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Fluoxetine is a widely used antidepressant compound having selective serotonin reuptake inhibitor properties. In this study, the actions of fluoxetine were analyzed in guinea pig, rat, rabbit and canine ventricular myocardiac preparations using conventional microelectrode and whole cell voltage clamp techniques. Low concentrations of fluoxetine (1-10 micromol/l) caused significant shortening of action potential duration (APD) and depression of the plateau potential in guinea pig and rabbit papillary muscles and single canine ventricular myocytes. In rat papillary muscle, APD was not affected by fluoxetine (up to 100 micromol/l), however, the drug decreased the force of contraction with EC50 of 10 micromol/l. Fluoxetine (10 micromol/l) also decreased the maximum velocity of depolarization and action potential overshoot in each species studied. At this concentration no effect was observed on the resting membrane potential; high concentration (100 micromol/l), however, caused depolarization. In voltage clamped canine ventricular myocytes, fluoxetine caused concentration-dependent block of the peak Ca2+ current at 0 mV with EC50 of 5.4+/-0.94 micromol/l and Hill coefficient of 1.1+/-0.14 (n=6). In addition, 10 micromol/l fluoxetine shifted the midpoint of the steady-state inactivation curve of the Ca2+ current from -20.7+/-0.65 to -26.7+/-1 mV (P<0.001, n=8) without changing its slope factor. These effects of fluoxetine developed rapidly and were fully reversible. Fluoxetine did not alter voltage-dependence of activation or time constant for inactivation of I(Ca). Fluoxetine had no effect on the amplitude of K+ currents (I(K1) and I(to)). The inhibition of cardiac Ca2+ and Na+ channels by fluoxetine may explain most cardiac side effects observed occasionally with the drug. Our results suggest that fluoxetine may have antiarrhythmic (class I + IV type), as well as proarrhythmic properties (due to impairment of atrioventricular or intraventricular conduction and shortening of repolarization). Therefore, in depressed patients with cardiac disorders, ECG control may be suggested during fluoxetine therapy.

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In spite of the accelerated evolution in antiarrhythmic drug research and design, the ideal antiarrhythmic compound has not yet emerged. Pure class III agents have not been clinically successful, mainly due to their torsadogenic side-effects. Combination of class III effect with class I, II or IV effects has given better therapeutic results, whilst combination of the various antiarrhythmic mechanisms within one molecule, rather than combination of drugs, seems to be an even more promising strategy. In this study, we briefly review the most frequently applied antiarrhythmic combinations, focusing primarily to those novel antiarrhythmics where class III effects are combined with class IV or class I actions within the same single molecule.

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1. The cellular electrphysiological effects of EGIS-7229, a novel antiarrhythmic agent, were studied in guinea pig papillary muscles with the use of conventional microelectrode techniques. 2. The drug had a concentration-dependent biphasic effect on action potential duration (APD). APD was significantly lengthened at low concentration (3 mumol/1), whereas it was shortened at concentrations higher than 10 mumol/l. 3. At concentrations higher than 10 mumol/l, the drug decreased the maximum velocity of action potential upstroke (Vmax), the force contraction, and altered the restitution kinetics of APD. 4. The effect of EGIS-7229 on Vmax was frequently dependent; it was most prominent at short pacing cycle lengths (use-dependent block). 5. On the basis of present results, EGIS-7229 appears to carry mixed class I and class III characteristics. Class III properties are present at low concentrations, whereas, at higher concentrations, class I actions may be predominant.

