Biomedical subjects

A Varró

Publications and source records attributed to A Varró.

At least 55 records · Page 3Linked to original sources

PubMed1996

ATP-sensitive potassium channel modulators: both pinacidil and glibenclamide produce antiarrhythmic activity during acute myocardial infarction in conscious rats.

We investigated the effects of pinacidil, an ATP-sensitive potassium channel opener, and of glibenclamide, an ATP-sensitive potassium channel inhibitor, on the incidence of arrhythmias and sudden cardiac death after coronary artery ligation in conscious rats. Occlusion of the left main coronary artery was produced by tightening a previously placed loose silk ligature. In the control group (n = 25) only 40% and 24% of the animals survived for 15 min and 16 hr after coronary artery ligation, respectively. Intravenous pretreatment with 0.1, 0.3 or 1 mg/kg pinacidil increased the survival rate to 67% (n = 15), 70% (n = 20) and 67% (n = 12) in the first 15 min and to 60%, 55% and 67% in the first 16 hr, respectively. Glibenclamide pretreatment (5.0 mg/kg i.p.) improved the survival rate at both time-points to 87% (n = 16). Both types of pretreatment significantly decreased the incidence of life-threatening arrhythmias and increased the number of animals that survived without developing any arrhythmia. In conclusion, the present findings demonstrate that in conscious rats, pretreatment with pinacidil and pretreatment with glibenclamide, although they obviously have different mechanisms of action, may result in a very similar final outcome with respect to arrhythmias and sudden cardiac death during the acute phase of experimental myocardial infarction.

Adenosine Triphosphate↗

PubMed1996

The cellular electrophysiological effects of tedisamil in human atrial and ventricular fibers.

The cellular electrophysiological effects of 1 microM tedisamil (KC 8857) were studied in human atrial and ventricular fibers. Conventional microelectrode technique was applied to record the transmembrane action potentials at stimulation frequency of 100 per min and 37 degrees C. Tedisamil lengthened action potential duration (APD) more in atrial than in ventricular muscle fibers; prolongation of APD90 was 28.9 +/- 3.3% (n = 6; p < 0.05) for atrial and 13.3 +/- 5.2% (n = 6; P < 0.05) for ventricular tissue. The maximal rate of depolarization was depressed slightly, but significantly by 1 microM tedisamil only in ventricular fibers (12.9 +/- 6.5%, n = 6, P < 0.05). From these cellular electrophysiological data it is concluded that the bradycardic/antiischemic agent tedisamil possesses marked Class III properties not only in cardiac tissues of experimental animals but also those of man.

Action Potentials↗

PubMed1996

Effect of restacorin on the early and delayed after depolarization in dog Purkinje fibres.

The effect of restacorin and flecainide on the early afterdepolarization (EAD) and on the delayed afterdepolarization (DAD) was studied in dog cardiac Purkinje fibers by applying the conventional microelectrode technique. Restacorin and flecainide at 5 microM concentration partially abolished EAD. Further increase of the concentrations of the drugs to 10 microM EADs were completely abolished. The amplitude of DADs were significantly decreased by both restacorin (9.9 +/- 2.1 mV v.s. 2.9 +/- 1.8 mV, p < 0.01, n = 5) and flecainide (11.1 +/- 1.3 mV v.s. 0.6 +/- 0.6 mV, p < 0.01, n = 7). These results suggest that the well-established antiarrhythmic effect of restacorin and flecainide at least partially may be explained by their beneficial action against triggered abnormal automaticity.

Animals↗

PubMed1996

Comparison of the effects of restacorin and flecainide on various cardiac transmembrane potassium currents.

The effect of restacorin (5 microM) and flecainide (5 microM) on the transmembrane ionic currents was compared in dog and rabbit ventricular muscle by applying the conventional microelectrode and patch-clamp techniques. Neither restacorin nor flecainide influenced significantly the ATP-sensitive and inward rectifier potassium currents. Flecainide moderately decreased the amplitude of the transient outward current while restacorin did not change this current. The delayed rectifier potassium current was depressed markedly by flecainide and moderately by restacorin. These results suggest that although flecainide and restacorin cause similar changes in the various transmembrane ionic currents, there are some differences between the effects of the two antiarrhythmic compounds.

Action Potentials↗

PubMed1995

Electrophysiological effects of tiracizin and its metabolites in dog cardiac Purkinje fibers.

