in the CA1 region of rat hippocampal slices were examined on the locally recorded field e.p.s.p. evoked by stimulation of the Schaffer collateral-commissural projection. 2. L-glutamate, L-aspartate and the more potent and selective excitatory amino acids quisqualate, kainate and N-methyl-DL-aspartate (NMA) depressed the e.p.s.p., presumably through depolarization and/or a change in membrane conductance. 3. The depression induced by kainate considerably outlasted the period of ejection whereas NMA depressions were rapidly reversible and were often followed by a potentiation of the e.p.s.p. In higher doses NMA also depressed the presynaptic fibre volley. The possible involvement of these effects in neurotoxicity and synaptic plasticity is raised. 4. The selective NMA antagonist, DL-2-amino-5-phosphonovalerate (APV) applied in doses which abolished responses to NMA, had no effect on the e.p.s.p. but prevented long term potentiation (l.t.p.) of synaptic transmission evoked by high frequency stimulation of the Schaffer collateral-commissural pathway. Other antagonists which had little or no effect on normal synaptic transmission included D-alpha-aminoadipate (DAA), the optical isomers of 2-amino-4-phosphonobutyrate (APB) and L-glutamate diethylester (GDEE). 5. In contrast, gamma-D-glutamylglycine (DGG), applied in amounts which affected quisqualate and kainate actions as well as those of NMA, was an effective synaptic antagonist whilst having no effect on the presynaptic fibre volley. 6. These results indicate that the synaptic receptor in the Schaffer collateral-commissural pathway may be of the kainate or quisqualate type. Although NMA receptors do not appear to be involved in normal synaptic transmission in this pathway they may play a role in synaptic plasticity. The interaction of L-glutamate and L-aspartate with these receptors is discussed.

Strength and cross‐sectional area of human skeletal muscle.

Abstract: The maximum voluntary force (strength) which could be produced by the knee-extensor muscles, with the knee held at a right angle, was measured in a group of healthy young subjects comprising twenty-five males and twenty-five females. Both legs were tested: data from the stronger leg only for each subject were used in the present study. Computed tomography was used to obtain a cross-sectional image of the subjects' legs at mid-thigh level, measured as the mid-point between the greater trochanter and upper border of the patella. The cross-sectional area of the knee-extensor muscles was determined from the image obtained by computer-based planimetry. The subjects' height and weight were measured. An estimate of body fat content was obtained from measurements of skinfold thicknesses and used to calculate lean body mass. Male subjects were taller (P less than 0.001), heavier (P less than 0.001), leaner (P less than 0.001) and stronger (P less than 0.001) than the female subjects. No significant correlation was found to exist between strength of the knee-extensor muscles and body weight in the male or in the female subjects. In the male subjects, but not in the female group, there was a positive correlation (r = 0.50; P less than 0.01) between strength and lean body mass. Muscle cross-sectional area of the male subjects was greater than that of the female subjects (P less than 0.001). The ratio of strength to cross-sectional area for the male was 9.49 +/- 1.34 (mean +/- S.D.). This is greater but not significantly so, than that for females (8.92 +/- 1.11). In both male and female groups, there was a significant (P less than 0.01) positive correlation between muscle strength and cross-sectional area. A wide variation in the ratio of strength to muscle cross-sectional area was observed. This variability may be a result of anatomical differences between subjects or may result from differences in the proportions of different fibre types in the muscles. The variation between subjects is such that strength is not a useful predictive index of muscle cross-sectional area.

A transient calcium‐dependent chloride current in the immature Xenopus oocyte.

Abstract: Ionic currents were studied in immature full-grown Xenopus oocytes using the two-micro-electrode voltage-clamp technique. Recordings of total membrane current showed a transient outward peak during depolarizations from the approximate resting voltage (-70 or -80 mV) to voltages more positive than -20 mV. The current-voltage relation for peak outward current was U-shaped, with a maximum at about 0 mV. Replacement of external Cl with methanesulphonate reversed this transient outward current to a transient inward current. Current relaxations recorded after the membrane potential was stepped to different voltages at the time of the peak showed a component that inverted at about -25 to -30 mV. This value was close to ECl as determined by measurement of the intracellular Cl ion concentration. The reversal potential for these current relaxations changed with the external Cl concentration as predicted by the Nernst relation. Replacement of external Ca with Mg, Sr or Ba, or addition of low concentrations of Ni in the presence of Ca, eliminated the transient outward current. Increasing the external Ca concentration increased the amplitude of the transient outward current without affecting the amplitude of the steady-state current. It was concluded that the outward peak in records of total membrane current represented the contribution of a transient outward current carried by Cl ions which was dependent on the entry of external Ca. It will be noted as ICl(Ca). Decay of ICl(Ca) could be described at the normal Ca concentration by a single exponential function whose time constant showed a shallow U-shaped voltage dependence. ICl(Ca) was maximally activatable by depolarizations from a holding potential of about -100 mV, but could not be activated by depolarizations from -40 mV. The amplitude of ICl(Ca) showed a large temperature dependence as compared to the steady-state current, suggesting complex control of its activation.

Sensations evoked by intraneural microstimulation of single mechanoreceptor units innervating the human hand.

Abstract: Intraneural microstimulation (i.n.m.s.) was performed in awake human volunteers, using tungsten micro-electrodes inserted into median and ulnar nerve fascicles supplying the skin of the hand. The same electrodes were used alternatively to record impulse activity from single nerve fibres at the i.n.m.s. sites. Monitoring occasionally, with a proximal electrode, the impulse traffic evoked by i.n.m.s. distally in the same fascicle, established that the stimulation procedure could be made selective enough to activate single myelinated fibres in isolation, while also permitting multifibre recruitment. Monitoring propagated impulses also established that i.n.m.s. of a single myelinated fibre supplying a low-threshold mechanoreceptor in the hand might evoke an elementary sensation. Such sensations were fully endowed with cognitive attributes amenable to psychophysical estimation: quality, magnitude and localized projection. Psychophysical tests were made during i.n.m.s. at intraneural sites where single-unit activity was recorded from classified RA, PC, SA I or SA II mechanoreceptors. Changes in excitability of the nerve fibre of an identified unit, induced by further i.n.m.s., certified that the recorded unit had been stimulated during psychophysical tests. Comparing physical location of the receptive field of a recorded unit and localization of the projected field of the corresponding elementary sensation, revealed that either predicted the other accurately. This further assisted identification of the unit activated by i.n.m.s. The type of a recorded unit and the quality of the elementary sensation evoked by its activation were also reciprocally predictive. RA units evoked intermittent tapping, PC units vibration or tickle and SA I units evoked pressure. SA II units evoked no sensation when activated in isolation. Afferent impulse frequency determined magnitude of pressure in the SA I system, and frequency of vibration in the PC system. In the RA system, stimulation frequency determined frequency of tapping-flutter-vibration sensation at relatively low rates and subjective intensity of sensation at high rates. These findings endorse the concept that quality of sensation is coded in specific sensory systems. Further, they provide novel evidence that sensory quality, magnitude and localization can be exquisitely resolved at cognitive levels on the basis of input initiated in a single mechanoreceptor unit.