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The cellular electrophysiological effects of EGIS-7229 (5-chlor-4-[N-(3,4-dimethoxy-phenyl-ethyl)-amino-propylamino]-3 (2H)-pyridazinone fumarate), a novel antiarrhythmic agent, was studied using conventional microelectrode techniques in canine cardiac Purkinje fibers and papillary muscle preparations obtained from man, rabbits and guinea pigs. Low concentration of EGIS-7229 (3 mumol/l) selectively lengthened action potential duration (both APD50 and APD90) in all preparations. The effect of higher concentrations (30-100 mumol/l) of EGIS-7229 on action potential duration was variable depending on the preparation studied: in rabbit and human papillary muscles both APD50 and APD90 were lengthened, in canine Purkinje fibers APD90 was lengthened but APD50 was shortened, while in guinea pig papillary muscles both APD50 and APD90 were shortened by high concentrations of the drug. At these higher concentrations EGIS-7229 also decreased the maximum velocity of action potential upstroke (Vmax) and depressed the plateau of action potentials without affecting the resting membrane potential or action potential amplitude. Both reduction of Vmax and lengthening of APD were frequency dependent. The former effect was more prominent at higher pacing frequencies, while the latter was more pronounced at lower driving rates. In guinea pig papillary muscle, the time constant of recovery from Vmax-block was 719 +/- 33 ms (n = 18) and the rate of onset of the block was 1.81 +/- 0.06 AP-1 (n = 16) in the presence of 100 mumol/l EGIS-7229. EGIS-7229 had a complex action on refractoriness in guinea pig papillary muscles: ERP was lengthened at low concentrations (3 to 10 mumol/l), unchanged at 30 mumol/l and shortened at 100 mumol/l. The ratio of ERP/APD90, however, was significantly increased at concentrations higher than 3 mumol/l. In canine Purkinje fiber, when the delayed rectifier K current (IK) was blocked by d-sotalol (60 mumol/l) and APD was shortened back to its control value by additional application of nicorandil (15 mumol/l), APD was not affected by 3 mumol/l but was shortened by 30 mumol/l of EGIS-7229. 100 mumol/l EGIS-7229 shortened APD in guinea pig papillary muscle. This effect of EGIS-7229 was effectively prevented by nifedipine pretreatment (10 mumol/ l). In this preparation, EGIS-7229 also decreased the Vmax of the slow action potential, evoked in the presence of 20 mmol/l external K+ plus 0.5 mmol/l Ba2+. It is likely that EGIS-7229 at low concentrations blocks IK in human, canine, rabbit and guinea pig cardiac preparations, but at higher concentrations also inhibits Ca and Na currents. Therefore, EGIS-7229 appears to carry mixed class III, IV and IB antiarrhythmic properties.

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The mechanism of electrical restitution was studied in isolated rat ventricular muscle using drugs that inhibit specific ion currents. The effect of transient changes in cytosolic Ca concentration and Na/Ca exchange in relation to the restitution process was also studied in single ventricular cardiomyocytes. Conventional microelectrode techniques were applied to record action potentials having gradually increasing coupling intervals, each evoked following a train of stimuli with a frequency of 1 Hz. Ion currents were recorded from enzymatically isolated cells using the whole cell patch clamp technique. Ca transients were monitored in myocytes loaded with the fluorescent dye, indo-1. The electrical restitution process in multicellular rat ventricular preparations at 37 degrees C was described as a sum of three exponential components: an early positive component, a subsequent fast negative component and a late negative component, having time constants of 21.9 +/- 1.9, 73.1 +/- 6.0 and 1053 +/- 61 ms, respectively (n = 9). Inhibition of the transient outward K current, the delayed rectifier K current, or the chloride current did not substantially alter these time constants. The early positive and fast negative components were fully abolished by nifedipine or MnCl2. In the presence of caffeine, the fast negative component was absent, while the time constant of the early positive component increased to 39.5 +/- 5.8 ms (n = 5). In single myocytes loaded with indo-1, the Ca transients decayed with a time constant of 151 +/- 12 ms at room temperature (n = 5). These Ca transients were accompanied by inward current tails, identified as a Na/Ca exchange current, having a decay time constant of 140 +/- 4.5 ms. It is concluded that electrical restitution in rat ventricular muscle is relatively little affected by recovery from voltage-dependent inactivation of ion channels, it is rather governed by transient changes in cytosolic Ca concentration possible via Ca-dependent inactivation of the L-type Ca current and activation of the Na/Ca exchange current.