1. Conventional microelectrode technique was used to study the effects of tiracizin and its two main metabolites on the action potential parameters in dog cardiac Purkinje fibers. 2. Tiracizin induced a use-dependent depression of the maximal rate of depolarization during the upstroke of the action potential (EC50 = 0.323 +/- 0.059 microM, n = 5) and decreased the action potential duration (EC50 = 0.230 +/- 0.024 microM, n = 5). 3. The two main metabolites exerted similar effects, but only at concentrations about one order of magnitude higher than tiracizin. 4. It was concluded that the electrophysiological effects of tiracizin in dog Purkinje fibers correspond to those of Class I antiarrhythmic drugs also in cardiac Purkinje fibers. The main metabolites are less potent than the parent compound, therefore it is likely that their effects play a less important role in the beneficial effect of tiracizin in cardiac arrhythmias.

Action Potentials↗

PubMed1994

Effects of veratridine on Na and Ca currents in frog skeletal muscle.

1. Voltage-clamp experiments were performed to determine the effects of veratridine on Na and Ca currents in frog skeletal muscle fibres. 2. Veratridine (1 microM) did not affect the kinetics of the fast Na current but it did induce a slowly inactivating tetrodotoxin-sensitive inward current that was apparent after Na current inactivation. This slow current had a peak amplitude of 6.7 +/- 0.7 microA/cm2 at -20 mV and decayed monoexponentially with a time constant of 606 +/- 77 ms. 3. The slow current had a voltage-dependence for activation that was similar to that of the fast Na current. Single depolarizing prepulses that induced complete inactivation of the fast Na channels, prevented development of the slow current. Trains of brief depolarizations at increasing frequencies increased the amplitude of the slow current. These results suggest that the slow current may be mediated by veratridine modified Na channels that must be in the open position. 4. The low concentration of veratridine (1 microM) did not affect the Ca current, while 100 microM veratridine reversibly suppressed the Ca current and shifted its peak current-voltage relation towards more negative potentials. Thus, veratridine appears not to be a selective fast Na channel modifier as it may also alter Ca channel gating properties in skeletal muscle fibres.

Animals↗

PubMed1994

Effects of veratrine on ion currents in single rabbit cardiomyocytes.

1. Voltage-clamp experiments were performed to determine the effects of veratrine (1 microgram/ml) on Na and K currents in isolated rabbit ventricular cardiomyocytes. 2. Veratrine did not affect the inward rectifier K current, increased the inactivation time constant of the transient outward current (I(to)) and induced a slowly decaying inward current component (Iv), which was sensitive to tetrodotoxin. 3. Inactivation of fast Na channels by application of short depolarizing prepulses to potentials between -90 and -50 mV prevented the development of Iv.Iv decayed biexponentially with time constants equal to 139 +/- 9.0 ms and 776 +/- 47 ms. The net amplitude of Iv and the time constants for its rapidly and slowly inactivating components were little affected by trains of conditioning prepulses to 0 mV. The contributions, however, of the fast and slow components to the net current were significantly altered by repetitive depolarizations. 4. These components of Iv are likely due to modification of open cardiac Na channels by veratrum alkaloids.

Animals↗

PubMed1994

Electrophysiologic effects of detajmium on isolated dog cardiac ventricular and Purkinje fibers.

We studied the electrophysiologic effects of the antiarrhythmic compound detajmium (Tachmalcor) on isolated dog and rabbit cardiac preparations, applying the conventional intracellular microelectrode techniques. In dog ventricular muscle fibers (37 degrees C, stimulation frequency 1 Hz), 1 microM detajmium did not change resting potential (RP), action potential amplitude (APA), AP duration measured at 90% of repolarization (APD90), or effective refractory period (ERP) significantly, but reduced maximum rate of depolarization (Vmax) significantly from 236.7 +/- 28.9 to 177.3 +/- 22.5 V/s (n = 6, p < 0.01). In dog Purkinje fibers (37 degrees C, stimulation frequency 1 Hz), 1 microM detajmium significantly decreased APA from 111.1 +/- 12.3 to 100.0 +/- 2.5 mV (n = 8, p < 0.003), APD90 from 359.0 +/- 17.5 to 262.1 +/- 12.3 ms (n = 8, p < 0.001) and Vmax from 687.5 +/- 57.2 to 523.7 +/- 58.2 V/s (n = 8, p < 0.001) without changing maximal diastolic potential or ERP/APD ratio significantly. The effect of detajmium on Vmax in both dog ventricular muscle and Purkinje fibers was frequency dependent. Fractional Vmax block was 0.185 +/- 0.008 1/AP. The recovery kinetics of Vmax (offset kinetics) was extremely slow (time constant = 348.16 +/- 57.43 s) considerably slower than most of those of other antiarrhythmic drugs yet reported. Detajmium in concentration < 32 microM did not influence the beta-adrenoceptors or slow response APs in dog ventricular tissue significantly. On the basis of its electrophysiologic effects, detajmium, like prajmaline, encainide, or flecainide, can be best classified as a class I/C antiarrhythmic drug according to the Vaughan Williams' classification scheme.