A voltage-clamp analysis of inward (anomalous) rectification in mouse spinal sensory ganglion neurones.

Abstract: Mouse embryo dorsal root ganglion neurones were grown in tissue culture and voltage-clamped with two micro-electrodes. Hyperpolarizing voltage commands from holding potentials of -50 to -60 mV evoked slow inward current relaxations which were followed by inward tail currents on repolarization to the holding potential. These relaxations are due to the presence of a time- and voltage-dependent conductance provisionally termed Gh. Gh activates over the membrane potential range -60 to -120 mV. The presence of Gh causes time-dependent rectification in the current-voltage relationship measured between -60 and -120 mV. Gh does not inactivate within this range and thus generates a steady inward current at hyperpolarized membrane potentials. The current carried by Gh increases when the extracellular K+ concentration is raised, and is greatly reduced in Na+-free solutions. Current-voltage plots show considerably less inward rectification in Na+-free solution; conversely inward rectification is markedly enhanced when the extracellular K+ concentration is raised. The reversal potential of Ih is close to -30 mV in media of physiological composition. Tail-current measurement suggests that Ih is a mixed Na+-K+ current. Low concentrations of Cs+ reversibly block Ih and produce outward rectification in the steady-state current-voltage relationship recorded between membrane potentials of -60 and -120 mV. Cs+ also reversibly abolishes the sag and depolarizing overshoot that distort hyperpolarizing electrotonic potentials recorded in current-clamp experiments. Impermeant anion substitutes reversibly block Ih; this block is different from that produced by Cs+ or Na+-free solutions: Cs+ produces outward rectification in the steady-state current-voltage relationship recorded over the Ih activation range; in Na+-free solutions inward rectification, of reduced amplitude, can still be recorded since Ih is a mixed Na+-K+ current; in anion-substituted solutions the current-voltage relationship becomes approximately linear. It is concluded that in dorsal root ganglion neurones anomalous rectification is generated by the time-and voltage-dependent current Ih. The possible function of Ih in sensory neurones is discussed.

Changes in motoneurone firing rates during sustained maximal voluntary contractions.

Abstract: Tungsten micro-electrodes have been used to record the electrical activity of single motor units in the human adductor pollicis during maximal voluntary contractions. The potentials were characteristic of those from single muscle fibres. In brief maximal contractions, the firing rates of over 200 motor units were obtained from five normal subjects. Four subjects had a similar range (mean 26.4 +/- 6.5 Hz) while the fifth was slightly higher (35 +/- 7.4 Hz). When maximal voluntary force was sustained for 40-120 s, there was a progressive decline in the range and mean rate of motor-unit discharge. In the first 60 s, mean rates fell from about 27 Hz to 15 Hz. There was some evidence to suggest that those units with the highest initial frequencies changed rate most rapidly. It is suggested that this decline in motor unit discharge rates is not responsible for force loss, but that it may enable effective modulation of voluntary strength by rate coding to continue during fatigue.

Responses in muscle afferent fibres of slow conduction velocity to contractions and ischaemia in the cat.

Abstract: The aim of the study was to find out to what extent muscle receptors with slowly conducting afferent fibres (group III and IV) are activated by muscular contractions of moderate force, and what kind of muscle afferents could mediate the pain of ischaemic exercise. In chloralose-anaesthetized cats, the impulse activity of single afferent units from the triceps surae muscle was recorded from dorsal root filaments during muscular contractions with intact blood supply and after occlusion of the muscle artery. Two types of responses were observed to contractions without muscular ischaemia. One was characterized by sudden onset and a graded response amplitude to contractions of increasing force. In most cases stretching the muscle was also an effective stimulus. Units showing this response behaviour were labelled c.s.m (contraction-sensitive with mechanical mechanism of activation). The other response type had a more delayed onset and often outlasted the exercise period; because of the unknown mechanism of activation, units of this kind were labelled c.s.x. The proportion of c.s.m receptors was significantly higher amongst group III than amongst group IV units. During ischaemic contractions of comparable force the c.s.m and c.s.x receptors exhibited an unchanged or a decreased response amplitude. Under these conditions another receptor type (N, for nociceptive) was activated which did not respond to contractions with intact blood supply. Vigorous activations during ischaemic work were only observed in group IV receptors. The majority of the 131 group III and IV units tested did not respond to contractions at all. These contraction-insensitive (c.i.) endings probably comprised different receptor populations (nociceptors, thermoreceptors, low-threshold mechanoreceptors). It is concluded that the various central nervous effects of muscular exercise without ischaemia which are known to be due to raised activity in thin muscle afferents (e.g. cardiopulmonary adjustments, spinal locomotor reflexes) are probably produced by the c.s.m and c.s.x types. The pain of ischaemic contractions is most likely mediated by the N receptors most of which possess non-myelinated afferent fibres.

The antagonism of amino acid-induced excitations of rat hippocampal CA1 neurones in vitro.

Abstract: 1. The effects of the ionophoretic application of a number of excitatory amino acids and antagonists to the dendrites of CA1 neurones of rat hippocampal slices maintained in vitro were examined. Cells were excited by N-methyl-DL-aspartate (NMA), kainate, quisqualate, L-aspartate and L-glutamate; NMA was unique in causing cells to fire in bursts of repetitive discharges in contrast to the sustained firing seen with the other compounds. 2. D-(-)-alpha-aminoadipate (DAA) and (+/-)-2-amino-5-phosphonovalerate (APV) were selective NMA antagonists, the latter appearing to be the more potent; in addition both compounds potentiated the responses to kainate and quisqualate. L-glutamate excitations were affected less by APV than were those of L-aspartate. The antagonist properties of APV appeared to reside with the D-(-)-isomer. 3. gamma-D-glutamylglycine (DGG) in low ionophoretic doses inhibited NMA-, kainate- and aspartate-induced cell firing but at higher doses the quisqualate and glutamate responses were also decreased. 4. Kainate and NMA responses were blocked by D-(-)-2-amino-4-phosphonobutyrate (D-APB) which also had some action against the excitatory effects of L-aspartate. L-APB had no antagonistic effects, but often produced potentiation of amino acid excitations or was itself an excitant. 5. The effects of NMA and those of kainate and quisqualate were blocked by (+/-)-cis-2,3-piperidine dicarboxylate (PDA), but this compound itself had a direct excitatory effect. L-glutamate diethylester (GDEE) did not show specific antagonism of any amino acid excitations. 6. DGG and APV did not affect ACh excitations and these selective antagonists should be of value in studying the involvement of the excitatory amino acids in synaptic transmission in the hippocampus. Because they are less potent and/or have complicating direct effects PDA, GDEE, D- and L-APB may be less useful in this regard.

