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PubMed1984

Effects of 4 antiarrhythmic drugs on sinoatrial conduction time in isolated and blood-perfused dog atria.

We examined the effects of four antiarrhythmic drugs (quinidine, disopyramide, procainamide and propranolol) on sinus cycle length (SCL), sinoatrial conduction time (SACT) measured by a constant atrial pacing technique, and atrial developed tension (DT), using isolated blood-perfused dog atrial preparations. When an infusion rate of 10-40 micrograms/min of quinidine, disopyramide or procainamide was continuously given into the sinus node artery and propranolol at a rate of 1-4 micrograms/min, all the agents prolonged SCL and SACT, and reduced DT dose-dependently, but not in the same fashion. Propranolol caused almost a parallel action in prolongation of SCL and SACT, and reduction of DT in increasing doses. Quinidine, disopyramide and procainamide caused negative inotropic and chronotropic effects with only a small prolongation of SACT in a relatively small dose. At larger doses, quinidine and disopyramide produced a relatively more marked prolongation of SACT than procainamide. In the doses used, quinidine, disopyramide and procainamide caused relatively small depression of DT in contrast to propranolol. The order of potencies for inducing a prolongation of SACT was propranolol greater than quinidine = disopyramide greater than procainamide.

Animals↗
PubMed1998

Antagonism by class I antiarrhythmic drugs of levcromakalim-induced relaxation in isolated rat aorta.

We have analyzed the effects of several class I antiarrhythmic drugs (propafenone, quinidine, its enantiomer quinine, disopyramide, flecainide and mexiletine), tetraethylammonium (TEA) and glibenclamide on the vasodilator effects of the adenosine 5'-triphosphate-dependent K+ channels channel opener levcromakalim in isolated rat aorta precontracted by 30 mM KCl. TEA (>1 mM) and disopyramide (>/=10 microM), induced a sustained contraction in resting aortic rings. Propafenone (>/=3 microM), quinidine (>/=30 microM), disopyramide (>/=100 microM) and flecainide (>/=100 microM) but not the other drugs decreased the contraction induced by 30 mM KCl in a concentration-dependent manner. Propafenone (>/=1 microM), quinidine (>/=10 microM), quinine (>/=1 microM), disopyramide (>/=3 microM), flecainide (>/=100 microM), mexiletine (>/=3 microM), TEA (>/=0.3 mM) and glibenclamide (>/=0.1 microM) caused a concentration-dependent inhibition of the vasodilation induced by levcromakalim in rat aortic rings. The order of potency of the drugs, expressed as pD2 values, to inhibit the vasodilation induced by 0.3 microM levcromakalim was the following: glibenclamide (6.84) > quinine (6.14) > propafenone (5.27) > disopyramide (5.03) > quinidine (4.80) > mexiletine (4.68) > flecainide (3.37) > TEA (3. 20). With the exception of flecainide and mexiletine, the slopes of the Schild plots were similar to unity. Based on the mode of antagonism these drugs could be classified in four groups: 1) glibenclamide which only shifted the curves to the right, 2) quinidine and disopyramide that, at low concentrations, shifted the curve to the right but, at higher concentrations, it also reduced the maximal relaxant effect, 3) propafenone, quinine and TEA that shifted the curve rightwards and reduced the maximal relaxation at all concentrations and 4) flecainide and mexiletine whose Schild slopes were clearly different from unity. In conclusion, class I antiarrhythmic drugs inhibited levcromakalim-induced relaxation in isolated rat aorta. The concentrations at which these effects were observed were within the therapeutic range (except for flecainide) and similar to those reported to inhibit adenosine 5'-triphosphate-dependent K+ channel currents. Analysis of the concentration-response curves revealed that these drugs produced a noncompetitive antagonism of levcromakalim-induced relaxations.

Animals↗
PubMed1993

Stereoselective interactions of organic cations with the organic cation transporter in OK cells.