Action Potentials↗

PubMed1993

Ionic basis for OPC-8212-induced increase in action potential duration in isolated rabbit, guinea pig and human ventricular myocytes.

Changes in transmembrane ionic currents induced by OPC-8212 (3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2(1H)-quinoline) , a recently introduced positive inotropic agent which lengthens cardiac action potential duration, were examined using whole-cell voltage-clamp techniques in single rabbit, guinea pig and human ventricular myocytes. In rabbit, OPC-8212 (12 mumol/l) significantly increased membrane action potential duration measured at 90% of repolarization by an average of 88 ms (from 462 +/- 25 to 550 +/- 35 ms, n = 4; P < 0.05). In rabbit this increase in duration was not associated with significant changes in either the inward rectifier or transient outward K+ currents. The magnitude of the secondary inward current evoked from a holding potential of -50 mV was significantly increased by 97 +/- 8% (n = 6; P < 0.01) while a demonstrable delayed rectifier outward current could not be identified in the rabbit myocytes examined at room temperature. In guinea pig ventricular myocytes, where the delayed rectifier was large, 12 mumol/l OPC-8212 significantly depressed the current by 58 +/- 10% (n = 6; P < 0.01). The effects of OPC-8212 in human ventricular myocytes obtained from the explanted heart of a single patient having an idiopathic cardiomyopathy most closely resembled those observed in isolated rabbit ventricular myocytes. Thus, in rabbit and a few human ventricular myocytes examined at room temperature, OPC-8212 appeared to lengthen cardiac membrane action potential duration primarily by increasing the amplitude of the secondary inward current believed to primarily represent current through L-type Ca2+ channels. In guinea pig preparations, OPC-8212 also decreased the delayed rectifier outward K+ current which also would account for an increase in action potential duration. OPC-8212 could not be demonstrated to affect Na+ current inactivation in a manner similar to that produced by 1 mg/l veratrine, a recognized Na+ channel agonist, which dramatically slowed this process.

Action Potentials↗

PubMed1993

Potassium currents in isolated human atrial and ventricular cardiocytes.

The whole-cell configuration of the patch-clamp technique was applied to study and compare ion currents in single ventricular and atrial cardiocytes isolated from human myocardium. In ventricular cardiocytes the K+ inward rectifier current (IK1) was three times larger than in atrial cardiocytes, while its inactivation kinetics were twice as slow when measured at -140 mV. The magnitude of these variables depended on the test potential but was independent of changes in holding potential. A transient outward current (I(to)) was observed in both ventricular and atrial cardiocytes. The amplitude of the inactivating component of Ito was not significantly different in atrial and ventricular cells, but the time course of inactivation was significantly longer in atrial than in ventricular cardiocytes. Steady-state inactivation of Ito in atrial cells was well described by a two-state Boltzmann function having a midpoint potential of -41.4 mV and a slope factor of 6.9 mV-1. No discernible K+ delayed rectifier current (IK) was observed in either cell type. In four of the 12 atrial cells studied, a time dependent inward current was observed at negative test potentials having a 240 +/- 21 ms time constant for activation and an amplitude of 101 +/- 28 pA. This current, which resembled the pacemaker current (I(f)), was not observed in any of the ventricular cells examined.

4-Aminopyridine↗

PubMed1993

Isolation of human ventricular and atrial cardiomyocytes: technical note.

Techniques suitable for the isolation of human cardiac cells have previously been reported. However, there are difficulties concerning the reliability and reproducibility of the available methods. In the present study, a technique developed for the isolation of canine cardiocytes was successfully applied to allow isolation of human atrial and ventricular myocytes from small samples of myocardium. Application of this method allowed a direct comparison of the ionic currents recorded from human atrial and ventricular myocytes with those recorded from other mammalian preparations.

