PubMed Health⌕ Search

Biomedical subjects

D Escande

Publications and source records attributed to D Escande.

At least 73 records · Page 4Linked to original sources
PubMed1993

Potassium channels as pharmacological targets in cardiovascular medicine.

Potassium channels are membrane receptor sites for various drugs in the field of cardiovascular diseases. These channel proteins are extremely diverse, not only as regards their molecular structure but also as regards their function. Heterogeneous expression of various K+ channel subtypes is an integral part of cell specialization in different tissues. K+ channels interfere with most of the physiological processes of the cardiac muscle, of the vascular smooth muscle and of the endothelial cells. K+ channel blockers are antidiabetic agents but also antiarrhythmic drugs. K+ channel openers are used in the treatment of hypertension and most recently in the treatment of coronary heart disease. In the experimental setting, K+ channel openers afford cytoprotection during ischaemia. This exciting property opens a new field in clinical research.

Adenosine Triphosphate↗
PubMed1992

A hyperpolarization-activated inward current in human myocardial cells.

Normally-polarized tissue from the human atrial myocardium usually exhibits a diastolic depolarization phase which can be suppressed reversibly by Cs+ or enhanced by inhibiting the inward rectifier K+ current, iK1, with Ba2+. (Escande et al., 1986). Because the suppression of the diastolic slope by Cs+ leads to a hyperpolarization of the cell membrane at the end of the diastolic phase, it was suggested that Cs+ might inhibit an inward current responsible for diastolic depolarization. Among the ionic mechanisms underlying the diastolic depolarization phase of cardiac tissues, the hyperpolarization-activated inward current, if, fits well to explain the small diastolic slope of human atrial fibres. In other preparations, this inward current carried both by Na+ and K+ ions is rapidly deactivated during the action potential and entirely blocked by millimolar concentrations of Cs+ (DiFrancesco 1981; DiFrancesco, et al., 1986; Kokubun et al., 1982; Callewaert et al., 1984; Denyer and Brown, 1990). Such a current in human myocardial cells has not been characterized so far although its existence in human atrial trabeculae was previously reported in an abstract (Carmeliet, 1984). In the present study, we describe an inward current which activates upon hyperpolarization in patch-clamped single human atrial cells and shares similar characteristics with the if pacemaker current described in unicellular and intact preparations of mammalian cardiac tissues.

Barium↗
PubMed1992

RP 58866 and its active enantiomer RP 62719 (terikalant): blockers of the inward rectifier K+ current acting as pure class III antiarrhythmic agents.

The present article presents an overview of the pharmacologic profile of the benzopyran derivative RP 58866, a racemic mixture, and of RP 62719 (terikalant), its active enantiomer. In normal cardiac tissues studied in vitro, both drugs dose-dependently prolonged the atrial and ventricular action potential but affected neither the upstroke of the action potential nor the diastolic potential. Patch-clamp experiments demonstrated that the prolongation of the action potential induced by the drugs is due to a specific blockade of the inward rectifier K+ current. In vivo, intravenous administration to anesthetized dogs of low doses of RP 62719 consistently induced bradycardia and prolonged the atrial, nodal, and ventricular refractory periods, but did not affect the conduction velocity. Because of these properties, RP 58866 and RP 62719 exert potent antiarrhythmic and antifibrillatory actions both at the atrial and ventricular levels in various experimental models of arrhythmia. Our results demonstrate that RP 58866 and RP 62719 are K(+)-channel blockers acting as pure class III antiarrhythmic drugs.

Action Potentials↗
PubMed1992

Positive inotropic effects of RP 62719, a new pure class III antiarrhythmic agent, on guinea pig myocardium.

