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A Varró

Publications and source records attributed to A Varró.

At least 37 records · Page 2Linked to original sources
PubMed1998

Effect of disopyramide on potassium currents in rabbit ventricular myocytes.

The effects of disopyramide (1-30 microM) on the 4-aminopyridine sensitive transient outward current (I(to)), on the rapid component of the delayed rectifier potassium current (I(Kr)) and on the inward rectifier potassium current (I(kl)) were studied in single rabbit ventricular myocytes at 35 degrees C by applying the whole-cell configuration of the patch clamp technique. Disopyramide significantly decreased the amplitude of I(to) (from 1510 +/- 122 pA at control to 1015 +/- 21 pA after 30 microM disopyramide at +50 mV; n = 5). This effect was not voltage- or use-dependent. Disopyramide (10 microM) influenced neither the recovery from inactivation of I(to) nor the steady-state inactivation curve. The drug dose dependently decreased the time constant of the fast component of the decay of I(to) (tau(f) = 6.41 +/- 0.25 ms, n = 24 for control; and 2.20 +/- 0.38 ms, n = 5 after 30 microM disopyramide at +50 mV). The fractional block caused by 30 microM disopyramide as a function of time was well fitted by a single exponential function with time constant of 1.48 +/- 0.18 ms (n = 5), most likely reflecting the binding kinetics of the drug to the open channel. The offset kinetics of the drug was estimated by using a double-pulse protocol and its time constant was 3.9 +/- 0.5 ms. Disopyramide (30 microM) did not influence significantly the onset of inactivation measured at -20 mV. The estimated EC50 value for the I(to) block by disopyramide was 14.1 microM. Our results are consistent with an open-channel block of I(to) by disopyramide, however, a weak, drug-induced increase of the rate of inactivation and a moderate tonic block cannot be excluded. The amplitude of the outward tail current attributed to I(Kr) was depressed dose dependently by disopyramide (after clamping the cells back to the holding potential from +30 mV, 139.5 +/- 10.9 pA for control, and 30.7 +/- 3.2 pA in the presence of 10 microM disopyramide; n = 11). The estimated EC50 was 1.8 microM. I(to) is thus less sensitive to disopyramide than I(Kr). I(kl) was not influenced significantly by disopyramide, even when applied in the highest tested concentration (30 microM). It is concluded that in rabbit ventricular myocytes disopyramide blocks not only I(Kr), but also I(to), both of which may play an important role in the well established repolarization lengthening and antiarrhythmic effects of the drug.

Animals↗
PubMed1998

Delayed rectifier potassium current in undiseased human ventricular myocytes.

OBJECTIVE: The purpose of the study was to investigate the properties of the delayed rectifier potassium current (IK) in myocytes isolated from undiseased human left ventricles. METHODS: The whole-cell configuration of the patch-clamp technique was applied in 28 left ventricular myocytes from 13 hearts at 35 degrees C. RESULTS: An E-4031 sensitive tail current identified the rapid component of IK (IKr) in the myocytes, but there was no evidence for an E-4031 insensitive slow component of IK (IKs). When nifedipine (5 microM) was used to block the inward calcium current (ICa), IKr activation was fast (tau = 31.0 +/- 7.4 ms, at +30 mV, n = 5) and deactivation kinetics were biexponential and relatively slow (tau 1 = 600.0 +/- 53.9 ms and tau 2 = 6792.2 +/- 875.7 ms, at -40 mV, n = 7). Application of CdCl2 (250 microM) to block ICa altered the voltage dependence of the IKr considerably, slowing its activation (tau = 657.1 +/- 109.1 ms, at +30 mV, n = 5) and accelerating its deactivation (tau = 104.0 +/- 18.5 ms, at -40 mV, n = 8). CONCLUSIONS: In undiseased human ventricle at 35 degrees C IKr exists having fast activation and slow deactivation kinetics; however, there was no evidence found for an expressed IKs. IKr probably plays an important role in the frequency dependent modulation of repolarization in undiseased human ventricle, and is a target for many Class III antiarrhythmic drugs.