Effects of adrenaline and of spontaneous labour on the secretion and absorption of lung liquid in the fetal lamb.

Abstract: In the chronically catheterized fetal lamb, intravenous infusion of adrenaline at 0.5 microgram/min produced slowing of the secretion of lung liquid or its absorption, an effect which increased exponentially with advancing gestation. Between 120 and 130 days, the characteristic response was slowing of secretion, whereas after 130 days it was absorption. Stimulus-response curves, relating secretion or absorption rate to plasma adrenaline concentration, were obtained by infusing adrenaline into the fetus intravenously at rates between 0.1 and 1.0 microgram/min (0.55-5.5 nmol/min). These curves allowed estimation of the minimum concentration of adrenaline required to inhibit secretion [( Ai]) and this was found to decrease from 0.43 ng/ml. (2.35 nM) at 132-4 days' gestation to 0.029 ng/ml. (0.16 nM) at gestations above 140 days. During spontaneous labour there was a slowing of lung liquid secretion in the early stages followed by absorption during the last 50-150 min. The mean concentration of adrenaline in plasma increased from 0.087 ng/ml. (0.48 nM) in early labour to 6.86 ng/ml. (37.5 nM) in the last 50 min and to 7.17 ng/ml. (39.2 nM) in the early post-natal period. Mean noradrenaline levels at the same times were 1.71 ng/ml. (10.1 nM), 12.14 ng/ml. (71.8 nM) and 9.10 ng/ml. (53.9 nM). The relationship between the plasma adrenaline concentration and the rate of absorption during labour was similar to that found when adrenaline was infused at various rates into the non-labouring fetus of comparable gestational age. The upper airway of the fetus was shown to be capable of acting as a one-way valve allowing outflow but not inflow of liquid. Thus withdrawal of liquid at 5-20 ml./hr from the fetal trachea below the larynx caused closure of the upper airway and this result was obtained both when the recurrent laryngeal nerves were intact and when they were divided.

Relation between shapes of post-synaptic potentials and changes in firing probability of cat motoneurones

Abstract: 1. The shapes of post-synaptic potentials (p.s.p.s) in cat motoneurones were compared with the time course of changes in firing probability during repetitive firing. Excitatory and inhibitory post-synaptic potentials (e.p.s.p.s and i.p.s.p.s) were evoked by electrical stimulation of peripheral nerve filaments. With the motoneurone quiescent, the shape of each p.s.p. was obtained by compiling post-stimulus averages of the membrane potential. Depolarizing current was then injected to evoke repetitive firing, and the post-stimulus time histogram of motoneurone spikes was obtained; this histogram reveals the primary features (peak and/or trough) of the cross-correlogram between stimulus and spike trains. The time course of the correlogram features produced by each p.s.p. was compared with the p.s.p. shape and its temporal derivative. 2. E.p.s.p.s of different sizes (0.15-3.1 mV, mean 0.75 mV) and shapes were investigated. The primary correlogram peak began, on the average, 0.48 msec after onset of the e.p.s.p., and reached a maximum 0.29 msec before the summit of the e.p.s.p; in many cases the correlogram peak was followed by a trough, in which firing rate fell below base-line rate. The height of the correlogram peak with respect to base-line firing rate increased in proportion to both the amplitude of the e.p.s.p.s and the magnitude of their rising slope (in these data, amplitude and rising slope also covaried). 3. The mean half-width of the correlogram peaks (0.65±0.28 msec (S.D.)) agreed better with the average half-width of the e.p.s.p. derivatives (0.55±0.33 msec) than with the half-width of the e.p.s.p.s (4.31±1.50 msec). The shape of the primary correlogram peak produced by simple e.p.s.p.s often resembled the temporal derivative of the e.p.s.p. rise. For larger e.p.s.p.s, the shape of the correlogram peak closely matched the e.p.s.p. derivative, while smaller e.p.s.p.s in appreciable synaptic noise often generated correlogram peaks somewhat wider than their derivatives. On the other hand, the match between the correlogram trough that followed the peak and the negative slope of the e.p.s.p. was better for the small e.p.s.p.s than for the large e.p.s.p.s; for large e.p.s.p.s the drop in firing rate during the trough was typically limited at zero. These relations were tested further by comparing the integral of the correlogram with the time course of the e.p.s.p. For large e.p.s.p.s, the correlogram integral matched the rising phase of the e.p.s.p. quite well, although it underestimated the rate of decline of the e.p.s.p. 4. Complex e.p.s.p.s with distinct components during their rising phase often produced correlogram peaks that did not accurately reflect the features in their temporal derivative. Temporal summation of large e.p.s.p.s and summation of their derivatives was linear, but the resulting correlogram peaks did not add linearly; the second correlogram peak was often smaller than the first. However, when small e.p.s.p.s were summed, the correlogram peaks more closely matched the e.p.s.p. derivatives. 5. Compound i.p.s.p.s produced primary correlogram troughs followed by a shallow compensatory peak. The width of the trough extended through the peak of the i.p.s.p., well into the falling phase of the i.p.s.p. During the trough the firing rate usually dropped to zero. Thus, the primary correlogram features produced by large i.p.s.p.s did not resemble any linear combination of the shape of the i.p.s.p. and/or its temporal derivative. Moreover, the integral of the correlogram did not resemble the i.p.s.p. 6. The major observations are consistent with a motoneurone model in which a membrane potential ramp approaches a voltage threshold for spike initiation. Near threshold, e.p.s.p.s superimposed on the ramp advance the occurrence of spikes to their rising phase, producing a correlogram peak resembling their temporal derivative. Synaptic noise would increase the probability of sampling the peak of the e.p.s.p., leading to wider correlogram peaks. I.p.s.p.s would delay the occurrence of spikes to their falling phase.

Sarcoplasmic reticulum calcium release in frog skeletal muscle fibres estimated from Arsenazo III calcium transients.

