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W T Clusin

Publications and source records attributed to W T Clusin.

At least 37 records · Page 2Linked to original sources
PubMed1985

Paradoxical electromechanical effect of lanthanum ions in cardiac muscle cells.

Although lanthanum ions (La+++) block calcium influx in cardiac cells, they may paradoxically accentuate the sodium-free contracture. We have therefore studied the effects of La+++ on the zero sodium response in chick embryonic myocardial cell aggregates. Zero sodium alone causes: (a) A maintained contracture; (b) Asynchronous localized contractions that are selectively inhibited by caffeine or ryanodine, and presumably reflect release of calcium from the sarcoplasmic reticulum; (c) A nonspecific conductance increase that is ascribable to calcium-activated ion channels. Addition of La+++ potentiates the sodium-free contracture, and causes similar potentiation of the localized contractions and the conductance increase. All three phenomena occur 5-10-fold faster in 1 mM La+++ than in sodium-free fluid alone. In contrast, when La+++ is combined with caffeine or ryanodine, the zero sodium response is suppressed. We conclude that the paradoxical effect of La+++ on the contracture is not due to calcium influx, but to enhancement, or disinhibition of intracellular calcium release. Relaxation of normal myocardium may involve control of spontaneous calcium release by lanthanum- and sodium-sensitive calcium transport across the surface membrane.

Animals↗
PubMed1984

Reduction of ischemic depolarization by the calcium channel blocker diltiazem. Correlation with improvement of ventricular conduction and early arrhythmias in the dog.

Calcium channel blockers suppress early ischemic arrhythmias, possibly by diminishing intracellular calcium overload and its effect on the ventricular action potential. To explore this, we compared the effects of diltiazem on ischemic "injury" potentials and ventricular fibrillation during serial coronary artery occlusions in dogs. Injury potentials and ventricular fibrillation were elicited every 15-25 minutes by simultaneous occlusion of the left anterior descending and circumflex arteries during rapid atrial pacing. DC epicardial electrograms were recorded differentially between the ischemic region and a small nonischemic region supplied by a proximal branch of the left anterior descending artery. Injury potentials developed with a uniform time course during five control occlusions, but were reduced by diltiazem infusion (0.5 mg/kg over 25 minutes) in each of eight dogs. The mean diastolic injury potential (T-Q depression) at 150 seconds of ischemia was 9.1 +/- 2.7 mV before diltiazem and 6.1 +/- 1.6 mV afterward (P less than 0.001). Diltiazem increased the mean time between coronary occlusion and ventricular fibrillation from 186 to 366 seconds (P less than 10(-5), but did not change the magnitude of the diastolic injury potential at onset of ventricular fibrillation. Diltiazem also delayed ischemia-induced conduction impairment to the same extent that it delayed injury potential development. In five dogs, the effect of diltiazem on regional blood flow near the epicardial electrodes was measured by infusion of radionuclide-labeled microspheres. Coronary occlusion reduced flow to the ischemic zone from 0.86 to 0.05 ml/min per g (P = 0.001). Diltiazem increased preocclusion flow by 11% (P = 0.03), but did not significantly alter flow during occlusion. Hemodynamic measurements show that diltiazem did not diminish cardiac work. Diltiazem therefore produced a flow-independent reduction of cellular depolarization during ischemia, which may be due to relief of calcium overload, and which may explain the antifibrillatory effect.

Action Potentials↗
PubMed1984

Origin of the background sodium current and effects of sodium removal in cultured embryonic cardiac cells.

Cardiac automaticity is partly due to a diastolic sodium current. Possible mediators of this include tetrodotoxin-sensitive "fast" channels, cesium-sensitive time-dependent pacemaker current channels, calcium-gated nonspecific channels, and electrogenic sodium-calcium exchange. We have studied the effects of abrupt sodium removal on membrane current and conductance in voltage-clamped chick embryonic myocardial cell aggregates, in the presence of various sodium flux inhibitors. Total replacement of sodium by lithium, Tris, or tetraethylammonium ions in aggregates clamped in the pacemaker range caused a brief outward current followed by a sustained net inward current. The outward current reached a peak value of 1.1 +/- 0.5 microA/cm2 at a mean latency of 5.4 +/- 1.2 sec. (n = 6; V = -70.5 +/- 8.9 mV; Tris). Conductance often decreased during the outward current. The inward current developed exponentially (t = 19 +/- 5 sec) and reached a steady state value of -1.6 +/- 0.4 microA/cm2. This current was reversed by depolarization (mean reversal potential = -13 +/- 13 mV), and was accompanied by increased conductance and spontaneous mechanical activity. Neither of the sodium-removal currents was affected by 20 microM tetrodotoxin. Cesium (up to 20 mM) had no effect on the late inward current or the mechanical activity, but decreased the early outward current by 80 +/- 12%. Manganese (25 mM), which blocks sodium-calcium exchange, abolished the late inward current and the mechanical activity. Manganese also reduced the early outward current by 27 +/- 10%. Manganese and cesium together blocked all the effects of sodium removal. We conclude that removal of extracellular sodium interrupts a cesium-sensitive "background" current, that may be related to the time-dependent pacemaker current, If. Sodium removal also causes gradual activation of a nonspecific conductance, which can ultimately depolarize the cells, and which may be gated by cytoplasmic calcium.