Action Potentials↗
PubMed1998

Action-potential duration and contractility in canine cardiac tissues: action of inotropic drugs.

1. Inotropic and electrophysiologic effects of veratrine, vesnarinone, d-sotalol and tetraethylammonium (TEA) were compared. Action-potential duration (APD) and contractility were measured in isolated canine Purkinje fiber and ventricular trabecular muscle preparations by using standard microelectrode techniques. Each drug significantly increased APD and force development in either tissue. 2. Drug-induced increases in force development were normalized to increases in APD. The order of efficacy was found to be vesnarinone>veratrine>TEA in ventricular myocardium, whereas it was veratrine>>vesnarinone=d-sotalol=TEA in Purkinje fibers. 3. The force-APD relation was linear for all drugs in the concentrations used. 4. Simultaneous measurements of APD, force development and intracellular sodium ion activity (a(i)Na) in the presence of either veratrine or lidocaine indicated a linear relation between force development and changes in a(i)Na. 5. The relation between APD and force development was different in ventricular and Purkinje fiber preparations. Differences in the veratrine sensitivity of the force-APD relation observed between Purkinje and ventricular preparations suggest that a(i)Na-dependent changes in Na+/Ca2+ exchange may play a more important role in regulation of force generation in Purkinje fibers than in ventricular myocardium.

Action Potentials↗
PubMed1998

Intracellular calcium and electrical restitution in mammalian cardiac cells.

The role of calcium current and changes in intracellular calcium concentration ([Ca2+]i) in regulation of action potential duration (APD) during electrical restitution process was studied in mammalian ventricular preparations. Properly timed action potentials were recorded from multicellular preparations and isolated cardiomyocytes using conventional microelectrodes and EGTA-containing patch pipettes. APD increased monotonically in canine and guinea pig ventricular preparations with increasing diastolic interval (DI), while in rabbit papillary muscles the restitution process was biphasic: APD first lengthened, then shortened as the DI increased. When the restitution process was studied in single cardiomyocytes using EGTA-containing patch pipettes, the restitution pattern was similar in the three species studied. Similarly, no difference was observed in the recovery time constant of calcium current (/Ca-L) measured under these conditions in voltage clamped myocytes. Loading the myocytes with the [Ca2+]i-chelator BAPTA-AM had adverse effects in rabbit and canine cells. In rabbit myocytes steady-state APD lengthened and the late shortening component of restitution was abolished in BAPTA-loaded cells. In canine myocytes BAPTA-load shortened steady-state APD markedly, and during restitution, APD decreased with increasing DI. The late shortening component of restitution, observed in untreated rabbit preparations, was greatly reduced after nifedipine treatment, but remained preserved in the presence of 4-aminopyridine or nicorandil. Beat to beat changes in APD, peak/Ca-L and [Ca2+]i, measured using the fluorescent dye, Fura-2, were monitored in rabbit ventricular myocytes after a 1-min period of rest. In these cells, the shortening of APD was accompanied by a gradual reduction of the peak/Ca-L and elevation of diastolic [Ca2+]i during the initial eight post-rest action potentials. It is concluded that elevation of [Ca2+]i shortens, while reduction of [Ca2+]i lengthens APD in rabbit, but not in canine ventricular myocytes. These differences may probably be related to different distributions of [Ca2+]i-dependent ion currents and/or to differences in calcium handling between the two species.

Action Potentials↗
PubMed1998

Comparison of the cellular electrophysiological characteristics of canine left ventricular epicardium, M cells, endocardium and Purkinje fibres.