Animals↗

PubMed1992

Biphasic effect of tetraethylammonium on canine purkinje fibre action potential configuration.

1. Using conventional microelectrode techniques a biphasic effect of tetraethylammonium (5 mmol/l) on the configuration of action potentials recorded from isolated canine Purkinje fibres: action potentials were first shortened (early effect) and then lengthened (late effect) by tetraethylammonium. 2. The early effect of tetraethylammonium also included lengthening of phase 1 duration and elevation of the plateau amplitude. These early effects reached steady-state within the first 3 min of superfusion and were readily reversed within 3 min of initiating washout of the drug. 3. The late effect (gradual lengthening of repolarisation during phase 3) failed to reach steady-state within the initial 60 min of superfusion and was not reversible. 4. The early effects of tetraethylammonium were more marked at slow driving rates and were not affected by blockade of alpha- and beta-adrenoceptors using 1 mumol/l phentolamine and 1 mumol/l propranolol. 5. The early effects of tetraethylammonium were mimicked by 4-aminopyridine (0.5 mmol/l), and in the presence of 4-aminopyridine tetraethylammonium failed to induce further changes in action potential morphology. 6. The early effects of tetraethylammonium may be due to inhibition of the transient outward current. 7. The rapid onset and reversibility of these early effects suggest that tetraethylammonium may act from outside the cell membrane.

Action Potentials↗

PubMed1992

Active and passive electrical properties of isolated canine cardiac Purkinje fibers under conditions simulating ischaemia: effect of diltiazem.

The effect of a calcium channel blocker diltiazem on the electrical properties of canine Purkinje fibers superfused in a milieu similar to that occurring in acute myocardial ischaemia was studied. Action potential parameters, passive electrical properties, and conduction velocity were measured using conventional microelectrode techniques. Superfusion with glucose-free Tyrode's solution containing 9 mM K+, gassed with 100% N2 at pH = 6.5 ('ischemic solution') significantly reduced the maximal diastolic potential, action potential duration, maximal upstroke velocity, conduction velocity and length constant, while input resistance and longitudinal resistance were elevated and membrane resistance remained unchanged. Diltiazem (1 microM) alone reduced only the action potential duration, while all other parameters were unaffected. Pretreatment with diltiazem did not fully prevent the effects of ischemic superfusion; however, the ischaemia-induced decrease in length constant was not significant in the presence of diltiazem. In addition, the increase in longitudinal resistance during ischaemia was significantly reduced following diltiazem pretreatment. This decrease in longitudinal resistance may contribute to the improvement of ischaemia-induced conduction delay observed in intact animals and may be related to a reduction of ischaemia-induced increase in intracellular free Ca2+.

Action Potentials↗

PubMed1992

Nonlinear relationship between V+max and h infinity in frog skeletal muscle.

The relationship between the maximum velocity of action potential upstroke (V+max) and steady-state Na+ channel inactivation (h infinity) was studied in frog skeletal muscle during repetitive discharges evoked in the presence of cevadine (1 mumol/l). Conventional microelectrodes and vaseline-gap voltage-clamp techniques were used. A severe degree of nonlinearity was found between (h infinity) and (V+max) especially when the Na+ conductance (gNa) was small. The observed nonlinearity could be explained as a property of the normal Na+ channel gating in skeletal muscle rather than that of cevadine-modified channels. Part of this work has been published in abstract form in Biophys. J. 57: 105A, 1990.

Action Potentials↗

PubMed1992

Ionic currents in ventricular myocytes isolated from the heart of a patient with idiopathic cardiomyopathy.

Whole-cell configuration of the patch-clamp technique was applied to record ionic currents from human ventricular myocytes isolated from a cardiac transplant patient with idiopathic cardiomyopathy. Inward calcium current, transient outward current, and inward rectifier potassium current were recorded, while no discernible delayed rectifier potassium current was observed. Thus the currents that underlie electrical activity in human ventricular myocytes appear to resemble those reported earlier in canine and rabbit ventricular myocytes.

Calcium↗

PubMed1992

The impact of single cell voltage clamp on the understanding of the cardiac ventricular action potential.