Abstract: Single twitch fibres, dissected from frog muscle, were injected with the metallochromic dye Arsenazo III. Changes in dye-related absorbance measured at 650 or 660 nm were used to estimate the time course of myoplasmic free [Ca2+] following either action potential stimulation or voltage-clamp depolarization (temperature, 15-17 degrees C). The amplitude of the Ca2+ transient decreased when fibres were stretched to sarcomere spacings approaching 4 microns. The effect appeared to be less marked in H2O Ringer than in D2O Ringer, where a reduction of about 40% was observed in going from 3.0 microns to 3.7-3.9 microns. In fibres heavily injected with dye (1.5-2.2 mM-dye) at least 0.1 mM-Ca2+ was complexed with Arsenazo III following a single action potential, implying that at least 0.1 mM-Ca2+ was released from the sarcoplasmic reticulum (s.r.) into the myoplasm. Computer simulations were carried out to estimate the flux of Ca2+ between the s.r. and myoplasm (in fibres containing no more that 0.8 mM-dye). The amounts and time courses of Ca2+ bound to the Ca2+-regulatory sites on troponin and to the Ca2+, Mg2+ sites on parvalbumin were estimated from the free [Ca2+] wave form and the law of mass action. In the computations the total myoplasmic [Ca2+] was taken as the total amount of Ca2+ existing either as free ion or as ion complexed with dye, troponin or parvalbumin. The time derivative of total myoplasmic [Ca2+] was used as an estimate of net Ca2+ flux (release minus uptake) from the s.r. into myoplasm. Rate constants for formation of cation: receptor complex were taken from published values. For the Ca2+-regulatory sites on troponin, three sets of rate constants, corresponding to two values of dissociation constant (0.2 and 2 microM) were used. Each set of three simulations was carried out both with and without parvalbumin. The simulations show that following action potential stimulation, 0.2-0.3 mM-Ca2+ enters the myoplasm from the s.r. The wave form of s.r. Ca2+ release is early and brief compared with the wave form of free [Ca2+]. Neither the selection of troponin rate constants nor the inclusion of parvalbumin has much effect on the shape of the release wave form; the main effect of varying these parameters is to change the magnitude. After the initial, rapid phase of Ca2+ release from the s.r. there is a longer, maintained period of Ca2+ uptake.(ABSTRACT TRUNCATED AT 400 WORDS)

The function of the antagonist muscle during fast limb movements in man.

Abstract: We have examined fast flexion movements of the human thumb and fast extension movements of the elbow over three different distances at a variety of speeds in order to elucidate the function of the antagonist muscle in these circumstances. All movements were of such a velocity that they showed the typical bi- or triphasic pattern of muscle activation in agonist and antagonist. Slower movements, with continuous agonist activity, were not analysed. For movements made through the same angle at different velocities, there was a linear relationship between the amount of antagonist activity needed to halt the movement and the peak velocity. However, the slope of this relationship was a function of the distance moved. Movements made through large angles showed less antagonist activity than those made through small angles at the same speed. The timing of the antagonist activity also changed as a function of both distance and speed. Fast, small movements showed earlier onset of antagonist activity than slow, large ones. Movements which were halted mechanically with the subject's prior knowledge had little or no antagonist activity, since it was no longer necessary in these conditions. The complexity of these relations indicates that the triphasic pattern of muscle activity underlying these movements can no longer be regarded as a simple immutable 'programme'. The size and timing of the bursts of muscle activity are subtly adjusted to the precise nature of the task.

The afferent volleys responsible for spinal proprioceptive reflexes in man

Abstract: 1. To define the neural volleys responsible for the Achilles tendon jerk and the H reflex, muscle afferent activity was recorded using micro-electrodes inserted percutaneously into appropriate fascicles of the tibial nerve in the popliteal fossa.2. The response of soleus muscle afferents to tendon percussion consisted of a dispersed volley, starting 3.5-7.0 ms after percussion, increasing to a peak over 6.5-11.0 ms, and lasting 25-30 ms, depending on the strength of percussion. Electrical stimuli to the sciatic nerve at a level adequate to evoke an H reflex but subthreshold for the M wave produced a more synchronized volley, the fastest fibres of which had conduction velocities of 62-67 m/s, and the slowest 36-45 m/s.3. The wave of acceleration produced by percussion subthreshold for the ankle jerk spread along the skin at over 150 m/s. Midway between the bellies of the gastrocnemii it consisted of a damped oscillation with four to five separate phases and maximum amplitude approximately one-twentieth of that recorded on the Achilles tendon.4. With ten primary spindle endings, tendon percussion subthreshold for the ankle jerk elicited two to five spike discharges per tap, the shortest interspike intervals being 4-7 ms. Tendon percussion elicited single discharges from two Golgi tendon organs, and altered the discharge pattern of a single secondary spindle ending. The degree of dispersion of the multi-unit muscle afferent volley can be explained by the pattern of discharge of primary spindle endings.5. Percussion on the Achilles tendon evoked crisp afferent volleys in recordings from nerve fascicles innervating flexor hallucis longus, tibialis posterior, the intrinsic muscles of the foot and the skin of the foot. Electrical stimuli delivered to the tibial nerve in the popliteal fossa at a level sufficient for the H reflex of soleus produced either a volley in muscle afferents from the intrinsic muscles of the foot or a volley in cutaneous afferents from the foot.6. For comparable stimuli in the two positions, the H reflex was inhibited but the Achilles tendon jerk enhanced when the ankle was dorsiflexed from 105 degrees to 90 degrees .7. The duration of the rise times of the excitatory post-synaptic potentials (e.p.s.p.s) produced in soleus motoneurones by electrical stimulation, and by tendon percussion subthreshold for the H reflex and the ankle jerk respectively, was estimated from post-stimulus time histograms of the discharge of voluntarily activated single motor units in soleus. The mean e.p.s.p. rise times were 1.9 ms for electrical stimulation and 6.6 ms for tendon percussion. There was evidence that the duration of the electrically evoked e.p.s.p. was curtailed by an inhibitory post-synaptic potential (i.p.s.p.) of only slightly longer latency than the e.p.s.p.8. The mechanically induced and electrically induced afferent volleys are not homogeneous volleys in group I a afferents from triceps surae. The afferent volleys differ in so many respects that it is probably invalid to compare the H reflex and tendon jerk as a measure of fusimotor activity. It is suggested that neither reflex can be considered a purely monosynaptic reflex.

An intracellular analysis of geniculo-cortical connectivity in area 17 of the cat.

Abstract: The latencies of excitatory and inhibitory post-synaptic potentials (e.p.s.p.s and i.p.s.p.s) evoked by electrical stimulation of afferents from the lateral geniculate nucleus were recorded in neurones of area 17 of the cat visual cortex. After application of an extrapolation procedure to compensate for the conduction time of the afferent axons, a histogram of latencies formed three distinct peaks. Potentials in each of these were interpreted as being mediated by mono-, di- and trisynaptic pathways. Characteristic laminar differences in the extracellular field potentials evoked from the lateral geniculate nucleus (l.g.n.) and in the antidromic activation of neurones from the l.g.n. and superior colliculus were used to determine the laminar position of recorded neurones. It was found that within a given layer, all cells maintained similar connexions with relay cells in the l.g.n. Cells in layers 3, 4, upper 5 and 6 were monosynaptically excited by geniculate afferents, while cells in layers 2 and lower 5 received only indirect excitation via other cortical neurones. Layer 3 cells were unique in receiving a prominent disynaptic e.p.s.p. in addition to the direct excitation from the l.g.n. Late, trisynaptic e.p.s.p. components were seen in many layer 5 and 6 cells. The orderly laminar arrangement of the connexions had the consequence that identified cortico-geniculate neurones were monosynaptically excited and cortico-collicular neurones di- and trisynaptically excited by geniculate afferents. Cortico-cortical neurones in layers 2 and 3 received di- or mono- plus disynaptic excitation, depending on laminar position. Post-synaptic inhibitory potentials were evoked in all impaled cells, following stimulation of the geniculo-cortical pathway. Except for a few layer 2 cells, this inhibition was mediated through disynaptic pathways of the feed-forward type. There was a good positive correlation between conduction times for monosynaptic e.p.s.p.s and disynaptic i.p.s.p.s in the same cells, suggesting that cortical neurones receive excitation and inhibition from the same type of geniculate afferents. The stimulating electrodes activated not only geniculo-cortical afferents, but antidromically activated cortical efferent neurones from their extracortical axons. These neurones possess intracortical collaterals, and care must be taken to distinguish the resulting potentials from those mediated by orthodromic activation of geniculate afferents. In doing so, evidence was obtained for excitatory connexions from layers 2 and 3 to layer 5, from layer 5 to layer 6, and from layer 6 to layer 4. Typical recurrent inhibition was not observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Structure-activity relationships for some substance P-related peptides that cause wheal and flare reactions in human skin.