Recent studies have suggested that certain organic cations, such as pindolol and the diastereomers, quinine and quinidine, may be stereoselectively secreted by the kidney in humans. The goal of this study was to determine if the enantiomers of pindolol, verapamil, and disopyramide and the diastereomers, quinine and quinidine, interact stereoselectively with the organic cation transporter in the brush border membrane of the opossum kidney cell line. All organic cations tested inhibited the uptake of tetraethylammonium (TEA). The IC50 values (mean +/- SD) were as follows: quinine (17 +/- 2 microM). quinidine (51 +/- 13 microM), S-(-)-pindolol (23 +/- 4 microM), R-(+)-pindolol (30 +/- 4 microM), S-(-)-verapamil (0.4 +/- 0.04 microM), R-(+)-verapamil (7 +/- 2 microM), R-(-)-disopyramide (27 +/- 4 microM), and S-(+)-disopyramide (66 +/- 12 microM). Each individual organic cation pair showed significant stereoselective differences in their IC50 values, with quinine, S-(-)-pindolol, S-(-)-verapamil, and R-(-)-disopyramide being the more potent species. Both enantiomers of pindolol, quinine, and quinidine appear to exhibit simple competitive inhibition of TEA uptake based upon a derived slope similar to 1.0, using a sigmoidal inhibition model. The enantiomers of verapamil and disopyramide exhibited a slope of much less than 1.0, suggesting a more complex interaction of these organic cations with the TEA transporter. Our results suggest that organic cations stereoselectively interact with the organic cation transporter in the brush border membrane of OK cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Comparative studies of ATP sensitive potassium channels in heart and pancreatic beta cells using Vaughan-Williams class Ia antiarrhythmics.

OBJECTIVE: Actions of cibenzoline and disopyramide, agents with Vaughan-Williams class Ia antiarrhythmic action, on ATP sensitive K+ (KATP) channels were examined in heart and pancreatic beta cells. METHODS: Single ventricular myocytes and beta cells were prepared enzymatically from adult Wistar rat hearts and pancreatic islets. Using patch clamp techniques, KATP channel activities were recorded in whole cell and single channel modes. In whole cell experiments, myocytes were bathed with Tyrode's medium (34 degrees C); inside out patches were bathed with internal solutions (22-24 degrees C) containing 1 microM ATP and varying concentrations of cibenzoline or disopyramide. Myocytes were voltage clamped at -40 mV and glibenclamide blockade conductance was produced by cromakalim. RESULTS: Micromolar concentrations of both cibenzoline and disopyramide suppressed cromakalim induced conductance. When applied to the cytosolic surface of the cell membrane in inside out configuration, both drugs reversibly inhibited single KATP channel activities. Neither unitary conductance nor intraburst fast kinetics was affected by the compounds. At a holding potential of -40 mV under symmetrical approximately 150 mM K+ conditions, half maximum doses (IC50) were 0.9 microM [Hill coefficient (h) = 1.3] for cibenzoline induced block of cardiac KATP channels and 1.8 microM (h = 1.0) for disopyramide block. At +40 mV, IC50 for cibenzoline block was 1.4 microM (h = 0.9). Thus there was little voltage dependence in cibenzoline induced channel block. A similar IC50 value of 2.5 microM (h = 1.2 at -60 mV under symmetrical approximately 150 mM K+) was observed for cibenzoline induced block of KATP channels. CONCLUSIONS: Near therapeutic concentrations of cibenzoline and disopyramide inhibit KATP channel activities in both heart and pancreatic beta cells. This may be causally related to the fasting hypoglycaemia which is sometimes reported in patients receiving the drugs. These antiarrhythmic agents may also modulate myocardial electrical properties during hypoxia or ischaemia.

Adenosine Triphosphate↗
PubMed1988

Effect of SUN 1165, a new potent antiarrhythmic agent, on the kinetics of rate-dependent block of Na channels and ventricular conduction of extrasystoles.