In this article we review results obtained during the last decade by the single cell voltage clamp technique on cardiac ventricular myocytes, and we re-evaluate the major ionic currents underlying the cardiac action potential. Since its introduction into cardiac electrophysiology in the late seventies this technique has greatly contributed to our knowledge about the role of the transmembrane ionic currents in the heart. Recent findings gained with this method have confirmed that the inward sodium current is responsible not only for the fast depolarization, but, in part, also for the maintenance of the plateau phase of the action potential. The kinetics of the inward calcium current measured by the single cell voltage clamp technique proved to be much faster than was previously thought. In addition, two types of the inward calcium current with different physiological roles have recently been identified. The L-type calcium current plays an important part in maintaining the plateau phase of the action potential and may cause depolarization at less negative potentials. Although the physiological significance of the T-type calcium current is less clear, it appears to be involved in the pacemaker function of cardiac tissues. Single cell voltage clamp experiments have shown that the inward rectifier potassium current is not independent of time, as described earlier, but it helps to terminate the final phase of repolarization, and presumably controls the resting membrane potential. Recent studies with the single cell voltage clamp method have revealed that the delayed rectifier potassium current has, most probably, more than one component and is extensively modulated by neurotransmitters. Its main role is to initiate and terminate cardiac repolarization. This current is of particular importance in regulating rate-dependent repolarizations. The transient outward current, which rapidly activates and inactivates after depolarization, initiates early fast repolarization and may also take part in rate-dependent repolarization. The ionic carriers of this current are most likely potassium and chloride. The use of the single cell voltage clamp technique has led to the discovery of formerly unrecognized currents, like the ATP-dependent potassium current, the sodium activated potassium current and the chloride currents. The application of the new technique has made it possible to focus more attention on currents which were difficult to study previously, such as Na/K pump and Na/Ca exchanger currents.

Action Potentials↗

PubMed1991

Electrophysiologic effects of FPL 13210 on canine Purkinje fiber action potential duration and Vmax comparison to disopyramide.

The frequency-dependent effects of FPL 13210, a new disopyramide derivative, were examined in isolated canine cardiac Purkinje fibers paced at a frequency of 2 Hz and following abrupt changes in pacing cycle length. At 2 Hz, FPL 13210 depressed Vmax, while shortening action potential duration measured at 50% of repolarization (APD50) and not affecting duration measured at 90% of repolarization (APD90). These effects were concentration dependent over the range of 1-30 microM. The depression of Vmax produced by 5 microM FPL 13210 was not significantly different than that produced by 18 microM disopyramide while the preparations were paced constantly at 2 Hz. At these concentrations, recovery of Vmax was slowed by both FPL 13210 and disopyramide. The slow time constant estimated for this relation after exposure to FPL 13210 was approximately 6.5 times longer than that estimated following administration of disopyramide. In addition, APD90s evoked by early premature stimuli in the presence of 5 microM FPL 13210 were longer than those produced in the absence of drug when the diastolic intervals longer than 100 ms produced shorter APD90s after FPL 13210 administration. Therefore, when FPL 13210 is compared to disopyramide using concentrations selected to produce equivalent degrees of Vmax depression, FPL 13210 produced effects on APD90 that were opposite to those produced by disopyramide when the diastolic interval was longer than normal. These effects of FPL 13210 would suggest that this compound should be classified as a class Ic antiarrhythmic agent, unlike disopyramide, a class Ia antiarrhythmic agent.

Action Potentials↗

PubMed1991

Effect of sotalol on transmembrane ionic currents responsible for repolarization in cardiac ventricular myocytes from rabbit and guinea pig.

The effects of sotalol, a beta-adrenoceptor blocker and class III antiarrhythmic agent, on transmembrane ionic currents were examined in single rabbit and guinea pig ventricular myocytes using whole-cell voltage-clamp techniques. In neither of these species did 60 microM sotalol appreciably effect the inward rectifier, the transient outward or the inward calcium currents. In addition, sotalol did not elicit a slowly inactivating component of the sodium current as did 1 microgram/ml veratrine. In guinea pig ventricular myocytes, sotalol also significantly depressed the outward delayed rectifier current. An outward delayed rectifier current was not observed in rabbit ventricular myocytes examined at room temperature; and, under these conditions sotalol did not lengthen action potential duration. Sotalol induced lengthening of cardiac action potential duration can, therefore, be explained by depression the outward delayed rectifier current.

Action Potentials↗