Beta-adrenoceptor blocking and electrophysiological effects of bufetolol in the guinea pig atria.

The potency of blockade of bufetolol, a beta-adrenoceptor blocking drug, and effects of bufetolol on the action potential, contractile force and various electrophysiological properties of the atrium were investigated in comparison with propranolol and quinidine. Bufetolol had a pA2 of 8.65 against the positive chronotropic action of isoproternol on the guinea pig sinus node. Bufetolol, 10(-7) g/ml, did not affect the action potential of the atrial muscle, while the drug, 3 X 10(-5) g/ml, significantly decreased the overshoot potential, the amplitude and the maximum rate of rise of the action potential and prolonged the times for 50% and 90% repolarization. The contractile force was reduced by bufetol, 3 X 10(-5) g/ml. The maximum responsive frequency to the driving stimulus was decreased by bufetol, 3 X 10(-5) g/ml. The excitability of the muscle membrane was suppressed by bufetolo, 3 X 10(-5) g/ml, as indicated by changes in membrane responsiveness, membrane reactivation and strength-duration curve. Propranolol, 10(-5) g/ml and quinidine, 10(-5) g/ml showed similar effects on excitability. The authors suggest that these effects of bufetolol are responsible for its antidyshythmic effects.     

Implantable device for long-term electrical stimulation of denervated muscles in rabbits

Although denervating injuries produce severe atrophic changes in mammalian skeletal muscle, a degree of functional restoration can be achieved through an intensive regime of electrical stimulation. An implantable stimulator was developed so that the long-term effects of different stimulation protocols could be compared in rabbits. The device, which is powered by two lithium thionyl chloride batteries, is small enough to be implanted in the peritoneal cavity. All stimulation parameters can be specified over a wide range, with a high degree of resolution; in addition, up to 16 periods of training (10–180 min) and rest (1–42 h) can be set in advance. The microcontroller-based device is programmed through a bidirectional radiofrequency link. Settings are entered via a user-friendly computer interface and annotated to create an individual study protocol for each animal. The stimulator has been reliable and stable in use. Proven technology and rigorous quality control has enabled 55 units to be implanted to date, for periods of up to 36 weeks, with only two device failures (at 15 and 29 weeks). Changes in the excitability of denervated skeletal muscles could be followed within individual animals. Chronaxie increased from 3.24±0.54 ms to 15.57±0.85 ms (n=55, p<0.0001) per phase in the 2 weeks following denervation.     

Modification of the human motor cortex by associative stimulation

Manipulation of afferent input is capable of inducing reorganisation of the motor cortex. For example, following 1 h of paired electrical stimulation to the motor point of two hand muscles (associative stimulation) the excitability of the corticospinal projection to the stimulated muscles is increased. Here we investigated the mechanisms responsible for such change using transcranial magnetic stimulation (TMS). Cortical excitability changes were investigated by measuring motor evoked potentials (MEPs), intracortical inhibition (ICI), intracortical facilitation (ICF), and short-interval intracortical facilitation (SICF). Following 1 h of associative stimulation MEP amplitudes in the stimulated muscles significantly increased. Additionally, there was a significant increase in ICF and of SICF at interstimulus intervals in the range of 2.3–3.3 ms. There was no significant change in ICI. These findings confirm previous observations that a 1-h period of associative stimulation can increase the excitability of the cortical projection to stimulated muscles. Additionally, these results suggest that the observed modifications of excitability are due to changes in intracortical excitatory circuits.     

Phosphene threshold as a function of contrast of external visual stimuli

Transcranial magnetic stimulation (TMS) of the occipital lobe is frequently used to induce visual percepts by direct stimulation of visual cortex. The threshold magnetic field strength necessary to elicit a visual percept is often regarded as a measure of electrical excitability of visual cortex. Using single-pulse TMS during visual motion stimulus presentation, we investigated the relationship between different degrees of visual cortical preactivation and cortical phosphene threshold (PT). The two possible, mutually exclusive, predictions on the outcome of this experiment were that a) PT increases with stronger preactivation because of a decrease in the signal-to-noise ratio, or b) that PT decreases with increased preactivation because of the increase in neuronal response towards some threshold. PTs for single-pulse stimulation of the occipital lobe were determined for eight subjects while they passively viewed a horizontally drifting luminance-modulated sinewave grating. Gratings used were of four different luminance contrasts while the spatial and temporal frequencies remained constant. PTs were shown to increase significantly as the background grating increased in contrast. These results suggest that the neural activity underlying the perception of a phosphene can be considered a type of signal that can be partially masked by another signal, in this case the visual cortical activation produced by passive viewing of drifting gratings.

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This revised version was published online in May 2005. The preceding version was showing a false article.     