Abstract: Substance P (6.25-25 p-mole) produced dose-dependent flare and wheal responses when injected intradermally into the volar surface of the human forearm. The maximum flare response was obtained within the first 3 min of injection and declined thereafter. The wheal response reached a maximum after 12 min following the injection. Only those peptides having one or more basic residues in the N-terminal region were effective in producing a flare reaction. Eledoisin-related peptide and SP1-9 were 17 and 7 times less active than substance P respectively, whilst [D-pro2, D-phe7, D-trp9]SP1-11 was twice as active. The N-terminal tetrapeptide, SP1-4 and eledoisin were inactive in the dose range tested. Wheal-producing activity was not dependent on the presence of basic residues and the rank order of relative potencies was: physalaemin (2.0): [D-pro2, D-phe7, D-trp9]SP1-11 (1.1): SP1-11 (1.0): SP4-11 (0.4): SP1-9 (0.15): eledoisin-related peptide (0.08): eledoisin (0.06). The N-terminal tetrapeptide failed to produce a wheal response in the dose range tested. Substance P was approximately equi-active with poly-L-arginine in the production of wheal and flare and both of these agents were about 10 times more potent than histamine. Adenosine triphosphate (25-400 n-mole) produced dose-dependent wheal and flare responses and was 10,000 times less potent than substance P. Pre-treatment of the subjects with the H1 histamine antagonist, chlorpheniramine, (20 mg I.V.) reduced the wheal and flare responses to substance P. Local anaesthetic injection into the skin reduced the spread of the flare response but did not affect the development of the wheal response. Pre-treatment of the skin with capsaicin reduced the flare but not the wheal response to intradermal injection of histamine. The results are discussed in relation to the mechanism of the ‘axon reflex’ vasodilatation in skin. This is thought to involve mast cells in addition to substance P-containing primary afferent neurones.

Actions on gamma-motoneurones elicited by electrical stimulation of group II muscle afferent fibres in the hind limb of the cat.

Abstract: The reflex actions, elicited by graded electrical stimulation of hind-limb muscle, skin and joint nerves were studied in an extended series of experiments in extra-and intracellular recordings from 120 lumbar gamma-motoneurones of cats anaesthetized with chloralose. The present report deals with the action of group I muscle afferent fibres, which was examined in ninety-five gamma-cells. Of the gamma-cells 83% were classified as either static or dynamic by stimulation in the mesencephalic area for dynamic control. The general responsiveness (i.e. number of input nerves with effect/number of input nerves tested) of the cells was very high (89.9%). The responsiveness to stimulation of group I muscle afferent fibres was extremely low, both in flexor and extensor gamma-motoneurones and irrespective of whether they were static or dynamic. There was no difference, as regards the low incidence of group I muscle reflex action, between stimulation of autogenetic and heteronymous nerves. Among the rare reflex effects elicited from group I muscle fibres inhibition was four times as frequent as excitation. Inhibitory effects could be provoked from the autogenetic as well as from the heteronymous nerves. In contrast, excitatory effects were almost always autogenetic. The scarcity of group I muscle action on gamma-motoneurones is in striking contrast to the well known and powerful reflex actions of Ia and Ib fibres on alpha-motoneurones. These findings are discussed in relation to the concept of alpha-gamma linkage, and it is concluded that skeletomotor and fusimotor activity cannot be rigidly linked under all conditions.

N‐methyl aspartate activates voltage‐dependent calcium conductance in rat hippocampal pyramidal cells.

Abstract: The depolarizing actions of N-methyl-DL-aspartate (NMA) and L-glutamate on pyramidal neurones were compared in a hippocampal slice preparation. Tetrodotoxin (1 microM) was added to the perfusion solution to suppress regenerative Na conductances. Depolarization evoked by ionophoretic application of NMA triggered slow, high-threshold regenerative spikes. These are considered to be Ca spikes since the amplitude and rate of rise could be reduced by verapamil, D-600, Co2+ and Mn2+, and increased by Ba2+. Multiple Ca-spike thresholds could be demonstrated in the same cell. In contrast, depolarizations evoked by L-glutamate only rarely triggered Ca-spikes. The minimum latency to the onset of depolarization evoked by NMA was less than 20 ms. The latency and amplitude of NMA-evoked responses were highly dependent on the position of the ionophoretic pipette; movements of the pipette by as little as 10-50 micron could markedly change the size of the response. Spatially separate hot spots for NMA and glutamate were not found. Depolarizations evoked by small to moderate ionophoretic currents of NMA were usually associated with an apparent rise in input resistance, as tested by the response to transmembrane current pulses. Ionophoresis of L-glutamate, or high NMA doses, however, usually caused a fall in input resistance. Both the depolarization and the conductance change evoked by NMA were highly voltage-dependent within the approximate range -50 to -80 mV; they could be increased by modest depolarization and reduced by hyperpolarization of the membrane. No reversal potential could be demonstrated in the hyperpolarizing direction. Rather, the NMA response approached zero asymptotically at sufficiently hyperpolarized membrane potentials. Subthreshold depolarizations and conductance changes elicited by NMA could be blocked by Co2+, Mn2+ and Cd2+, and reduced by D-600 and verapamil. These Ca2+ antagonists had little or no effect on resting membrane potential or input resistance, or on responses to L-glutamate. Ba2+ increased the amplitude of subthreshold NMA responses. Intracellular injection of Cs+ plus tetraethylammonium caused cells to fire large, prolonged (up to 15 s) Ca spikes, presumably because most K+ conductances were blocked. Under these conditions the effect of NMA was unchanged or enhanced. Raising [K+]o to 10.5 mM (from the normal 3.5 mM) caused a depolarization and fall in input resistance, but did not change the amplitude or voltage dependence of the NMA response. Reducing [Na+]o caused an initial increase, then usually a delayed decrease in the amplitude of the NMA response.(ABSTRACT TRUNCATED AT 400 WORDS)

Reduction of long-term potentiation in the dentate gyrus of the rat following selective depletion of monoamines.