The mechanical effects of RP 62719 [(-)1-[-2-(3,4-dihydro-2H-1- benzopyran-4-yl)ethyl]-4-(3,4-dimethoxyphenyl)-piperidine] were tested in vitro on guinea pig left ventricular papillary muscle. RP 62719 is a novel pure class III antiarrhythmic agent known to prolong the cardiac action potential duration by selectively blocking the inward rectifying K+ current. Mechanical parameters were determined from contraction and relaxation phases under isotonic and isometric conditions. At a concentration of 0.02 microM, RP 62719 did not produce significant effects on inotropy or lusitropy. At 0.2 and 2 microM, the drug improved contraction under both heavy and low loading conditions, as evidenced by a 30% increase in maximum unloaded shortening velocity (Vmax, P < .001), peak amplitude of shortening (delta L, P < .001), peak isometric active force normalized per cross-sectional area (AF/s, P < .001) and positive peak of the force derivative per mm2 (+dF/s, P < .001). At the same concentrations, positive lusitropic effects were evidenced by an increase in maximum lengthening velocity (maxVr) and negative peak of force derivative per mm2 (-dF/s, P < .001). At a higher concentration (20 microM), effects of RP 62719 on inotropy and lusitropy were less marked, thus accounting for the bell-shaped form of the dose-response curve. An increase in the extracellular Ca++ concentration from 2.5 to 3.75 mM improved inotropy to a similar extent (+30-50%) as did 2 microM RP 62719. However, lusitropy and mechanical coupling between contraction and relaxation were not modified in the same proportion under RP 62719 and under 3.75 mM Ca++.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Riluzole specifically blocks inactivated Na channels in myelinated nerve fibre.

The effects of 0.15-250 microM riluzole, a novel psychotropic agent with anticonvulsant properties, were studied on voltage-clamped nodes of Ranvier of isolated nerve fibres of the frog. When added to the external solution, the drug rapidly and reversibly inhibited both K and Na currents with an apparent dissociation constant of 0.09 mM. The riluzole-induced decrease of these currents was not "use-dependent". At concentrations up to 100 microM, the drug had no noticeable effect on the time course of Na current inactivation nor on the shape and the position along voltage axis of the Na conductance/voltage relationship. On the other hand, it induced substantial shifts towards negative voltages of the steady-state Na inactivation/voltage curve. From these results, according to the modulated-receptor model, an apparent dissociation constant of 0.29 microM could be calculated for riluzole-induced blockage of inactivated Na channels. The recovery from Na current inactivation was also affected by the drug. It is concluded that riluzole is a highly specific blocker of inactivated Na channels, which is more than 300 times more effective on these channels than on K or resting Na channels.

Animals↗
PubMed1990

Potassium accumulation in the globally ischemic mammalian heart. A role for the ATP-sensitive potassium channel.

We investigated the contribution of opening of the ATP-sensitive K+ channel to extracellular accumulation of K+ during ischemia with the use of glibenclamide, a specific blocker of this K+ channel. To characterize the electrophysiological effects of glibenclamide during metabolic inhibition (by either application of dinitrophenol or hypoxia) we performed patch-clamp studies in isolated membrane patches of guinea pig myocytes and in intact guinea pig myocytes and studied action potential parameters in isolated superfused guinea pig papillary muscle. We studied the effect of glibenclamide on extracellular accumulation of K+ and H+ in isolated retrogradely perfused globally ischemic hearts of rat, guinea pig, and rabbit. Experimental evidence is presented that supports the conclusions that glibenclamide 1) effectively blocks open K+ATP channels, 2) reverses the dinitrophenol-induced increase of the outward current and prevents the hypoxia-induced shortening of the action potential, 3) decreases the rate of K+ accumulation during the first minutes of ischemia in stimulated hearts, an effect which was entirely absent in quiescent hearts, and 4) does not influence the rate and extent of ischemia-induced extracellular acidification.

Action Potentials↗
PubMed1989

A long lasting Ca2+-activated outward current in guinea-pig atrial myocytes.

Among other characteristics, the steady-state current-voltage relationship of patch-clamped single atrial myocytes from guinea-pig hearts is defined by an outward current hump in the potential region -15 to +40 mV. This hump was reversibly suppressed by Co2+ (3 mM) or nitrendipine (5 microM) and enhanced by Bay K 8644 (5 microM). The maintained outward current component suppressed by Co2+ extended between -15.2 +/- 1.9 mV and +39.5 +/- 1.7 mV (mean +/- SEM of 14 cells) and has an amplitude of 95.7 +/- 9.4 pA at +10 mV. In isochronal I-V curves, the hump was already visible at 400 ms with essentially the same amplitude as at 1500 ms. The Co2+-sensitive outward current underlying the hump was poorly time-dependent during 1.5 s voltage pulses but slowly relaxed upon repolarization. Tail currents reversed near the K+ equilibrium potential under our experimental conditions. The current hump of the steady-state I-V curve was also abolished by caffeine (10 mM) or ryanodine (3 microM), both drugs that interfere with sarcoplasmic reticulum function. Apamin (1 microM) or quinine (100 microM) but not TEA (5-50 mM) markedly reduced its amplitude. However, at similar concentrations as required to inhibit the hump, both apamin and quinine appeared to be poorly specific for Ca2+-activated K+ currents in heart cells since they also inhibited the L-Type Ca2+ current. It is concluded that a long lasting Ca2+-activated outward current, probably mainly carried by K+ ions but not sensitive to TEA, exists in atrial myocytes which is responsible for the current hump of the background I-V curve.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1989

Potassium channel openers act through an activation of ATP-sensitive K+ channels in guinea-pig cardiac myocytes.