Electrophysiological differences among M cells, epicardium, endocardium and Purkinje fibres of the canine ventricle were studied over a wide range of stimulation cycle lengths, and the pharmacological response of these cell types to the sodium channel blocker tetrodotoxin, calcium channel blocker nifedipine and ATP-sensitive potassium channel activator pinacidil was compared. The experiments were carried out by applying standard intracellular microelectrode technique in isolated dog left ventricular preparations. The results confirmed the existence of M cells in the canine ventricle, in addition, the distribution of the rate of rise of the action potential upstroke and action potential amplitude values reflecting probably the inhomogeneity of the fast sodium current in these cells was revealed. It was also demonstrated that M cells differ from Purkinje fibres in some aspects which were not expected from previous investigations: (1) The early portion of the action potential duration restitution curve in M cells is more similar to that of endocardial and epicardial cells than to Purkinje fibres. (2) The plateau phase of the action potentials in Purkinje fibres developed at a more negative potential range than that in the other cell types studied. (3) The pharmacological response to tetrodotoxin and pinacidil in M cells resembles to that in the endocardial and epicardial cells more than in the Purkinje fibres. Our results provide further evidence in support of the existence of M cells but also indicate that there are important electrophysiological as well as pharmacological differences between M cells and Purkinje fibres.

Action Potentials↗
PubMed1998

Suppression of erythromycin-induced early afterdepolarizations and torsade de pointes ventricular tachycardia by mexiletine.

Erythromycin is a selective IKr-blocking, action potential duration (APD)-prolonging drug, which may induce early afterdepolarizations (EADs) and torsade de pointes ventricular tachycardia. The successful termination of an erythromycin-induced clinical torsades de pointes by the authors with mexiletine prompted them to investigate in vitro whether erythromycin is able to induce EADs in Purkinje fibers and, if so, whether EADs are suppressible or not by mexiletine. Electrically stimulated canine Purkinje fibers (n = 9) were superfused with erythromycin (200 mg/l) and action potentials were recorded by an intracellular microelectrode technique. Erythromycin induced a pronounced prolongation of APD and the appearance of EADs in all Purkinje preparations (9/9). After the addition of mexiletine (10 mM), a marked shortening of APD and the disappearance of EADs (7/9) were observed. Mexiletine, an inhibitor of the tetrodotoxin-sensitive window Na(+)-current, may prevent IKr-blocking drug-induced torsade de pointes ventricular tachycardia by abolishing APD prolongation and EADs.

Action Potentials↗
PubMed1997

Electrophysiological effects of EGIS-7229, a new antiarrhythmic agent, in isolated mammalian and human cardiac tissues.

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.

Action Potentials↗
PubMed1997

Electrophysiological effects of EGIS-7229, a new antiarrhythmic agent, in isolated guinea pig papillary muscle.

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.

Action Potentials↗
PubMed1997

Frequency-dependent Cardiac Electrophysiologic Effects of Tedisamil: Comparison With Quinidine and Sotalol.

BACKGROUND: Tedisamil is a potent bradycardiac/antiischemic drug known to lengthen cadiac repolarization by blocking various potassium channels. Recent in vivo experiments revealed that it is an antiarrhythmic agent. It was therefore of interest to compare the cellular electrophysiologic effects of tedisamil with those of quinidine and sotalol in isolated cardiac preparations. METHODS AND RESULTS: The conventional microelectrode technique was applied in isolated dog cardiac Purkinje and ventricular muscle fibers and in rabbit left atrial muscle. Tedisamil (1 µM) and sotalol (30 µM) lengthened, while quinidine (10 µM) shortened action potential duration in dog Purkinje fibers. The phase 1 repolarization was delayed by tedisamil and quinidine and not changed by sotalol. In dog ventricular muscle and in rabbit atrial muscle, all three drugs studied lengthened repolarization. In dog Purkinje fiber, tedisamil and sotalol lengthened action potential duration more at slow than at high stimulation frequency (reverse use-dependence). In dog ventricular muscle fibers, the effect of the drugs was not clearly frequency dependent. In rabbit atrial muscle fibers, the quinidine-evoked repolarization lengthening was most pronounced at intermediate cycle lengths (500-1000 ms). Tedisamil and quinidine but not sotalol depressed the maximal rate of depolarization (V(max)), which depended on the stimulation frequency (use-dependence). The nature of the use-dependent V(max) block differed between quinidine and tedisamil. Quinidine decreased V(max) at a relatively wide range of stimulation frequencies whle tedisamil. Quinidine decreased V(max) at a relatively wide range of stimulation frequencies while tedisamil decreased V(max) largely at high rate of stimulation. Tedisamil and quiinidine prevented or decreased the pinacidil-evoked action potential shortening in dog ventricular muscle, suggesting block of the ATP-dependent potassium channels (I(KATP)), while with sotalol such effect was not observed. CONCLUSIONS: Although tedisamil, quinidine, and sotalol are known to lengthen the QT interval, their cellular electrophysiologic effects substantially differ. Tedisamil lengthens repolarization and prevents pinacidil-evoked action potential duration shortening, suggesting I(K(ATP)) blockade. Its effect on the V(max) is limited mostly to fast heart rate. These electrophysiologic effects of tedisamil resemble those of chronic amiodarone treatment.