Animals↗
PubMed1983

Calcium overload, "injury" current, and early ischaemic cardiac arrhythmias--a direct connection.

Intracellular calcium ions induce a depolarising inward current by reacting with specific sites on the inner surface of cardiac muscle cell membranes. Since intracellular calcium overload invariably occurs with myocardial ischaemia, it may be that the early electrophysiological manifestations of ischaemia, including cellular depolarisation, diastolic current flow, and early ischaemic arrhythmias, are directly mediated by calcium. A simple explanation for the effects of many drugs upon the electrical behaviour of ischaemic myocardium is proposed.

Adrenergic beta-Antagonists↗
PubMed1983

Caffeine induces a transient inward current in cultured cardiac cells.

Electrical excitation of cardiac muscle may sometimes be due to initiation of inward current by the presence of Ca2+ ions at the inner surface of the cell membrane. During digitalis toxicity and other conditions that abnormally augment cellular Ca2+ stores, premature release of Ca2+ from the sarcoplasmic reticulum leads to a transient inward current, which is large enough to initiate premature beats and is accompanied by a transient contractile response. This inward current may be mediated either by electrogenic sodium-calcium exchange or by specific Ca2+-activated cation channels that have recently been characterized in tissue cultures of cardiac myocytes. An obvious question raised by these observations is whether release of the sequestered Ca2+ stores during each normal beat exerts a similar influence on membrane potential. To explore this, chick embryonic myocardial cell aggregates were voltage-clamped during abrupt exposure to caffeine, which is known to release Ca2+ from the sarcoplasmic reticulum. The speed of the perfusion system and the relative absence of diffusion barriers in the tissue-cultured cells allowed the effects of caffeine-induced Ca2+ release to be studied on a time scale comparable to that of a single normal beat. We report here that abrupt exposure of the cells to caffeine produced a transient inward current having similar features to that of digitalis toxicity, and which was both large enough and rapid enough to potentially contribute to the action potential.

Action Potentials↗
PubMed1983

Mechanism by which metabolic inhibitors depolarize cultured cardiac cells.

To elucidate the means by which metabolic inhibition depolarizes cardiac cells, spontaneously beating chicken embryonic myocardial cell aggregates were voltage clamped during superfusion with 2,4-dinitrophenol and iodoacetic acid. In aggregates continuously clamped in the pacemaker potential range, abrupt exposure to these metabolic inhibitors produced a slow transient inward current. This inward current was not due to an alteration of the pacemaker current, IK2, because it could still be elicited after IK2 was abolished by Cs+ ions. The inward current was increased by hyperpolarization and decreased by depolarization. It became larger and more sustained if intermittent action potentials were allowed during exposure or if the aggregates were pretreated with either 10 mM Ca2+ or 2.7 microM acetylstrophanthidin. The inward current was suppressed by removal of extracellular Na+ or Ca2+. These observations suggest that early depolarization of cultured cardiac cells by metabolic inhibitors involves some of the same mechanisms as the transient inward current of digitalis toxicity--specifically, an effect of intracellular Ca2+ ions on membrane permeability. Similar phenomena could occur during other forms of metabolic inhibition such as myocardial ischemia.

2,4-Dinitrophenol↗
PubMed1983

Caffeine-induced current in embryonic heart cells: time course and voltage dependence.

Abrupt exposure of 90- to 130-micron diameter chick embryonic myocardial cell aggregates to 10 mM caffeine has been shown to induce a transient inward current. In the present study, we recorded a similar current in small cell clusters (less than 10 cells) in which access of caffeine to each of the cells was rapid. The resulting inward current consisted of a single peak, which decayed exponentially (predominant time constant 335 +/- 130 ms at -40 mV) and had a peak amplitude of up to 15.5 microA/cm2. The caffeine-induced current persisted when the slow inward current was abolished by a 30-s pretreatment with 2 microM D 600 and could be observed at potentials where the fast sodium channels were fully inactivated. The current-voltage relation of the caffeine response was linear between -110 and -40 mV, giving an extrapolated voltage intercept of +12 mV. However, the inward current did not diminish or reverse with further depolarization. A substantial inward current occurred at potentials up to +60 mV, which is more positive than the reversal potential of the tetrodotoxin-sensitive inward current. We conclude that the caffeine-induced current is mediated in part by electrogenic Na+-Ca2+ exchange.