Effects of SUN 1165, disopyramide, lorcainide, and mexiletine were studied either on the kinetics of onset of and recovery from rate-dependent depression of maximum rate of rise of phase 0 action potential (Vmax) in isolated guinea pig papillary muscles using standard microelectrode techniques or on intraventricular conduction time of extrasystoles evoked at varied coupling intervals in anesthetized dogs. SUN 1165 and lorcainide produced a slow-developing rate-dependent block of Vmax with the rate constant of 0.12 AP-1 and 0.09 AP-1, respectively. Mexiletine also produced a rate-dependent block of Vmax, but with very rapid onset so as not to be fitted by a single exponential curve. Disopyramide produced an intermediate rate-dependent block of Vmax with the rate constant of 0.46 AP-1. The time constants for recovery from the rate-dependent block for SUN 1165, lorcainide and disopyramide were 27.3-28.2, 23.2, and 17.0 s, respectively, while that for mexiletine was 0.118 s. SUN 1165, lorcainide, and disopyramide slowed ventricular conduction time of extrasystoles at all coupling intervals of 800-250 ms. On the other hand, mexiletine slowed conduction time at short coupling intervals of 500-250 ms. These findings suggest that, like lorcainide, SUN 1165 belongs to class Ic antiarrhythmic agents, and that SUN 1165 and lorcainide as well as disopyramide with slow and intermediate kinetics and mexiletine with fast kinetics may inhibit ventricular extrasystoles conducted at long and short range of coupling intervals, respectively.

Animals↗
PubMed2003

Abnormal response to sodium channel blockers in patients with Brugada syndrome: augmented localised wall motion abnormalities in the right ventricular outflow tract region detected by electron beam computed tomography.

OBJECTIVE: To investigate the relation between the wall motion abnormalities and sodium channel abnormalities in cases of the Brugada syndrome. DESIGN: Consecutive prospective case-control study in a single hospital. SETTING: Tertiary referral centre. PATIENTS: 13 consecutive patients with Brugada syndrome and 13 age and sex matched control subjects. INTERVENTIONS: Each subject underwent electron beam computed tomography (EBT) and a 12 lead ECG before and after disopyramide injection. MAIN OUTCOME MEASURES: QRS width and the magnitude of ST segment elevation in the 12 lead ECG; wall motion by EBT. RESULTS: After disopyramide, EBT revealed deterioration of focal wall motion abnormalities in the right ventricular outflow tract region in eight of the 13 patients (62%). Prolongation of the QRS width after disopyramide injection in lead V2, which usually reflects the electrical activity in right ventricular outflow tract region, was greater in these eight patients (p < 0.01) than in the other five patients, in whom wall motion did not change after disopyramide. The degree of augmentation of ST segment elevation did not differ significantly between the two groups CONCLUSIONS: The deterioration of wall motion abnormalities in the right ventricular outflow tract region after disopyramide suggests the presence of functional abnormalities of the sodium channel. Some patients with Brugada syndrome may have arrhythmogenic substrates with abnormal responses to sodium channel blockers.

Adult↗
PubMed1983

Electrophysiologic evaluation of antiarrhythmic drugs on supraventricular tachyarrhythmias.

The effects of the intravenous administration of three drugs, i.e., verapamil, disopyramide, and procainamide, on paroxysmal supraventricular tachycardia (PSVT), atrial fibrillation (Af) and atrial flutter (AF) were evaluated electrophysiologically. Efficacy on PSVT was 94.7% (36/38) with verapamil, 61.5% (13/18) with disopyramide and 100% (4/4) with procainamide. Efficacy on Af and AF was 9.1% (1/11) with verapamil and 80.0% (12/15) with disopyramide. PSVT termination mechanisms were as follows: 1) Verapamil: A-H block in 5 cases and H-A block in 5 cases with Type 1 A-V nodal reentrant tachycardia (AVNRT). H-A block in 6 cases with Type 2 and Type 3. A-H block in 17 of 18 cases with A-V reciprocating tachycardia (AVRT). Cycle length alternans were observed in 13 of 34 cases. 2) Disopyramide: H-A block in 2 cases with AVNRT and V-A block in 2 cases with AVRT. 3) Procainamide: V-A block in 4 cases with AVRT. These results suggest that verapamil and disopyramide are most effective on PSVT and Af, respectively.