Journal Article↗
PubMed1996

Action potential duration and force-frequency relationship in isolated rabbit, guinea pig and rat cardiac muscle.

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.

4-Aminopyridine↗
PubMed1996

Three distinct components of the negative inotropic action of lidocaine in dog Purkinje fiber.

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.

Action Potentials↗
PubMed1996

Cardiac electrophysiological effects of levosimendan, a new calcium sensitizer.

1. The conventional microelectrode and the patch-clamp techniques were used to study the electrophysiological effects of levosimendan, a new calcium-sensitizing cardiotonic drug, in cardiac ventricular muscle. 2. Levosimendan (5 microM) did not change the main repolarizing currents, such as the inward rectifier potassium, transient outward and the delayed rectifier outward potassium current, in rabbit ventricular myocytes. 3. In rabbit ventricular muscle, levosimendan, at relatively low concentrations (0.1-1 microM), did not change significantly the amplitude of the inward calcium current but increased the amplitude of the twitch tension. 4. In guinea pig ventricular muscle, levosimendan, at higher concentrations (1-5 microM), significantly increased the amplitude of the inward calcium current and the slow-response action potential parameters. 5. It is concluded that levosimendan, in addition to its calcium sensitizing properties characterized by "silent electrophysiology," exhibits cardiac electrophysiological effects similar to those of phosphodies-terase inhibitors.

Action Potentials↗
PubMed1996

Electrical restitution in diseased human ventricular myocardium.

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.

Action Potentials↗
PubMed1996

Comparison of the chronic and acute effects of amiodarone on the calcium and potassium currents in rabbit isolated cardiac myocytes.

1. The acute and chronic effects of amiodarone were studied on the transmembrane ionic currents in rabbit single ventricular myocytes at 35 degrees C by applying the whole-cell configuration of the patch-clamp technique. 2. Acute exposure to 1 and 5 microM amiodarone significantly reduced the amplitude (-53.9 +/- 3.9%, n = 5 and -64.0 +/- 2.0%, n = 3, P < 0.01), but chronic amiodarone treatment (i.p. 50 mg kg-1 day-1 for 3-4 weeks) changed neither the amplitude nor the kinetics of the inward calcium current. 3. Both acute superfusion with amiodarone (1 and 5 microM) and chronic amiodarone treatment significantly decreased the amplitude of the delayed rectifier outward potassium current (IK). 4. Acute application of amiodarone (1 and 5 microM) did not alter but chronic amiodarone treatment moderately depressed the transient outward current (Ito). 5. Neither the acute (1 and 5 microM) nor the chronic amiodarone treatment changed the magnitude of the inward rectifier potassium current (Ik1). 6. It is concluded that acute amiodarone application and chronic amiodarone treatment alter transmembrane ionic currents of ventricular myocytes differently. This may explain, at least in part, the marked differences in the cardiac electrophysiological effects observed after acute and chronic amiodarone treatment in patients.

Amiodarone↗
PubMed1996

Differences in the Effects of d- and dl-Sotalol on Isolated Human Ventricular Muscle: Electromechanical Activity After Beta-Adrenoceptor Stimulation.

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.

Journal Article↗
PubMed1996

Comparison of the Electromechanical Effects of Vesnarinone and Amrinone in Isolated Dog Purkinje Strands and Ventricular Trabeculae.