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Action potential configuration and electrical restitution were studied in diseased human ventricular muscle by comparing the characteristics of hypertrophic (HYP) and dilated (DIL) human ventricular preparations. Conventional microelectrode techniques were used to evaluate action potentials evoked at increasingly longer diastolic intervals. The steady-state action potential duration (APD90) was significantly longer in DIL than in HYP preparations (393 +/- 5 ms, n = 4 and 296 +/- 11 ms, n = 4, respectively; P < 0.001, mean +/- SEM). In the dilated preparations studied at long diastolic intervals, the initial period of rapid repolarization (phase 1) was absent, and the rate of final repolarization (phase 3) was reduced. Electrical restitution relations in these preparations were fitted as the sum of two exponentials. The time constant of the fast component was significantly longer in DIL than in HYP preparations (242 +/- 9 ms and 121 +/- 4 ms, respectively; P < 0.001). No difference was observed in the time constants for the slow component of restitution in the two groups. Electrical restitution was also studied in single human ventricular myocytes by using patch clamp techniques. The initial 600 ms period of restitution was fitted in these cells to a monoexponential function. The time constant for this period of the restitution relation was significantly longer, while the estimated amplitude of this early rising phase was significantly lower in human cells obtained from DIL hearts than the respective parameters obtained in the healthy canine and guinea pig cells also examined. The observed changes in the restitution kinetics of the dilated human heart are, likely, the consequence of alterations in the ionic currents that underlie the cardiac action potential.

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The effects of atrial natriuretic peptide (ANP) on action potential characteristics were studied in various (human, rabbit, guinea-pig) atrial and guinea-pig right ventricular papillary muscles. ANP (1-100 nM) did not modify the resting membrane potential nor the maximum rate of depolarization phase (Vmax). Up to 10 nM, ANP dose-dependently decreased the action potential amplitude both in guinea-pig atrial and ventricular muscles, but it did not affect this parameter in the other atrial preparations. ANP caused a dose-dependent, marked decrease of action potential duration (APD) in practically every cardiac preparation studied (exception of guinea-pig left atrium). The strongest effect on APD can be observed in human atrial and guinea-pig ventricular fibers. The K+ channel blocker 4-aminopyridine (1 mM) and the ATP-dependent K+ channel inhibitor glibenclamide (10 microM) prevented the effect of ANP on APD in both ventricular atrial preparations. ANP prevented the appearance of isoprenaline (0.5 microM) induced slow AP in K+ depolarized myocardium. The present data suggest that ANP may inhibit the slow inward Ca2+ channel activity and facilitate the K+ channel activity.

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Oxygen free radical-induced oxidative damage is involved in both aging and ischemia-reperfusion. The purpose of this study was to determine the aging-induced oxidative alterations in rat heart as well as the age-dependence of heart injury following ischemia-reperfusion. A comparative study was performed on young and old ischemic-reperfused rat hearts. Protein oxidation and the ascorbyl radical level in heart tissue were determined in order to characterize the oxidative stress. Comparing the control conditions, old hearts have 31% more oxidized proteins as measured by protein carbonyl content, and 18% lower ascorbyl radical level as determined by ESR, than young ones. The extent of increase of protein oxidation and ascorbyl free radical depletion induced by ischemia-reperfusion is less pronounced in the old hearts (7 and 8% respectively), as compared to the young ones (55 and 21% respectively). Pre-treatment with a free radical scavenger, such as centrophenoxine, diminished the ischemia-reperfusion injury in both young and old rat hearts.

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1. The negative inotropic action of 10 microM lidocaine and 100 microM nicorandil was compared as a function of the pacing cycle length, ranging from 300-3000 ms, in isolated canine Purkinje fiber preparations. 2. The applied concentrations of lidocaine and nicorandil produced similar shortening of action potential duration; however, lidocaine compromised contractility stronger than nicorandil at each cycle length. 3. Normalizing the inotropic action of the drugs to their shortening effect on action potential duration, the negative inotropic action of lidocaine can be regarded as a sum of three distinct components: negative inotropy associated to the shortening of action potential duration per se, reduction of contractility likely due to direct inhibition of the fast sodium current and of the "window" sodium current by lidocaine.

