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Biomedical subjects

Y Shimoni

Publications and source records attributed to Y Shimoni.

At least 73 records · Page 4Linked to original sources
PubMed1987

Negative inotropic effect of extracellular calcium buffering in cardiac muscle.

Heart muscle contracts more vigorously when calcium levels are raised. A transient depletion of calcium from restricted extracellular spaces occurs with each contraction. We decided to maintain the concentration of this ion at a constant level by using an external calcium buffering system. It was found that buffering calcium at a millimolar level (using citrate as a buffer) caused a decrease, rather than an increase in the strength of contraction. The mean reduction in peak tension was by 27% in guinea pig and by 50.5% in frog atrium. This finding is analyzed; its most plausible explanation is the hypothesis that the buffer dissipates a calcium inhomogeneity, consisting of a higher calcium concentration adjacent to the membrane. Alternative interpretations such as intracellular acidosis, were tested experimentally and ruled out.

Animals↗
PubMed1987

Separation of Na-Ca exchange and transient inward currents in heart cells.

Enzymatically dispersed single cells from rabbit ventricle were voltage clamped using the suction pipette method to investigate whether in isolated cardiac cells a recently described slow inward current (IEX) due to the electrogenic Na+-dependent Ca2+ extrusion also underlies a transient inward current (ITI), which can trigger certain cardiac arrhythmias. The cells were held at -40 mV to inactivate the fast sodium current. After depolarizing pulses (to 0 or +10 mV for 50 to 200 ms), slow inward "tail" currents were consistently recorded. Previous results indicate that this tail current IEX is generated by the Na+-Ca2+ exchanger. After loading the cells with Ca2+ by blocking the Na+-K+ pump [either with strophanthidin (10(-5) M) treatment or by reducing external K+ to 1 mM or less], ITIS appeared. These were usually spontaneous but occasionally were time locked to the clamp pulses. It was possible to separate IEX and ITI by a variety of methods. These include the following. 1) Different stimulation protocols; repolarizing to more negative potentials augmented IEX and decreased or eliminated ITI. Increasing the rate of stimulation diminished IEX and increased ITI. 2) Pharmacological methods; adding BaCl2 (0.5-2.0 mM) or caffeine (5-10 mM) decreased IEX but abolished ITI. The findings suggest that different mechanisms regulate these two currents.

Animals↗
PubMed1987

Quantitation of variations in regional left ventricular function in isolated disease of the left anterior descending coronary artery.

The pattern of contraction of the endocardial wall of the left ventricle in the right anterior oblique cineangiogram was studied by using a frame by frame radial technique and a fixed centroid without correction for rotation and translation motion during the cardiac cycle. Spatial defects of contraction were quantitated by measuring the shortening fraction of each radius and temporospatial defects by using a time-contraction integral. Twelve normal subjects were used as a basis for comparison. Thirty-two patients with isolated disease of the left anterior descending (LAD) coronary artery were divided into seven arbitrary clinicopathological subsets. Five subsets showed significant quantitative differences in contraction from the normal subjects but there was no significant difference between the subsets. They had a typical defect of contraction in the distal two thirds of the anterior wall, the apex and distal quarter of the inferior wall of the left ventricle. The subsets included: (1) patients who had undergone an anterior myocardial infarction and who had total occlusion of the LAD artery and a large anterior infarction on ECG; (2) patients with a previous classical myocardial infarction but with only 95% residual narrowing of the LAD; (3) patients with an anterior infarction and total occlusion of the LAD with return of the R waves in the anterior precordial leads; (4) patients with anterior infarction, LAD obstruction and left bundle branch block and (5) patients with anterior infarction but with early successful reperfusion with intracoronary streptokinase. Two other subsets, (1) patients with total obstruction of the LAD without a clinical myocardial infarction or (2) subtotal occlusion of the LAD without infarction, had mild left ventricular dysfunction at rest and did not differ significantly from normal.

Adult↗
PubMed1986

T-2 toxin effect on cultured myocardial cells.

Beat rate, contractility and viability of cultured myocardial cells perfused with solutions containing various concentrations of T-2 toxin were studied. While doses below 50 micrograms/ml had no immediate effect, those above 250 micrograms/ml decreased beat rate and amplitude. After 10-30 min of perfusion most cells stopped beating and did not restart after withdrawal of toxin. Nevertheless, most cells remained viable as judged by morphology and trypan blue exclusion. A 24-h exposure to doses of 5 or 2.5 micrograms/ml of toxin decreased the beat rate and inotropic responses of the myocytes. After 48 h cell death ensued. Thus T-2 toxin has some direct toxicity to myocardial cells but the lethal dose seems too high to make this the cause of cardiovascular failure.