Anti-Arrhythmia Agents↗
PubMed1980

The effect of quinidine and other oral antiarrhythmic drugs on serum digoxin. A prospective study.

We compared the effects of quinidine and three alternate antiarrhythmic drugs on serum digoxin concentration in 63 patients before and during administration of quinidine, procainamide, disopyramide, or mexiletine. Quinidine increased digoxin concentration by at least 0.5 nmol/L in 21 of 22 patients: Mean serum digoxin rose from 1.2 nmol/L to 2.4 nmol/L (P less than 0.001). Procainamide, disopyramide, or mexiletine increased serum digoxin by 0.5 nmol/L in one of 41 patients. Anorexia, nausea, and vomiting develop soon after starting quinidine therapy in 10 of the 22 patients who received quinidine but in only five of the 41 patients who received procainamide, disopyramide, or mexiletine (P less than 0.01). Quinidine prolonged the PR intervals from 160 +/- 14 ms to 183 +/- 26 ms, but procainamide, disopyramide, and mexiletine did not change the PR interval (P less than 0.005). In digitalized patients, quinidine increases serum digoxin concentration, increases digoxin's effect on atrioventricular conduction, and produces more adverse gastrointestinal effects than procainamide, disopyramide, or mexiletine.

Aged↗
PubMed1991

Electrophysiological effects of sodium channel blockers on guinea pig left atrium.

The electrophysiological effects of five sodium channel blockers (mexiletine, lidocaine, disopyramide, aprindine and flecainide) on the guinea pig left atrium were investigated by recording the action potential and its maximum rate of rise (Vmax). The onset and offset kinetics of use-dependent block of Vmax were analyzed. Lidocaine, aprindine and flecainide were classified clearly as fast, intermediate and slow, respectively. Mexiletine and disopyramide had two components in onset and offset of use-dependent block. Mexiletine showed fast and intermediate kinetics, whereas disopyramide showed intermediate and slow kinetics. Action potential duration at 90% repolarization (APD) was prolonged by disopyramide and mexiletine. The other drugs did not change the action potential duration. Effective refractory period was prolonged by all drugs with relative potency in the following order: disopyramide greater than mexiletine greater than lidocaine greater than aprindine = flecainide. In conclusion, the modes of actions of sodium channel blockers on the atrium were disclosed to be different from those on the ventricle. The pharmacological therapy for atrial arrhythmias should be based on the electrophysiological effects of the drugs on the atrium, not on the ventricle.

Action Potentials↗
PubMed1983

Responses to ligation of a coronary artery in conscious rats and the actions of antiarrhythmics.

A method for ligating the left anterior descending coronary artery in conscious rats and measuring the resultant cardiovascular responses, arrhythmias, cardiac tissue loss, electrocardiogram (ECG), and mortality is described. Analyses of such responses identified statistically acceptable measures for which precision and interrelationships were defined. Responses to ligation were a variable function of the amount of ligated myocardial tissue. For example, arrhythmia score was a linear function of the square root of the occluded zone size. To test the ability of the model to detect beneficial drugs, verapamil, lidocaine, disopyramide, and quinidine were given. Low doses of verapamil (0.2 mg/kg i.v. + 0.3 mg X kg-1 X h-1), and of disopyramide (10 mg/kg) had few antiarrhythmic, or other actions, whereas high doses of verapamil (20 mg/kg) and disopyramide (40 mg/kg i.v. repeated) were markedly antiarrhythmic as measured by all indices. Quinidine (20 mg/kg i.v. repeated) was also antiarrhythmic but less so than high dose disopyramide and verapamil. Lidocaine (10 mg/kg i.v. + 5 mg X kg-1 X h-1) reduced the incidence of ventricular flutter and fibrillation. High-dose verapamil and quinidine, but not disopyramide, increased the number of nonarrhythmic deaths and the incidence of atrioventricular conduction defects.