Abstract: 1. Brief, high-frequency stimulation of the perforant path results in a long-term potentiation (l.t.p.) of the field response evoked in the dentate gyrus by single shocks to the perforant path. We have compared the magnitude and duration of l.t.p. in normal, anaesthetized rats with animals depleted of noradrenaline (NA), 5-hydroxytryptamine (5-HT), or both. 2. All animals were exposed to an identical sequence of eight high-frequency trains of increasing intensity given over a period of 140 min to the perforant path of one hemisphere. The potential evoked by test shocks to the perforant path was monitored in both hemispheres throughout this period and for a further 96 min after the last train. 3. Plots of the mean potentiation of the population e.p.s.p. as a function of time were computed for all animals in each group. L.t.p. in the NA-depleted group was about 50% of that in the non-depleted control group throughout the course of the experiment. L.t.p. in the 5-HT-depleted group was more severely affected; mean potentiation did not exceed 30% of that in the control group at any time. 4. The duration of l.t.p. was unaffected by NA depletion and reduced by 5-HT depletion. 5. The threshold for the intensity of high-frequency current pulses necessary to elicit l.t.p. was unaffected by NA depletion and raised by 5-HT depletion. 6. Short-term potentiation of the population e.p.s.p. was unaffected by either NA depletion or 5-HT depletion. 7. The effect of monoamine depletion on granule cell excitability was investigated. 5-HT depletion, but not NA depletion, induced an increase in the excitability of the granule cell population, in the sense that a population e.p.s.p. of a given size was associated with a larger population spike. 8. Long-term potentiation of granule cell excitability was not affected by NA depletion, but was reduced by 5-HT depletion. 9. These results show that monoamines can modulate long-term changes in synaptic function in the dentate gyrus, and suggest that 5-HT is more potent in this respect than NA.

Detections of movements imposed on finger, elbow and shoulder joints.

Abstract: The angular displacements necessary for 70% correct detection were determined in normal subjects at the shoulder and elbow joints and at the terminal joint of the middle finger. Angular velocities of displacement between 0.125 degrees and 160 degrees/s were tested. Each joint was tested in the mid-range of its normal excursion. The joints were carefully supported for testing and the muscles acting at the joints were relaxed. When assessed in terms of angular displacements and angular velocities, proprioceptive performance at the shoulder and elbow joints was superior to that at the finger joint. Optimal performance at the finger joint was attained over the range of angular velocities from 10 degrees to 80 degrees/s. Optimal performance at both more proximal joints was optimal over a wider range (2 degrees-80 degrees/s). Active pointing movements made without vision of the moving part were performed at each joint at velocities within the range of optimal proprioceptive performance. However, when detection levels and displacement velocities were expressed in terms of linear displacements and velocities at the finger tip for all three joints, the finger joint gave the best performance and the shoulder the worst. In practical terms, therefore, displacements of a given linear extent are best detected if they move distal joints and worst if they move proximal joints. For the elbow and finger joints the detection level and velocity data were expressed also in terms of proportional changes in the lengths of muscles operating at these joints, and as proportional changes in the distance between the points of attachment of the joint capsules. Analysis in terms of proportional changes of muscle length showed remarkably similar performance levels at both joints. This suggests that intramuscular receptors are important determinants of proprioceptive performance. Analysis in terms of joint capsular displacement did not unify the data: on this form of analysis proprioceptive performance at the elbow joint was superior.

Analysis of potassium dynamics in mammalian brain tissue.

Abstract: Equations are derived for potassium (K+) dynamics in simplified models of brain tissue. These describe K+ movement in extracellular space, transfer of K+ associated with current flow through cells (the so-called spatial buffer mechanism) and equilibration between extracellular space and cytoplasm. Numerical calculations show that the principal data on K+ dynamics from various laboratories can be accounted for with simple assumptions about spatial buffer action and uptake. Much of the data is inconsistent with extracellular diffusion being the main mechanism for K+ flux through brain tissue, including some that has earlier been cited in support of this hypothesis. The buffering actions of spatial buffer transfer of K+ and of cytoplasmic equilibration, in which these mechanisms reduce rises of [K+]o that would otherwise occur, are analysed quantitatively for specific K+ source distributions and for spatial and temporal frequency components of general disturbances. Spatial buffer action has most effect in reducing [K+]o rises with net release over extensive zones of tissue (greater than ca. 200 micron in diameter) for periods of the order of minutes. Reductions greater than 75% may be achieved. With localized but prolonged release, the maximum [K+]o rise is little affected but the volume of tissue affected by more moderate rises is substantially reduced. Cytoplasmic K+ uptake also has most effect with widespread release, but its effect diminishes with prolonged periods of release. The effects of the buffering mechanisms and of K+ re-uptake into active neurones in determining the decline of [K+]o after a period of stimulation are considered. Re-uptake is unlikely to be the major factor responsible for [K+]o decline when this has a time course of only a few seconds. The properties necessary for the cells mediating the spatial buffer mechanisms, possibly glial cells, are assessed.

Mechanisms of hypoxia-induced periodic breathing during sleep in humans.

Abstract: Ventilation was studied during wakefulness and sleep in six healthy humans in normoxia (mean barometric pressure (PB) = 740 torr), and in hypobaric hypoxia (PB = 455 torr). Hypoxia caused hyperventilation and hypocapnic alkalosis (delta Pa,CO2 = -7 torr) during wakefulness and in all sleep states. Periodic breathing was the predominant pattern of breathing in all stages of non-rapid eye movement (non-r.e.m.) sleep in hypoxia, but was rarely observed during wakefulness or r.e.m. sleep. Periodic breathing was composed of repetitive oscillations of reproducible cycle length characterized by clusters of breaths with augmented inspiratory effort (VT/TI) and highly variable distribution of breath-to-breath minute ventilation (VE) and tidal volume (VT), which alternated regularly with prolongations of the expiratory pause of the last breath of each cluster (apnea duration = 5-18 sec). Hypoxia-induced periodic breathing was eliminated by: (a) acute restoration of normoxia coincident with a 3-6 torr increase in Pa,CO2; and (b) augmented FI,CO2 (at constant arterial oxygen saturation) which rapidly and reversibly eliminated apneas and stabilized breathing pattern with a less than 2 torr increase in Pa,CO2. If hypocapnia was prevented (by augmented FI,CO2) during acute induction of hypoxia in non-r.e.m. sleep, periodic breathing was also prevented. We propose that the genesis of hypoxia-induced periodic breathing requires the combination of hypoxia and hypocapnia. Periodicity results from oscillations in CO2 about a CO2-apnea threshold whose functional expression is critically linked to sleep state.

Low‐frequency characteristics of intracellularly recorded receptor potentials in guinea‐pig cochlear hair cells.