Animals↗
PubMed1986

Further characterisation of the inotropic effect of a bufodienolide glycoside--an endogenous ouabain like compound.

A ouabain like compound obtained from toad skin and plasma and identified to be a steroidal bufodienolide glycoside was found to displace ouabain from its binding site and to inhibit Na+-K+ ATPase, and have positive inotropic effects on cardiac muscle. The ionic and rate dependence of this positive inotropy was studied in the frog atrium. The effect was dependent on extracellular potassium, sodium, and calcium concentrations and on the rate of stimulation, which is similar to the properties of cardiac glycosides. Occasionally, the compound gave transient or even negative inotropic responses, as do the glycosides. The action potential configuration was also affected by the compound in the same complex pattern as is that of cardiac glycosides. It is concluded that the endogenous bufodienolide compound has the same physiological effects as cardiac glycosides. Since the same compound is present in toad plasma it may serve as an intrinsic humoral regulator of cardiac contractility. This study is the first detailed characterisation of the cardioactive properties of this compound.

Action Potentials↗
PubMed1986

Heat acclimation: cardiac performance of isolated rat heart.

Cardiac performance was studied in the isolated perfused hearts of rats heat acclimated at 34 degrees C (AC) and their age-matched controls (C). The pressure-volume curves during isovolumetric conditions showed a shift to the right in AC compared with C hearts. At similar left ventricular (LV) volumes end-diastolic and peak systolic pressures of AC hearts were lower, but no difference was observed in the maximal pressure developed at the highest LV volumes measured. In both C and AC hearts the developed force decreased as pacing rate increased. AC and C heart responses were the same up to 250 pulses/min. At higher frequencies the amplitude of the developed force of AC hearts was smaller than that of the controls. In accordance the tension produced by very early premature beat reduced in AC compared with C hearts. Since no hypertrophy was observed in AC hearts, it is concluded that heat acclimation results in a change in the intrinsic properties of the AC hearts exhibited by increased compliance, reduced chamber stiffness, and a decrease in the tension developed for each volume load. It is also suggested that at a high beating rate AC hearts fail to restitute its contractility as quickly as C hearts.

Acclimatization↗
PubMed1984

Two potentially arrhythmogenic mechanisms of adrenaline action in cardiac muscle.

The effects of rate changes and 'premature' stimulation on the slow inward current of cardiac muscle were studied in the frog atrium. The effects of adrenaline under these conditions was investigated. It was found that adrenaline markedly accelerates the repriming kinetics of the slow inward channel. Adrenaline at low concentrations, sufficient to augment this current, also increases the effect of rate changes. Thus there is a larger second inward current 'staircase' in the presence of adrenaline. It is proposed that the combination of these effects is a possible mechanism by which adrenaline can induce cardiac disorders of rhythm.

Animals↗
PubMed1983

The effects of low concentrations of cardiotonic steroids on membrane currents and tension in sheep Purkinje fibres.

1. Simultaneous measurements of voltage-clamp currents and tension were made in shortened sheep Purkinje fibres exposed to various concentrations of strophanthidin, ouabain and digoxin.2. In 5.4 mM-K moderate doses (mean 2.4 x 10(-7)M) of the drugs produced an inward shift of the current-voltage relationship at very negative potentials, consistent with an increase in cleft K concentration (Cohen, Daut & Noble, 1976b), which was always accompanied by an increase in tension. This change, which has been attributed to Na-K pump inhibition, was often better correlated with an increase in voltage-dependent tonic tension than in twitch tension.3. Exposure to dihydro-ouabain gave a monotonic increase in tension but a delayed increase in inward current. This suggests (cf. Lee, Kang, Sokol & Lee, 1980) that minor changes in pump activity may not always change the current-voltage relationship.4. Low concentrations of strophanthidin (5 x 10(-9) to 5 x 10(-7) M) produced an outward current shift at very negative potentials, this change becoming smaller with a more rapid onset and reversing on increasing the dose. This change is attributed to pump stimulation.5. The outward current shift was often associated with a negative inotropic effect, which always reversed either spontaneously or on removal of the drug.6. The alternative response at a narrower dose range (1 x 10(-8) to 2 x 10(-7) M) was an increase in twitch (not tonic) tension, termed the low-dose positive inotropic effect.7. After a low concentration of cardiotonic steroid had given an early negative inotropic effect the bulk Ca concentration was reduced and the drug re-applied. The low-dose positive inotropic mechanism was then observed.8. Outward current shifts and negative inotropy were also obtained with low concentrations of the clinically used glycosides digoxin and ouabain.9. Low concentrations of strophanthidin applied to externally stimulated sheep ventricular trabeculae produced negative inotropy with lengthening of the action potential duration. Positive inotropy and action potential shortening occurred with higher doses.10. A computer model of ionic currents and distributions in Purkinje fibres satisfactorily reproduced the changes in membrane currents and ionic gradients observed with cardiotonic steroids. The only perturbations capable of explaining our results were Na pump stimulation and inhibition.11. It is concluded that cardiotonic steroids possess two inotropic mechanisms. The first is a low-dose positive inotropic mechanism causally unrelated to changes in sodium pump activity and possibly a direct release of a membrane-associated calcium fraction. Should this mechanism be unavailable then net pump stimulation at low doses will produce negative inotropy. The second mechanism is the well known Na-lag process.