Animals↗
PubMed1982

Do calcium-dependent ionic currents mediate ischemic ventricular fibrillation?

Calcium ions mediate the adverse effects of myocardial ischemia and have been implicated in the genesis of arrhythmias. Calcium influx blocking drugs protect against early ventricular arrhythmias during experimental coronary occlusion, and recent studies suggest that this effect is at least partly due to inhibition of myocardial cell calcium influx. Most of the pharmacologic maneuvers used to simulate acute ischemic arrhythmias in vivo also produce intracellular calcium overload. Production of calcium overload in small myocardial cell clusters causes fibrillatory electrical and mechanical activity similar to that recorded from fibrillating hearts. Fibrillation in these cell clusters is mediated not by reentrant conduction, but by the same subcellular processes that give rise to depolarizing afterpotentials and abnormal automaticity. Agents favoring calcium influx, such as beta adrenergic agonists, accentuate these processes, while agents that depress calcium influx inhibit them. Although the relation of these experimental models to clinical ischemic arrhythmias has not been fully delineated, calcium influx blocking drugs may prove useful in reducing the incidence of sudden cardiac death.

Animals↗
PubMed1982

Programmed ventricular stimulation in predicting vulnerability to ventricular arrhythmias and their response to antiarrhythmic therapy.

In predicting vulnerability to ventricular arrhythmias and their response to antiarrhythmic therapy, several factors and questions need to be considered, including the following. (1) Ventricular tachycardia (VT) can be induced in most patients who have recurrent sustained VT. (2) Because induced VT can often be pace terminated, termination by pacing should be attempted before cardioversion is applied. (3) Acutely effective antiarrhythmic agents are no longer being found for the majority of patients undergoing electrophysiologic-pharmacologic study in our series. (4) Specific VT-induction programs affect both the inducibility of VT and acute efficacy of drugs at electrophysiologic study; this point requires examination. (5) Arrhythmia-induction studies may not product high yield in patients with clinical ventricular fibrillation or unsustained VT. (6) It is as yet unclear whether some drugs, such as amiodarone, can be accurately evaluated by using arrhythmia-induction techniques. (7) Induction of the repetitive ventricular response by V2 stimulation is not a useful method for antiarrhythmic drug selection in patients with recurrent ventricular tachyarrhythmias. (8) Adequate data do not yet exist to identify either the ECG-monitoring technique or the arrhythmia-induction technique as the preferred method for selecting antiarrhythmic drugs for chronic therapy of patients with recurrent ventricular tachyarrhythmias. A study to compare the accuracies of the two techniques is both feasible and needed.

Amiodarone↗
PubMed1982

Prolongation of the human cardiac monophasic action potential by sotalol.

Sotalol and propranolol are nonselective beta-adrenergic blocking agents. Sotalol at low concentration, unlike propranolol, prolongs the duration of the transmembrane action potential. In a double-blind study, the electrophysiologic effects of intravenous sotalol (0.30 or 0.60 mg/kg; n = 9) were compared with intravenous propranolol (0.15 or 0.20 mg/kg; n = 8) in 17 patients with use of bipolar suction electrodes in the right atrium and right ventricle to determine whether sotalol prolongs the monophasic action potential duration in man. After administration of sotalol, there were significant increases (paired t test) in the Q-T interval (p less than 0.001), right atrial effective refractory period (p less than 0.05), right ventricular effective refractory period (p less than 0.005), right atrial monophasic action potential duration at 90% repolarization (p less than 0.01), and right ventricular monophasic action potential duration at 90% repolarization (p less than 0.005). Prolongation of the monophasic action potential duration was dependent on plasma sotalol concentration. There were no significant changes in these variables after propranolol. The spontaneous cycle length and Wenckebach cycle length increased significantly in both groups, and the mean blood pressure decreased in both, although not significantly after propranolol. In summary, sotalol but not propranolol prolonged atrial and ventricular effective refractory periods and lengthened the monophasic action potential and the Q-T interval of human myocardium after intravenous infusion. The ability to acutely prolong repolarization at therapeutic plasma concentration is unique among known competitive beta-adrenergic receptor antagonists.