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BACKGROUND: The racemate of sotalol (dl-sotalol) and its dextrorotatory isomer (d-sotalol) are equally effective in increasing isolated cardiac action potential durations. dl-Sotalol, however, is reported to be more effective than d-sotalol in increasing ventricular effective refractoriness following coronary artery occlusion. These differences are attributed to the beta-adrenergic blocking properties of dl-sotalol. We wished to determine if in isolated human ventricular muscle preparations the effects of 30 µM d0 and dl-sotalol could be modified by preexposure to 1 µM isoproterenol. METHODS AND RESULTS: Microelectrodes were used to record action potential duration (APD) in the presence and absence of isoproterenol during continuous pacing. Preparations were obtained from explanted hears of transplant recipients suffering idiopathic cardiomyopathies. Without isoproterenol, APD measured at 90% of repolarization (APD(90)) was significantly increased by both d- and dl-sotalol (352.0 +/- 17.7 to 418.0 +/- 23.8 ms, P <.05; and 339.2 +/- 17.0 to 405.0 +/- 25.3 ms, P <.05; respectively). Isoproterenol alone, prior to sotalol exposure, tended to shorten APD(90) in the two groups first exposed to this beta-adenoceptor agonist and subsequently exposed to either d-sotalol or dl-sotalol (317.5 +/- 16.5 to 286.3 +/- 28.8 ms and 288.0 +/- 16.2 to 254.0 +/- 15.0 ms, respectively). dl-Sotalol significantly increased APD(90) from its baseline value after isoproterenol (288.0 +/- 16.2 to 359.0 +/- 25.1 ms, P <.005) while d-sotalol did not (317.5 +/- 16.5 to 316.2 +/- 28.5 ms, NS). CONCLUSIONS: The beta-adrenergic blocking properties of dl-sotalol may be important in determining antiarrhythmic efficacy when tonic sympathetic nervous activity is high.

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The effect of action potential duration and elevated cytosolic sodium concentration on the force-frequency relationship in isolated rabbit, guinea pig and rat papillary muscle preparations was studied. Shortening of action potential duration in guinea pig and rabbit from 150-200 ms to values characteristic of rat (20-40 ms), using the K(ATP) channel activator levkromakalim (15 mumol.l-1), markedly reduced the force of contraction and converted the positive force-frequency relationship into negative one at longer pacing cycle lengths. This conversion was greatly enhanced in the presence of acetylstrophanthidin (0.2-1 mumol.l-1), an inhibitor of the Na-K pump. Acetylstrophanthidin (1 mumol.l-1) alone, however, had no effect on the force-frequency relationship. Prolongation of action potential duration in rat with inhibitors of cardiac K channels (4-aminopyridine [10 mmol.l-1] plus tetraethylammonium [2 mmol.l-1) increased the force of contraction and abolished the negative force-frequency relationship observed in rat at longer pacing-cycle lengths. It is concluded that both action potential duration and cytosolic sodium concentration are major determinants of the force-frequency relationship in mammalian myocardium.

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The cellular electrophysiological effects of dridocainide (EGIS-3966), a novel class I antiarrhythmic agent, was studied using conventional microelectrode techniques in canine cardiac Purkinje fibres and papillary muscle preparations obtained from humans and guinea-pigs. In each preparation, dridocainide (0.6-2 mumol/l) decreased the maximum velocity of action potential upstroke (Vmax) in a frequency-dependent manner, although marked differences were observed in its effects in Purkinje fibre and ventricular muscle preparations. In canine Purkinje fibres, action potential duration measured at 50% and 90% of repolarization was decreased, while action potential duration measured at 10% of repolarization was increased by dridocainide. In addition, the plateau of the action potential was depressed by the drug. These changes in action potential configuration were not observed in guinea pig or human papillary muscles. The offset kinetics of the dridocainide-induced Vmax block were different in Purkinje fibres and in ventricular muscle: the slow time constant of recovery of Vmax was estimated to be 2.5 s in dog Purkinje fibre and 5-6 s in human and guinea-pig papillary muscle. In guinea-pig papillary muscle, the rate of onset of the Vmax block was 0.15 and 0.2 per action potential in the presence of 0.6 and 2 mumol/l dridocainide, respectively. Dridocainide also decreased the force of contraction in this preparation. On the basis of the present results, dridocainide appears to possess mixed class I.C and I.A properties, with I.C predominance in human and guinea-pig ventricular muscle. Present results also indicate that results of conventional classification of class I drugs may depend on the parameters chosen, as well as on the preparation selected.

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