Animals↗
PubMed1983

A pace-maker-like current in the sheep atrium and its modulation by catecholamines.

A modified single-sucrose-gap system was used to study sheep atrial trabeculae under voltage-clamp conditions. A time- and voltage-dependent current system is described, which resembles the current if in Purkinje fibres. This current was activated at membrane potentials of between -60 and -70 mV in many fibres. The addition of Ba2+ reduced the instantaneous current (the 'jump') and thus facilitated the study of the current if. Current tails were more prominent in the presence of TTX and Mn2+. Most experiments were done in the presence of Ba2+, Mn2+ and TTX. Standard envelope tests and conductance measurements indicated that this current is an inward current, activated on hyperpolarization. We have also labelled the atrial current if. The instantaneous fully activated current-voltage relationship, i(E) was found to be linear in the activation range. Increasing the level of K+, which increased the current magnitude, also increased the slope of the i(E) curve. The current magnitude was also dependent on the level of Na+ in the medium. The current magnitude was increased by adrenaline or isoprenaline. Only a small part of the increase could be attributed to a shift in the voltage dependence of the gating kinetics. The shifts in activation curves were much smaller (3-4 mV in the depolarizing direction) than those in Purkinje fibres. Large shifts in activation curves were obtained with theophylline, indicating that the presence of Ba2+ or Mn2+ did not occlude any shifts by adrenaline. The magnitude of if was increased by theophylline, with a further increase by adrenaline. There is therefore no mutual occlusion of the two effects on if. The slope of the i(E) curve was increased by isoprenaline, indicating that there was an increase in conductance. The presence of propranolol did not prevent the increase in current amplitude by isoprenaline. A direct effect of catecholamines on the channel is suggested.

Action Potentials↗
PubMed1983

Stereospecific glucose transport across motor nerve terminal membrane: an electrophysiological study.

Spontaneous transmitter release at the neuromuscular junction of the frog and rat was monitored during exposures to hyperosmotic solutions containing different sugars. Raising the osmolarity of the medium with D-glucose causes a marked, but transient, increase in the frequency of miniature end-plate potentials (MEPPs): after the initial elevation in frequency there is a subsequent decline towards the control levels, in spite of a continuous perfusion with the hyperosmotic solution. This decline occurs more rapidly in the frog. Two nonmetabolized analogues of glucose, 2-deoxy-D-glucose and 3-O-methylglucose, cause a transient hyperosmotic increase in MEPP frequency, which is very similar to the effect of D-glucose. The elevation of MEPP frequency with hyperosmotic glucose is stereospecific. Hyperosmotic solutions of L-glucose cause a sustained increase in transmitter release in the rat and frog. Insulin dramatically reduces the response of the frog nerve terminal to hyperosmotic D-glucose. Phenolphthalein, a glucose transport blocker, reduces or eliminates the secondary decline in MEPP frequency. It is suggested that the transient nature of the response to hyperosmotic solutions reflects the penetration of the hyperosmotic agent into the nerve terminal. The rate of decline of the MEPP frequency presumably indicates the rate of transport, which determines the rate of osmotic equilibration. This rate can then serve as an index of the relative permeability of the functioning presynaptic membrane to different sugars.

Animals↗
PubMed1983

Nature of the hypoblastic influence on the chick embryo epiblast.