Action Potentials↗
PubMed1982

The effects of diltiazem and reduced serum ionized calcium on ischemic ventricular fibrillation in the dog.

Calcium influx blockers reportedly suppress ventricular arrhythmias during acute ischemia. We therefore studied the effects of diltiazem and reduced serum ionized calcium on ventricular fibrillation (VF) in a reversible ligation model. VF was produced at 15-minute intervals by simultaneous occlusion of the left anterior descending and circumflex arteries of 31 dogs. Time from coronary occlusion to onset of VF showed no significant variation during 15 consecutive trials in six dogs that received saline alone. Intravenous infusion of diltiazem (0.02 mg/kg per min) markedly delayed the onset of VF in each of 10 dogs (P less than 0.0001). Mean VF latency increased from 138 to 295 seconds during a 45-minute diltiazem infusion, declined exponentially when the infusion ceased, and was strongly correlated with serum diltiazem concentration (r = 0.96, P less than 10(-6)). In five dogs, hemodynamic measurements, including coronary venous blood flow, were performed during each occlusion. The increase in VF latency by diltiazem was not due to increased coronary flow during occlusion or to reduction of left ventricular (LV) mechanical work. In six dogs, mean serum ionized calcium, [Ca++], was reduced from 1.11 to 0.59 mM by infusion of sodium citrate. Citrate infusion increased mean VF latency from 155 to 243 seconds, and the increase observed in each dog was correlated (r = 0.84, P less than 10(-6)) with the reduction in [Ca++]. VF latency was unaffected by lidocaine in nine dogs. The antifibrillatory effect of diltiazem during global LV ischemia may be an electrophysiological phenomenon related to reduction of cellular calcium influx.

Animals↗
PubMed1981

The mechanical activity of chick embryonic myocardial cell aggregates.

1. Simultaneous recordings of membrane potential and edge movement were obtained in spontaneously beating chick embryonic myocardial cell aggregates, which are known to behave as an isopotential syncytium.2. The time course of edge movement was similar in different aggregates, and in different regions of the same aggregate.3. Peak amplitude was increased by 10(-6)m-ouabain, and by rapid reduction of the external sodium concentration.4. Peak amplitude was decreased during single premature action potentials, but sustained rapid pacing produced an ascending staircase.5. Depolarizing current pulses increased both the amplitude and duration of the contraction, and caused potentiation of the next spontaneous beat. Edge displacement during a series of pulses was a monotonic function of membrane potential.6. Edge movement between action potentials (diastolic movement) was well fitted by an exponential with a mean time constant of 69 msec. Diastolic edge movement was due to a weak, slowly decaying contractile force, which was demonstrated in cells grown on a linear-elastic nylon bristle.7. The time course of diastolic edge movement remained constant, or nearly constant, during variations in peak amplitude that resulted from prematurity of the action potential, exposure to 10(-6)m-ouabain, spontaneous mechanical alternans, or prolongation of the action potential by current pulses.8. In contrast, reduction of the external sodium concentration produced marked, selective slowing of the diastolic edge movement. Similar slowing occurred during cooling and during staircase. Diastolic edge movement was selectively accelerated when the preceding interbeat interval was prolonged by a hyperpolarizing current pulse.9. The above observations are consistent with the hypothesis that edge displacement is a monotonic function of contractile force.10. The slow relaxation between action potentials probably reflects removal of intracellular calcium across the surface membrane in exchange for sodium. Changes in the rate of calcium removal may play a role in the regulation of contractility in this tissue.

Action Potentials↗
PubMed1980

Correlation between relaxation and automaticity in embryonic heart cell aggregates.

Diastolic depolarization in cardiac muscle is due to a decline in potassium permeability that has been ascribed to removal of intracellular free calcium. A continued decline in tension during the pacemaker potential might therefore occur. In this study, contractile responses of chicken embryonic heart cell aggregates are recorded with a photodiode. Photodiode output is well correlated with the position of the aggregate's edge. Movements of different edges are synchronous, and their amplitude and duration vary appropriately during experimental maneuvers that alter the magnitude and duration of contractile force. Edge movement during relaxation has two phases, a rapid phase lasting about 100 msec and a slow phase that may last over 10 sec. The slow phase is not due to viscoelasticity because its time course does not depend on the magnitude or duration of the initial deformation. The rate of relaxation is correlated with the rate of depolarization during the pacemaker potential. Reduction in automaticity during cooling, spontaneous variation, and overdrive pacing are associated with impairment of the slow component of relaxation. Electrophysiological evidence suggests that the diastolic potassium permeability of the aggregates is controlled by intracellular calcium. A possible explanation for the correlation between the slope of the pacemaker potential and the slow component of relaxation is that both phenomena reflect a common physiological process-i.e., the removal of free calcium from the cytoplasm.