Animals↗
PubMed1988

SC-36602, a new antiarrhythmic agent: comparison of its cardiovascular profile with that of other antiarrhythmic drugs.

The cardiovascular profile of SC-36602, a new class 1A/1B antiarrhythmic agent, was compared to those of disopyramide, lidocaine, mexiletine, flecainide, encainide, lorcainide, and quinidine. These drugs were compared at their respective canine antiarrhythmic doses in a hemodynamic evaluation using anesthetized dogs. In another test using anesthetized dogs, the cardiovascular effects of cumulative doses of SC-36602 were assessed. The direct negative inotropic potential of each drug was also determined using isolated cat papillary muscles. In the hemodynamic study, SC-36602 and quinidine did not cause significant myocardial depression, measured as a decrease in the maximal first derivative of the left ventricular pressure. (Heart rate and diastolic filling pressure were not controlled in order to mimic clinical conditions). SC-36602, mexiletine, flecainide, and quinidine increased heart rate. SC-36602 and mexiletine caused a small increase in mean arterial pressure, whereas disopyramide and quinidine decreased it. Disopyramide was the only drug studied that increased left ventricular end-diastolic pressure. SC-36602, quinidine, and mexiletine increased index of cardiac effort. Disopyramide caused a decrease in the latter. Disopyramide, flecainide, encainide, and lorcainide lengthened the ECG intervals. Cumulative intravenous doses of SC-36602 up to 50 mg/kg produced significant decreases in mean arterial pressure, increases in heart rate, and increases in P-R and QRS intervals of the ECG relative to placebo-matched controls. SC-36602 had the least direct negative inotropic action of the drugs studied, as measured in isolated papillary muscles. These data suggest SC-36602, when compared to the other antiarrhythmic drugs studied, has the least amount of hemodynamic side-effects at its antiarrhythmic dose.

Animals↗
PubMed1996

Binding characteristics of KNI-272 to plasma proteins, a new potent tripeptide HIV protease inhibitor.

The binding characteristics of KNI-272, a potent and selective human immunodeficiency virus (HIV) protease inhibitor, were evaluated in rat and human plasma, and in solutions of human alpha 1-acid glycoprotein (AAG) and human serum albumin (HSA). The unbound fractions (Fu) of KNI-272 were 12.13 and 2.24% in rat and human plasma, respectively, at the drug concentration of 1.0 microgram mL-1. Although KNI-272 binds to both AAG and HSA, the Fu of KNI-272 in AAG solution was 1.83%, and only one-quarter of that in HSA solution (Fu = 6.78%). Binding displacing agents, such as disopyramide, warfarin, diazepam, and digitoxin, were used to determine the binding site of KNI-272 on these plasma proteins. The Fu of KNI-272 in AAG solution increased 14-fold when disopyramide was added to the AAG solution. In addition, warfarin, diazepam, and digitoxin were added to HSA solution as representative drugs bound to distinct binding sites on HSA, namely sites I, II, and III, respectively. The Fu values of KNI-272 in HSA solution significantly increased when warfarin and diazepam were added. In particular, with the addition of warfarin to HSA solution, the Fu of KNI-272 increased to 16%. The modified Scatchard plots of KNI-272 binding to AAG and HSA both showed biphasic curves, and the KNI-272 binding sites at low concentration range on AAG and HSA disappeared with the addition of disopyramide and warfarin, respectively. Therefore, it is considered that KNI-272 binds to the identical site as disopyramide on AAG and site I on HSA in the low KNI-272 concentration range. By comparing the KNI-272 binding parameters obtained in human plasma and these protein solutions, we can assume that KNI-272 binding at low concentration in human plasma is mainly concerned with the binding on AAG. As KNI-272 concentration in plasma increases, HSA becomes concerned with KNI-272 binding.