In a previous article (Escande et al. 1988a), we have shown that cromakalim (BRL 34915), a potassium channel opener (PCO), is a potent activator of ATP-sensitive K+ channels in cardiac cells. In the present article, the influence on K+ channels of two other potassium channel openers chemically unrelated to cromakalim, RP 49356 and pinacidil, has been investigated in patch-clamped isolated cardiac myocytes. In the whole-cell configuration, K+ currents were recorded in the presence of 50 microM TTX and 3 microM nitrendipine or 3 mM cobalt. Like cromakalim, RP 49356 or pinacidil activated a time-independent outward current at 33-35 degrees C but not at 19-21 degrees C, which showed little voltage-dependency in the potential range -60 to +60 mV. Its amplitude was a function of the agonist concentration, e.g. it was 2.1 +/- 0.4 nA at +60 mV with 30 microM RP 49356 and 4.3 +/- 0.8 nA with 300 microM. In control conditions, glibenclamide, a blocker of K+-ATP channels in pancreatic and heart cells, affected neither the inward rectifier, iK1, nor the delayed K+ current, iK. At 3 microM, glibenclamide fully prevented the effects of 300 microM RP 49356 or pinacidil. At lower concentrations, glibenclamide partially counteracted the activation by PCOs of a K+ current. In the cell-attached configuration, externally applied RP 49356 or pinacidil caused opening of large channels which reversed around O mV in a high K+ external medium. In inside-out patches, both RP 49356 or pinacidil activated K+-ATP channels by increasing the time period for which the channels remained in the open state. It is concluded that, like cromakalim, RP 49356 and pinacidil are potent activators of K+-ATP channels in cardiac myocytes.

Adenosine Triphosphate↗
PubMed1989

Electrical activity of human atrial fibres at frequencies corresponding to atrial flutter.

Little information is available about rate dependent changes in electrical activity of human myocardial cells. We therefore studied, in vitro, the electrical activity of adult human atrial fibres driven at frequencies near that of atrial flutter by means of the standard microelectrode technique. Thirty two atrial samples exhibiting "normal" responses with fast upstroke were selected. At very high frequencies, the action potential (AP) upstroke arose from the repolarisation phase of the preceding AP in spite of marked frequency induced shortening of the plateau. As the stimulation rate was progressively increased, the take off potential (TOP) was less and less negative and the maximal rate of depolarisation (Vmax) decreased. Moreover, in most preparations, a clear alternation between two types of action potentials occurred. Calcium channel inhibitors cobalt (5 mM) or diltiazem (5 x 10(-6) M) shortened AP duration, increased Vmax and markedly reduced alternation. Sodium channel inhibitors, tetrodotoxin (7.5 10(-6) M) or lignocaine (10(-5) M) shortened AP duration and induced a transient increase in Vmax. Ouabain (10(-6) M) prolonged AP duration, decreased Vmax, enhanced alternation and finally suppressed the 1:1 capture of the atrial tissue. Our results show that, at high driving rates corresponding to the frequencies of atrial flutter, slight variations in action potential duration induced by drugs are associated with marked concomitant variations in Vmax and probably with consequent modifications of the conduction velocity.

Action Potentials↗
PubMed1989

Electrophysiological effects of penticainide (CM 7857) in isolated human atrial and ventricular fibers.