Action Potentials↗
PubMed1979

The oscillatory responses of skate electroreceptors to small voltage stimuli.

Tonic nerve activity in skate electroreceptors is thought to result from spontaneous activity of the lumenal membranes of the receptor cells which is modulated by applied stimuli. When physiological conditions are simulated in vitro, the receptor epithelium produces a current which flows inward across the lumenal surface. This epithelial current exhibits small spontaneous sinusoidal fluctuations about the mean that are associated with corresponding but delayed fluctuations in postsynaptic response. Small voltage stimuli produce damped oscillations in the epithelial current similar in time-course to the spontaneous fluctuations. For lumen-negative, excitatory stimuli, these responses are predominantly an increase over the mean inward current. For inhibitory stimuli they are predominantly a decrease. Increased inward current across the lumenal membranes of the receptor cells increases depolarization of the presynaptic membranes in the basal faces leading to increased release of transmitter and an excitatory postsynaptic response. Decreased inward current decreases depolarization of the presynaptic membranes leading to a reduction in transmitter release and an inhibitory postsynaptic response. Clear changes in postsynaptic response are detectable during stimuli as small as 5 microV with saturation occurring at +/- 400 microV. The evoked oscillations in epithelial current are damped and the postsynaptic responses decline during maintained stimuli with large off-responses occurring at stimulus termination. The initial peak of the off-response is similar to the response produced by onset of an oppositely directed stimulus. These observations substantiate the role of receptor cell excitability in the detection of small voltage changes.

Animals↗
PubMed1979

The ionic basis of oscillatory responses of skate electroreceptors.

When physiological conditions are simulated, skate electroreceptors produce small maintained oscillatory currents. Larger damped oscillations of similar time-course are observed in voltage clamp. Subtraction of leakage in voltage clamp data shows that the oscillations involve no net outward current across the lumenal surface of the epithelium. The oscillations are much faster than the late outward current generated by the lumenal membranes of the receptor cells. Treatment of the basal surface of the epithelium with tetraethyl ammonium (TEA), high K, Co, or EGTA reversibly blocks the oscillations in voltage clamp, but has little or no effect on the epithelial action potential in current clamp or on the current-voltage relation. The TEA sensitivity of the oscillations indicates that they involve a potassium conductance in the basal membranes of the receptor cells. Treatment of the basal membranes with TEA and high calcium, with strontium, or with barium causes these membranes to produce large regenerative responses. Direct stimulation of the basal membranes then elicits a lumen-positive action potential whereas stimulation of the lumenal membranes elicits a diphasic action potential. Excitability of the basal membranes is abolished by extracellular Co, Mn, or La. Modulation of the lumenal membrane calcium conductance by the basal membrane conductances probably gives rise to the oscillatory receptor currents evoked by small voltage stimuli. The slower calcium-activated late conductance in the lumenal membranes may be involved in sensory accommodation.

Animals↗
PubMed1979

Transduction at electroreceptors: origins of sensitivity.

Electroreceptors of four different classes were analyzed in terms of adaptations leading to high sensitivity. The large receptor of mormyrids is a sensitive phasic receptor. Voltage amplification is provided by an impulse-generating mechanism in the receptor cells. The cells are specialized in that their threshold is very close to the resting potential. Inward current may be mediated by Ca channels, which show little inactivation. Transmission to the afferent nerve is electrotonic and is apparently not otherwise specialized. Other phasic receptors appear to use regenerative responsiveness more for active filtering than for voltage gain. Tonic electroreceptors of freshwater fishes lack regenerative responses in their receptor cells. Stimuli act directly on the presynaptic membrane to alter Ca permeability and modulate the release of transmitter. The absence of regeneration is ascribable to shunting by fixed conductances. The relation between transmitter release and depolarization is much steeper than the corresponding relation at the squid giant synapse. Indirect arguments suggest that the great voltage sensitivity does not reside in any properties of the Ca channels, but in subsequent processes leading to transmitter release. The ampulla of Lorenzini is the most sensitive electroreceptor. Its sensitivity apparently resides in the regenerative oscillatory activity of the receptor cells. The receptor is kept in its operating range by accommodative processes, probably involving Ca-activated outward current. A number of mechanisms of electroreception appear relevant to mechanosensitive acoustico-lateralis receptors. The specialized accommodative processes and the adaptations increasing sensitivity are likely to be relevant to many other systems as well.

Action Potentials↗