Sub-nanomolar concentrations of ciguatoxin-1 excite preganglionic terminals in guinea pig sympathetic ganglia

The actions of low concentrations of ciguatoxin-1 (CTX-1, 0.2-0.8 nM) in guinea-pig sympathetic ganglia have been analysed using intracellular recording techniques in vitro. The effects of CTX-1 were graded with concentration but sensitivity varied markedly between neurones in the same preparation. Other than an initial transient (– 10 min) depolarization of some ganglion cells accompanied by an increase in input resistance, passive electrical properties did not significantly differ from controls. Amplitude and threshold of action potentials evoked by depolarizing current and threshold, latency and form of the initial responses to nerve stimulation were also not affected.Exposure to CTX-1 generated marked increases in the frequency of spontaneous excitatory synaptic potentials which often occurred in bursts (15–66 Hz) of similar amplitudes. Single stimuli to incoming nerves produced repetitive synaptic responses arising from preganglionic, but not from peripheral afferent, axons. Following brief (< 5 min) exposure to CTX-1, these effects declined over 30 min but, after longer exposure (> 15 min), they persisted for several hours despite continuous washing. All activity generated by CTX-1 was significantly reduced or abolished by d-tubocurarine (10^–5–10^–4 M), hexamethonium (10^–5 M), tetrodotoxin (10^–7–10^–6 M), -conotoxin (10^–7 M), reduced Ca²⁺ (0.1 mM)/raised Mg²⁺ (10 mM), raised Ca²⁺ (6 mM) or raised Mg²⁺ (25 mM).The data suggest that CTX-1 activates preganglionic axons by modifying the voltage sensitivity of a subpopulation of Na⁺ channels. Effects on these unmyelinated axons occur at much lower concentrations than have been reported to affect myelinated ones. Many of the symptoms of ciguatera poisoning might be explained by activity in autonomic and perhaps other unmyelinated nerve terminals.     

Effects of quinidine and quinine on the excitability of pyramidal neurons in guinea-pig hippocampal slices

Effects of quinidine (25M–1mM) and its stereoisomer, quinine (1–5 mM), on the excitability of CA3 pyramidal neurons were investigated in guinea-pig hippocampal slices using intracellular recording techniques. At concentrations of quinidine higher than 100 M (and higher than 1 mM for quinine), 1) the resting potential shifted to the depolarizing direction with an increase of the input resistance, 2) the spike duration was prolonged, 3) the spike amplitude was decreased, 4) the late component of the afterhyperpolarization (AHP) (caused by the activity of the Ca²⁺-mediated K conductance) were suppressed, and 5) finally, neurons became inexcitable. The results indicate that the blocking action of quinidine and quinine is not specific to the Ca²⁺-mediated K conductance in mammalian hippocampal neurons, and that this conductance is much less sensitive to the drugs in comparison with other preparations.     

Increased motor excitability produced by alerting stimuli

The proposal that increased excitability of sensory and motor systems occurs in response to dishabituated sensory stimuli was supported by experiments with cats in which excitability was measured by the amplitude of the response evoked by an electrical test stimulus. Evoked EMG, evoked head movement and the postsynaptic visual cortex response were briefly augmented following such stimuli, with a latency less than 20 msec for auditory and less than 50 msec for visual stimuli. Evoked EMG responses were rare during habituation, but even faint stimuli (40 db (SPL) tone pips) were effective during conditioning procedures. The proposed organization of the brain was thought to have adaptive significance, helping the subject to cope with emergency situations by enhancing the processing of sensory and motor information.     

Multichannel SEP-recording after paired median nerve stimulation suggests origin of paired-pulse inhibition rostral of the brainstem

Paired-pulse techniques are a common tool to investigate the excitability of the cerebral cortex. Whereas in the motor system short interval intracortical inhibition assessed by paired-pulse transcranial magnetic stimulation clearly could be demonstrated to be generated within the motor cortex, the mechanism of paired-pulse inhibition measured over the somatosensory cortex after paired-pulse median nerve stimulation is less clear. The aim of this study was to further investigate the level of somatosensory processing where this paired-pulse inhibition is generated. We applied single and paired electrical stimulation of the median nerve with an interstimulus interval of 30 ms. Somatosensory evoked potentials were recorded over the brachial plexus, the cranial cervical medulla and the primary somatosensory cortex. We analyzed peak-to-peak amplitudes evoked by the second stimulus of paired-pulse stimulation after digital subtraction of a single pulse (A2s), and referred it to the first response before linear subtraction (A1). Paired-pulse inhibition was expressed as a ratio (A2s/A1) of the amplitudes of the second (A2s) and the first (A1) peaks. We found a significant reduction of A2s as compared to A1 over S1, but no significant difference between A1 and A2s over brachial plexus and cranial medulla. In addition, the cortical amplitude ratio A2s/A1 was significantly reduced compared to the amplitude ratios over cranial medulla and brachial plexus. These results suggest that the underlying inhibitory mechanisms are generated rostral to the brainstem nuclei, probably due to the activity of thalamic or intracortical inhibitory interneurons.     

Cortical excitability in migraine

Cortical hyperexcitability in migraine has been suggested to play a pivotal role in triggering migraine attacks, possibly via generation of spreading depression. Low levels of plasma, intracellular and brain magnesium as well as increased amplitudes of visual evoked potentials support this theory. More recent data on evoked and even related potentials, i. e. lack of habituation and low initial amplitudes during repetitive stimulation, however, may indicate reduced levels of cortical excitability. Transcranial magnetic stimulations of motor and visual cortices, a direct method to assess cortical excitability, yielded contradictory results. Lower or elevated motor threshold, amplitudes and/or phosphene prevalence or even no significant differences at all were demonstrated suggesting also cortical hypo- rather than hyperexcitability in migraine. Methodological differences, selection of subjects, and timing of investigations might partly explain these marked differences. Clinical and genetic heterogeneity of migraine, for instance via opposite influence on neuronal excitability caused by recently described ion-channel mutations, might provide further explanation. Received: 24 January 2000, Accepted in revised form: 2 October 2000