The intracellular electrophysiological properties of a new antiarrhythmic agent, penticainide (5 x 10(-6) to 5 x 10(-5) M) were studied in isolated driven human right atrial appendage and papillary muscle superfused with oxygenated Tyrode's solution. In atrial fibers, penticainide decreased the amplitude, maximum rate of rise (dV/dtmax), plateau amplitude, and duration (APD) of action potentials (AP). In ventricular fibers, the main AP modification induced by penticainide was a dV/dtmax diminution. All those effects were frequency and concentration dependent. Penticainide decreased resting potential at 5 x 10(-5) M only. Ventricular APD variations were relatively weak: in most of the cases, 5 x 10(-6) M decreased APD and 5 x 10(-5) M shortened long APD (greater than 300 ms) and lengthened short APD (less than 300 ms). The class I antiarrhythmic property (dV/dtmax decrease) of penticainide was rate dependent in both human fibers and was obtained at lower drug concentrations than those used in other species. The relatively rapid rate of onset and the rather slow recovery kinetics of dV/dtmax block suggest a common mechanism of action of penticainide on sodium channels in human heart and others mammals.

Action Potentials↗
PubMed1989

Apparent competition between ATP and the potassium channel opener RP 49356 on ATP-sensitive K+ channels of cardiac myocytes.

The mechanism whereby RP 49356, a novel potassium channel opener, activates ATP-sensitive K+ channels (K+-ATP channels) in isolated cardiac cells was investigated with the patch-clamp technique. When directly applied onto the inner face of an inside-out membrane patch, RP 49356 (300 microM) had no effect on K+ channels opened in an ATP-free solution. In contrast, the same concentration of the drug reactivated K+-ATP channels that had experienced spontaneous "run-down" of their activity following long recording periods. In cell-attached experiments, externally applied RP 49356 (300 microM) opened K+-ATP channels at 35 degrees in spite of the high intracellular ATP concentration, which was sufficient to prevent channel openings in the absence of the drug. In control conditions, the dose-response relation for ATP closing the channels had a Hill coefficient of 2.37 and a half-inhibition concentration of 56 microM. With 30 microM RP 49356 present in the intracellular medium, the slope factor of this relation was unchanged but the curve was shifted to the right, with a half-inhibition concentration of 515 microM. Conversely, the dose-response relation of RP 49356 activating K+-ATP channels was shifted to the right in a parallel manner under the influence of increasing concentrations of ATP. It is concluded that RP 49356 acts on cardiac K+-ATP channels by decreasing their sensitivity to ATP. Our results are consistent with an apparent competition between ATP and RP 49356.

Adenosine Triphosphate↗
PubMed1988

The potassium channel opener cromakalim (BRL 34915) activates ATP-dependent K+ channels in isolated cardiac myocytes.

In cardiac myocytes, cromakalim (BRL 34915), a potassium channel opener, activates a time-independent K+ current exhibiting poor voltage-sensitivity. This effect of cromakalim is antagonized by low concentrations of glibenclamide, a specific blocker of ATP-dependent K+ channels in cardiac cells. Direct recording of the activity of K+ channels in inside-out membrane patches, confirmed that cromakalim is a potent activator of ATP-dependent K+ channels in cardiac myocytes.

Adenosine Triphosphate↗
PubMed1988

Comparative effects of three class I antiarrhythmic drugs on plateau and pacemaker currents of sheep cardiac Purkinje fibres.

The electrophysiological effects of three class I antiarrhythmic drugs, lignocaine, disopyramide, and penticainide, were compared in sheep cardiac Purkinje fibres. Action potential duration was shortened with all three drugs, the effect being small with disopyramide, moderate with penticainide, and greatest with lignocaine. Slowing down of the early phase of repolarisation was greatest with disopyramide, smaller with penticainide, and did not occur with lignocaine. Automaticity recorded in low potassium media was unaltered (disopyramide), depressed (penticainide), or stopped (lignocaine). Ionic currents were recorded in short fibres using the two microelectrode voltage clamp technique. The tetrodotoxin sensitive slow component of the sodium current was suppressed (lignocaine) or reduced (penticainide and disopyramide) and the instantaneous background potassium current slightly reduced (disopyramide more than penticainide), unaffected, or slightly increased (lignocaine). The three drugs depressed moderately and similarly the slow inward calcium current. The amplitude of the 4-aminopyridine sensitive transient outward potassium current was almost unaffected (lignocaine) or appreciably depressed (disopyramide more than penticainide). The pacemaker current was reduced greatly by lignocaine, moderately by penticainide, and slightly by disopyramide. Changes in ionic currents may explain the effects of the three drugs on action potential plateau and automaticity of sheep Purkinje fibres. It is concluded that the pronounced differences observed in the effects of these three class I antiarrhythmic drugs on pacemaker depolarisation and on initial repolarisation may justify a more discriminative subdivision of class I antiarrhythmic drugs.

Action Potentials↗