Stage XIII chick blastoderms deprived of the marginal zone, the area opaca and the posterior half of the hypoblast, when incubated further developed axes whose orientation in 50% of the cases was according to the original blastoderm's orientation, whilst in 50% of the cases they developed at 90 degrees from the posterior side. Those results illustrate the quantitative differences in inductivity between the anterior and the posterior hypoblastic halves. Normally the posterior region has the highest effect but other regions can also bring about the development of an embryonic axis if allowed to act upon the epiblast for a sufficiently long period of time. The possible ways in which a chick hypoblast influences the epiblast to develop an embryo are examined in the light of recent findings and of new experiments described below.

Animals↗
PubMed1981

The calcium and frequency dependence of the slow inward current 'staircase' in frog atrium.

1. Changes in the magnitude of the slow inward current in the frog atrium were monitored at different stimulation frequencies, using a double sucrose-gap technique. 2. After short rest periods (1.5-3.0 min), repetitive clamp depolarizations applied at frequencies ranging from 0.33 to 1 Hz (20-60/min) resulted in a progressive increase in the slow inward current towards a new level. Action-potential amplitudes and plateau levels usually showed similar increases under these conditions. 3. Changes in the magnitude of the slow inward current were also found when the frequency was changed during constant stimulation. 4. Replacement of calcium ions by strontium or barium ions led to an augmentation or reduction, respectively, of the 'staircase' effect, relative to the effect in calcium-containing solutions. Barium ions were found to greatly increase the slow inward channel 'recovery' time. 5. The results suggest that calcium influx into amphibian atrial fibres contributes to the regulation of the slow inward conductance mechanism. Progressively increasing currents may underlie positive tension staircases.

Animals↗
PubMed1981

Voltage-dependent potentiation of the slow inward current in frog atrium.

1. Slow inward currents, isi, were measured using a double sucrose-gap voltage-clamp technique during experiments involving different depolarization protocols. 2. Following short rest periods, repetitive stimulation gave rise to slow inward currents which changed progressively in a voltage-dependent manner. Small voltage depolarizations gave rise to initial small decreases in current (negative 'staircase'). The current usually then showed a secondary increase but still remained, in most cases, below the control amplitude. Larger depolarizations produced increasingly larger and more rapidly rising positive current 'staircases'. 3. The amount of increase in current magnitude during repetitive depolarization was more strongly dependent on the size of the voltage step than on the amplitude of the initial current. 4. Twin-pulse experiments having a fixed interval between pulses (usually 1.0 sec), showed that 'test' pulses produced more slow inward current than preceding 'conditioning' depolarizations. The augmentation was larger following conditioning pulses of longer duration. Current augmentation was larger during 'staircase' obtained with longer pulses. 5. Following constant duration 'conditioning' depolarizations, varying the interpulse interval showed that the slow inward current flowing during the 'test' pulse could be augmented following intervals of as long as 6-8 sec. 6. Small pre-pulses also augmented the slow inward currents obtained in response to 'tet' pulses. 7. Experiments in calcium-free solutions (with EGTA) showed qualitatively similar 'staircase' effects and current augmentation following preceding depolarizations. 8. Experiments in which sodium was replaced by lithium gave rise to larger slow inward currents. The 'staircase' for such currents developed in a similar manner to that seen under control conditions. 9. It is concluded that slow inward current augmentation is produced by membrane depolarization in a fashion which is at least partially independent of calcium or sodium ion influx.

Animals↗
PubMed1981

Parameters affecting the slow inward channel repriming process in frog atrium.

1. The time of recovery (from the inactivation) of the slow inward current was studied in the frog atrium, using the double sucrose gap voltage clamp technique. 2. The 'repriming' process was found to be distinct from the current inactivation, and to depend on experimental protocol: double pulses given at low frequencies (at 'rest') gave a faster recovery time when compared to recovery during constant stimulation, with interposed stimuli monitoring the recovery. Longer durations of the clamp pulses led to a faster recovery process. 3. Changing the holding potential of the membrane (with double pulses to the same absolute membrane potential monitoring the recovery process) greatly affect the repriming with depolarized levels slowing down the process. 4. The recovery time was fastest following clamp pulses to intermediate membrane potentials (in the plateau range). This was determined by double pulses, from a constant hold potentials, to different levels. 5. Decreasing extracellular Ca prolonged, and increasing Ca enhanced the recovery process. 6. The recovery process was markedly slowed down in Na or in K-free solutions. 7. The recovery process was enhanced in solutions with a raised concentration of Mg or H ions (lower pH). In higher Mg solutions, the inactivation of the slow inward current was slower. 8. It is proposed that the recovery process is sensitive to alterations in intracellular Ca ions and to variations in extracellular surface charges. The possible implications are discussed.

Animals↗