Animals↗
PubMed2004

Effects of antiarrhythmic agents on left ventricular function during exercise in patients with chronic left ventricular dysfunction.

This study was designed to determine the effects of antiarrhythmic agents on global left ventricular (LV) function during exercise in patients with chronic LV dysfunction. Thirty-five patients with LV dysfunction [LV ejection fraction (LVEF) < 45%] and ventricular arrhythmias were studied. They were randomly classified into 3 groups: patients who received a single oral dose of 6 mg/kg disopyramide phosphate (n = 12), those who received a single oral dose of 4 mg/kg mexiletine hydrochloride (n = 12), and those who received a single oral dose of 4 mg/kg pilsicainide hydrochloride (n = 11). First, all patients were subjected to baseline rest and peak exercise, equilibrium-gated cardiac-pool scintigraphy with 99mTc-human serous albumin of 740 MBq (baseline data). Second, on a separate day, they were given drugs once, and were subsequently subjected to rest and peak exercise equilibrium-gated cardiac-pool scintigraphy. Exercise LVEF and peak ejection rate (PER) after administration were significantly lower in the disopyramide and pilsicainide groups than in the mexiletine group (p < 0.05, respectively). The changes in LVEF and PER from rest to peak exercise after administration were significantly less than the baseline changes in those in the disopyramide and pilsicainide groups (p < 0.05, respectively). However, no significant changes in functional parameters were recognized in the mexiletine group. Due care should be taken when disopyramide and pilsicainide are administered to patients with chronic LV dysfunction since they reduce systolic LV function during exercise.

Aged↗
PubMed1997

Differences between blacks and whites in plasma protein binding of drugs.

OBJECTIVE: Disopyramide and salicylic acid were used as model compounds to characterize racial differences in binding of drugs by alpha 1-acid glycoprotein (AGP) and albumin, respectively. Drug-free plasma was collected from 29 healthy volunteers (15 white, 14 black). Disopyramide and salicylic acid unbound fractions (fu) in plasma were determined by equilibrium dialysis using 14C-disopyramide and 14C-salicylic acid. RESULTS: Disopyramide unbound fractions were significantly higher in blacks than whites (0.131 vs 0.113) as were salicylic acid unbound fractions (0.053 vs 0.048). When unbound fractions were corrected for AGP and albumin concentration, racial differences were no longer present. CONCLUSION: Many drugs which bind to AGP and/or albumin may exhibit racial differences in unbound fractions. However, these differences are likely explained by differences in protein concentrations rather than differences in the number of binding sites on the protein or racial differences in affinity of the protein for drugs.

Adult↗
PubMed1994

Atrioventricular block progression in patients with bifascicular block assessed by repeated electrocardiography and a bradycardia-detecting pacemaker.

Syncope may be due to intermittent high-degree atrioventricular (AV) block, but a cause-relation is sometimes difficult to prove. Diagnostic methods with high predictive value proven by instruments for safe and sensitive follow-up are needed. A bradycardia-detecting pacemaker was used in patients with bifascicular block, who had been the subjects of pharmacologic stress testing of the His-Purkinje system. Thirty-seven patients were included, of whom 26 had experienced at least 1 syncopal episode of suspected bradycardia origin, and 11 had previously documented transient high-degree AV block. The electrophysiologic study included injection of disopyramide 2 mg/kg (up to 150 mg) over 5 minutes. A positive test result was defined as spontaneous or pacing-induced His-Purkinje high-degree AV block after drug or a drug-induced HV prolongation of > or = 50%. Patients were followed an average 63 months with repeated electrocardiography and a diagnostic pacemaker (n = 23). Altogether, 24 patients had a significant bradycardia diagnosed by either or both methods. The sensitivity and positive predictive values were: HV interval > or = 70 ms at baseline, 47% and 88%; a positive disopyramide test result, 75% and 80%; and HV interval > or = 70 ms or a positive disopyramide test result, 93% and 74%, respectively. Thus, the diagnostic pacemaker is a safe and sensitive tool for evaluating the information obtained at electrophysiologic study, and pharmacologic stress testing with disopyramide has an informative value in patients with bifascicular block and syncope when results at baseline are inconclusive.