BACKGROUND: Conventional microelectrode techniques were used to compare the concentration-dependent effects of vesnarinone (0.1-100 µM) and amrinone (1 µM-1 mM) on action potential duration (APD) and developed force in both isolated dog ventricular trabeculae and Purkinje strands. METHODS AND RESULTS: Both drugs increased contractility of trabecular muscle preparations, while, in Purkinje strands, vesnarinone failed to increase developed force during continuous pacing at 2 Hz. Vesnarinone lengthened APD in both preparations; although this effect was more marked in Purkinje strands. Ventricular muscle APD was not affected by amrinone (1 µM to 1 mM), while, in Purkinje strands, amrinone produced a biphasic effect on APD. Low concentrations (1-100 µM) of amrinone shortened Purkinje fiber APD, while only the highest concentration (1 mM) used lengthened APD. In addition, in Purkinje strand preparations the effects of vesnarinone (10 µM) on APD and developed force were proportional to pacing cycle length at frequencies slower than 2 Hz; however, at frequencies faster than 2 Hz vesnarinone decreased developed force while APD was lengthened. In ventricular trabecular muscle preparations, the effects of vesnarinone were not affected by frequency. CONCLUSIONS: These results indicate clear differences between the effects of vesnarinone and amrinone in isolated cardiac preparations. These differences in experimental effects in isolated cardiac preparations may help provide an explanation for the disappointing clinical response of patients in heart failure to amrinone, while vesnarinone has appeared to be beneficial.

Journal Article↗
PubMed1996

Differential Electrophysiologic Effects of Chronically Administered Amiodarone on Canine Purkinje Fibers versus Ventricular Muscle.

BACKGROUND: Acute and chronic treatment with amiodarone has been reported to cause different electrocardiographic changes in patients. The cellular electrophysiologic effects of chronic administration (50 mg/kg/day orally for 6 weeks) and acute superfusion (5 µM in the tissue bath) of amiodarone were therefore studied in dog cardiac ventricular muscle and Purkinje fibers using conventional microelectrode techniques. METHODS AND RESULTS: During stimulation at 1 Hz, chronic amiodarone treatment lengthened the ventricular muscle action potential duration (APD) from 227.8 +/- 6.3 ms (n = 20) to 262.3 +/- 5.2 ms (n = 21; P <.01), but shortened that of Purkinje fibers from 337.6 +/- 9.2 (n = 21) to 308.3 +/- 7.1 (n = 19; P <.05). Acute superfusion of 5 µM amiodarone in cardiac tissue obtained from chronically treated dogs did not change ventricular muscle APD but shortened Purkinje fiber AP from 309.7 +/- 13.6 ms to 281.9 +/- 11.9 ms (n = 8; P <.05). Neither the chronic nor the acute amiodarone exposure prevented the APD shortening in ventricular muscle evoked by 10 µM pinacidil, suggesting that amiodarone does not interfere with the ATP-dependent potassium channels. The normal difference in APD between ventricular muscle and Purkinje fibers in untreated, control preparations was 110 ms but decreased to 46 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in the presence of 30 µM sotalol, a class III antiarrhythmic drug used for comparison. Amiodarone (5 µM) applied directly abolished early afterdepolarizations (EADs) (induced by 1 µM dofetilide + 20 µM BaCl(2) + 2 mM CsCl) in 5 of 6 experiments and caused strong use-dependent V(max) block with relatively fast onset kinetics (rate constant = 1.23 +/- 0.13 AP(-1), n = 5) and offset (time constant = 364 +/- 62.5 ms, n = 5). After chronic amiodarone treatment, in contrast with acute sotalol application (30 µM), no reverse use-dependent effect was observed on the APD in Purkinje fibers. CONCLUSIONS: These results provide further evidence that amiodarone differs from other recognized class III antiarrhythmic drugs (ie, it is a mixed type agent with acute fast kinetic class I [type B] and a unique class III antiarrhythmic action characterized by decreased dispersion of APDs between ventricular muscle and Purkinje fibers). Amiodarone can abolish EADs unlike other class III agents that are usually associated to induction of EADs. These features might be responsible not only for the antiarrhythmic efficacy, but also for the relative safety (low incidence of torsade de pointes) of amiodarone in clinical settings.

Journal Article↗