Abstract: Intracellular receptor potentials were recorded from inner and outer hair cells in response to low-frequency tones, from the basal, high-frequency region of the guinea-pig cochlea. The receptor potentials recorded from inner hair cells are asymmetrical about the resting membrane potential with the depolarizing phase, which corresponds to rarefaction in sound pressure, exceeding the phase of hyperpolarization by a factor of about 3. It was found that the relationship between the peak-to-peak voltage responses and sound pressure level could be described by rectangular hyperbolae. When the frequency of the sound stimulus was progressively increased from 100 Hz to 4 kHz, the 'periodic' (a.c.) component of the receptor potential was attenuated with respect to the 'continuous' (d.c.) component. The characteristics of the inner hair cells could be described by two stages of low-pass filtering, with one of the filters having the same corner frequency as the electrical time constants which varied in different cells between 178 and 840 Hz. Receptor potentials recorded intracellularly from two morphologically identified outer hair cells were symmetrical about the resting membrane potential (about -65-70 mV) and had a maximal amplitude of only 5 mV at frequencies and intensities which yield 20-30 mV voltage responses from inner hair cells. No d.c. component receptor potentials were recorded in response to high-frequency tones. Phase and amplitude measurements were made from receptor potentials from inner hair cells, and from 'cochlear microphonic potentials' which were recorded from the organ of Corti and scala tympani. The phase of depolarization in both potentials was associated with displacement of the basilar membrane towards the scala vestibuli. The phase of the intracellular receptor potentials leads the cochlear microphonic by about 90 degrees and the sound pressure by about 180 degrees at frequencies below 100 Hz. Above this frequency the phase lead progressively declines and at higher frequencies becomes a phase lag. These phase relationships indicate that inner hair cells respond to the velocity of the basilar membrane at frequencies below 200-600 Hz, and to its displacement above this, and that the voltage responses of the inner hair cells are limited by their membrane time constants. It is suggested that outer hair cells respond to basilar membrane displacement throughout their frequency range. It is shown that, with respect to frequency, the different growth rates of the cochlear microphonic potentials and inner hair cell receptor potentials, and the dominance of cochlear microphonic potentials in the organ of Corti, result in an effective electrical interaction between inner hair cells and cochlear microphonic potentials.

Anoxia and endothelium-dependent reactivity of the canine femoral artery.

Abstract: Experiments were designed to determine the role of the endothelium in the responsiveness of the arterial wall to anoxia. Paired rings of canine femoral arteries were mounted for isometric tension recording in organ chambers filled with aerated Krebs-Ringer bicarbonate solution (37 degrees C). One ring served as control; in the other the intimal layer was removed mechanically. Anoxia was induced by gassing the organ chamber with 95% N2/5% CO2. In control rings anoxia augmented contractile responses to noradrenaline, KCl and BaCl2. On return to O2 the contractile responses were transiently depressed. Removal of the endothelium reduced the anoxic augmentation, but did not affect the post-anoxic inhibition. Indomethacin did not affect the response to anoxia. Anoxia abolished the endothelium-dependent inhibitory effect of acetylcholine and thrombin, reduced that of adenosine triphosphate, but augmented that of arachidonic acid. These experiments indicate that endothelial cells may contribute to anoxic facilitation of the responsiveness of the canine arterial wall.

Spatio-temporal interactions in cat retinal ganglion cells showing linear spatial summation.

Abstract: The spatio-temporal characteristics of cat retinal ganglion cells showing linear summation have been studied by measuring both magnitude and phase of the responses of these cells to drifting or sinusoidally contrast-modulated sinusoidal grating patterns. It has been demonstrated not only that X cells behave approximately linearly when responding with amplitudes of less than about 10 impulses/sec to stimuli of low contrast but also that cells of another type with larger receptive field centres (Q cells) behave approximately linearly under the same conditions. These Q cells appear to form a homogeneous group which is probably a subset of the tonic W cells (Stone & Fukuda, 1974) or sluggish centre-surround cells (Cleland & Levick, 1974). The over-all spatio-temporal frequency characteristics of cells showing linear spatial summation are not separable in space and time. The form of the spatial frequency responsivity function of these cells depends upon the temporal frequency at which it is measured while the temporal phase of their resonse measured at any constant temporal frequency depends upon the spatial frequency of the stimulus. The behaviour of X and Q cells is quite well explained by an extension of the model in which signals from centre and surround mechanisms with radially Gaussian weighting functions are summed to provide the drive to the retinal ganglion cell. While the general form of the temporal frequency response characteristics of these ganglion cells are probably provided by the characteristics of elements common to the centre and surround pathways, the spatio-temporal interactions can be explained by assuming that the surround signal is delayed relative to the centre signal by a few milliseconds.

Effects of altered extracellular and intracellular calcium concentration on hyperpolarizing responses of the hamster egg.

Abstract: Upon fertilization the hamster egg shows transient, periodic hyperpolarizing responses (h.r.s) due to a Ca-activated K conductance; these are superimposed on a gradual, hyperpolarizing shift of the resting potential (h.s.) (Miyazaki & Igusa, 1981a, 1982a). The h.r.s and h.s. were further analysed by changing external divalent cations or by injection of Ca2+ into the egg, to study the mechanisms of the increase in the intracellular Ca2+ concentration ([Ca2+]i). The series of h.r.s was abolished by the removal of external Ca2+. The frequency of the h.r. was decreased by lowering the [Ca2+]o or by adding Mn2+ or Co2+, and it was increased by raising the [Ca2+]o in a time- and concentration-dependent manner. The h.r. frequency was decreased on sustained depolarization with steady current, and increased on hyperpolarization. In contrast to the h.r. frequency, the amplitude, conductance increase and reversal potential of each h.r. were little affected by [Ca2+]o, Mn2+ or Co2+. The h.s. was decreased by lowering the [Ca2+]o, by adding Mn2+ or Co2+, or by injection of EGTA. The h.s. may reflect continuous Ca influx stimulating a Ca-activated K conductance (GK). In unfertilized eggs a regenerative h.r. was induced by Ca injection with an apparent threshold. The relationship between GK and the injected Ca2+ showed a steep jump at the critical current, associated with a four-fold increase in GK. The regenerative h.r. was followed by a refractory period of 1-2 min. In inseminated eggs the periodic sperm-mediated h.r.s. (s.-h.r.s) were interrupted by interposed h.r.(s) induced by Ca injection(s): the periodicity of s.-h.r.s was reset by Ca-induced h.r. In inseminated eggs the regenerative h.r. was induced by Ca injection with a much smaller pulse than necessary in unfertilized eggs. The refractory period was shortened to 40-50 sec, comparable to the period of s.-h.r.s. In inseminated eggs periodic h.r.s similar to s.-h.r.s were produced by continuous, repetitive injections of Ca2+ with constant pulses. The frequency of these h.r.s was dependent on the injection current. It is concluded that each h.r. indicates an enhancement of the increase in [Ca2+]i, probably the result of Ca-induced Ca release from intracellular stores. A possible mechanism for periodic increase in [Ca2+]i reflected in s.-h.r.s is proposed, based on a linkage of the continuous Ca influx to Ca release.

The responses of cells in macaque lateral geniculate nucleus to sinusoidal gratings.

Abstract: Responses of cells in the parvocellular (p.c.l.) and magnocellular (m.c.l.) layers of the macaque lateral geniculate nucleus to sine-wave gratings were studied. Both p.c.l. and m.c.l. cells responded best at a temporal frequency (drift rate) of 10-20 Hz. P.c.l. cells responded at temporal frequencies lower than 1 Hz; m.c.l. cells did not. With coloured- or white-black luminance-modulated gratings, responses of m.c.l. cells were weaker at low than at medium spatial frequencies. With coloured gratings, p.c.l. cell responses were not attenuated at low spatial frequencies. With white gratings a few p.c.l. cells did show such attenuation. Optimal responses from p.c.l. cells were obtained with coloured gratings; white gratings evoked weaker responses. With a grating of a colour causing suppression of a p.c.l. cell's activity, the modulation of firing was much less than with a grating of a colour excitatory for the cell. M.c.l. on- and off-centre cells responded equally well to moving gratings. The ability of p.c.l. cells to resolve fine gratings was dependent on cell type as well as on the colour of grating used. The ability of m.c.l. cells to resolve fine gratings was comparable to that of p.c.l. cells. The contrast sensitivity of m.c.l. cells was much higher than that of p.c.l. cells. This may account for their ability to resolve fine gratings, despite their larger centre size. In comparison with luminance-modulated gratings, chromatically modulated gratings could evoke larger or smaller responses, depending on p.c.l. cell type and the colours in the grating. M.c.l. cells responded poorly or not at all.

Calcium dependence of open and shut interval distributions from calcium-activated potassium channels in cultured rat muscle.

Abstract: The stochastic properties of single Ca-activated K channels in excised patches of surface membrane from cultured rat muscle cells were studied using the patch-clamp technique. The distribution of all open intervals was described by the sum of two exponential distributions of short and long mean open time, suggesting at least two major open-channel states. Increasing the concentration of Ca at the inner membrane surface, [Ca]i, increased the mean duration of the long open distribution, while having little effect on the mean duration of the short open distribution. The frequency of openings to each distribution increased with [Ca]i. The rate of increase was a much steeper function of [Ca]i for openings in the long open distribution than for openings in the short open distribution; about 80% of the openings were to the long open distribution with 0.1 microM-Cai, increasing to 97% with 1 microM-Cai (+ 30 mV). These results suggest that openings in both open distributions are Ca-dependent, with openings in the long open distribution requiring the binding of more Ca ions than openings in the short open distribution. The distribution of all shut intervals at 0.5 microM-Cai and + 30 mV was described by the sum of three exponential distributions with mean durations of: 0.21 msec (short shut distribution), 1.90 msec (intermediate shut), and 44 msec (long shut). These results indicate that the channel typically enters at least three closed channel states during normal channel activity. In addition, a few longer shut intervals not accounted for by the above distributions suggested that there was a fourth infrequently occurring inactivated closed-channel state. The mean duration of the distribution of long shut intervals decreased with a power of about 2 with increasing [Ca]i under conditions where most openings were to the long open state (+ 30 mV, 0.25-1 microM-Cai). This observation suggests that openings to the long open distribution typically require the binding of two or more Ca ions. The mean intermediate shut interval appeared to increase slightly with increasing [Ca]i while the mean short shut interval was relatively Cai-independent. The percentage of all shut intervals that were short shut intervals increased with increasing [Ca]i while the percentage of long shut intervals decreased.(ABSTRACT TRUNCATED AT 400 WORDS)

Passive biaxial mechanical properties of isolated canine myocardium.

Abstract: Excised sheets of canine myocardium were subjected to cyclic loading and unloading in the predominant fibre and cross-fibre directions to determine passive mechanical properties. Myocardium under biaxial loading exhibits both non-linear elasticity and viscoelasticity with some strain-rate dependence in the position of the stress-strain relations, but very little rate dependence in the area enclosed by the loading and unloading portions of the stress-strain loops. Fibre and cross-fibre directions demonstrate anisotropic behaviour, with both the degree and direction of the anisotropy being dependent upon the region of the heart from which specimens are obtained. In the same specimen biaxial as compared with uniaxial loading yields different interpretations as to the material properties.

The strength-duration relationship for excitation of myelinated nerve: computed dependence on membrane parameters.

Abstract: Thresholds to applied current pulses have been determined for the myelinated nerve model of Goldman & Albus (1968). Strength-duration curves have been plotted, and compared with three strength-duration equations that have been proposed in the past. The simple, linear relation between stimulus charge and stimulus duration proposed by Weiss (1901) provided the best fit to the computed data. The effects on the strength-duration relationship of changes in twelve parameters of the model were determined and expressed in terms of the strength-duration time constant and rheobasic current. The rheobase depended primarily on conductances, whereas the strength-duration time constant depended on the electrotonic time constant and also on the rate of sodium activation. The model predicts strength-duration curves of the same form, for extracellular or intracellular stimulation where the external resistance is low and uniform. Tripolar stimulation, with anodes over adjacent rather than remote nodes, is predicted to result in much shorter strength-duration time constants, but with a similar sensitivity to nodal membrane parameters. The limitations of strength-duration measurements on myelinated nerves are discussed in the light of these simulations.

Inhibitory interactions between interneurones in reflex pathways from group Ia and group Ib afferents in the cat.

Abstract: A hypothesis has been verified that laminae V-VI interneurones which mediate non-reciprocal inhibition of motoneurones from group I muscle afferents have collateral actions on other laminae V-VI interneurones. Stimulation within the areas of projection of these inhibitory interneurones in motor nuclei and in Clarke's column would be expected to give rise to monosynaptic i.p.s.p.s in interneurones with disynaptic i.p.s.p.s from group I afferents if the hypothesis were correct. Intracellular records were made from eighty-five laminae V-VI interneurones with input from group Ia muscle spindle and/or group Ib tendon organ afferents. Weak intraspinal stimuli applied in motor nuclei in L7 and S1 segments, or in the lateral funiculus just caudal to Clarke's column in L4, were found to evoke monosynaptic i.p.s.p.s in seventy-two interneurones. These i.p.s.p.s were systematically correlated with disynaptic inhibition from group Ia or Ib afferents but not from other fibres. Such monosynaptic i.p.s.p.s evoked by intraspinal stimuli were seen in forty-two interneurones which themselves projected to the level of Clarke's column and therefore (on the basis of previous evidence) should mediate inhibition of motoneurones. For seven of these interneurones it was also shown directly that they projected to motor nuclei. The inhibition of such interneurones demonstrates mutual interactions between those interneurones which are interposed in inhibitory pathways from group I afferents. Only indirect indications have been obtained for inhibition of interneurones in the excitatory pathways.