Aged↗
PubMed1979

Single column high pressure liquid chromatographic determination of drugs in blood.

1. Analysis of anticonvulsants (phenobarbital, diphenylhydantoin and carbamazepine), theophylline and an antiarrhythmic agent (disopyramide) in blood using a simple high pressure liquid chromatography apparatus equipped with a reversed -- phase column is described. A simple extraction of plasma or serum with organic solvent is used to isolate the anticonvulsants and theophylline. Disopyramide is extracted with ether and is further purified by a back extraction into acid. 2. Hexanesulfonic acid -- methanol solutions are used for chromatography of the anticonvulsants and disopyramide while the mobile phase for theophylline is a NH4H2PO4 -- methanol mixture. Chromatographic analysis time for the drugs is approximately 15 minutes. The drugs are monitored by a UV detector at 254 nm except for theophylline which is measured at 280 nm. Quantitation is accomplished by comparison of peak heights with those of internal standards. Quantities of serum or plasma routinely used for analysis are: 200 ul for the anticonvulsants, 100 ul for theophylline and 0.5 ml for disopyramide. Detection limits are less than 1 ug/ml for these quantities.

Anticonvulsants↗
PubMed2000

Nicorandil attenuates both temporal and spatial repolarization alternans.

T-wave alternans (TWA) on the electrocardiogram have been frequently associated with long QT syndrome (LQTS) and abrupt rate change. The present study investigated the effect of the potassium channel opener nicorandil on the repolarization alternans at the endocardium and the epicardium in the left ventricle. Electrocardiogram and transmural monophasic action potentials from the endocardium and the epicardium were simultaneously recorded in Langendorff-perfused guinea pig hearts. The hearts were paced at a basic cycle length (BCL) of 240 ms and the cycle length (CL) was abruptly shortened to 170 ms to induce repolarization alternans. Disopyramide and nicorandil were used to increase or attenuate repolarization alternans, respectively. Repolarization alternans were numerically expressed as the sum of the absolute difference between consecutive monophasic action potential durations at 90% repolarization (MAPD90) in the first 10 beats. In the control hearts, the MAPD90 alternans were 78.6 +/- 14.9 ms at the endocardium, and 49.8 +/- 58 ms at the epicardium (P = .03 endocardium vs epicardium). Disopyramide (2 microg/mL) increased the MAPD90 alternans to 186.6 +/- 30.6 ms at the endocardium and 116.4 +/- 16.5 ms at the epicardium, and enhanced the difference of repolarization alternans between the endocardium and the epicardium (transmural dispersion) from 28.8 +/- 11.3 ms to 70.2 +/- 18.7 ms (P = .02 vs controls). Nicorandil (400 ng/mL) suppressed the MAPD90 alternans to 79.6 +/- 16.3 ms at the endocardium and 56.0 +/- 11.8 ms at the epicardium, and attenuated the transmural dispersion to 23.6 +/- 6.0 ms (P = .02 vs disopyramide-administrated hearts). Our results suggest that nicorandil attenuates both temporal (beat-to-beat) and spatial (between the endocardium and the epicardium) repolarization alternans induced by the combination of cycle length changes and disopyramide administration.

Animals↗
PubMed1995

Complex frequency-dependent interaction of class-I antiarrhythmic drugs as they affect intraventricular conduction.

We investigated the interaction of class-I antiarrhythmic drugs as they affect intraventricular conduction of human hearts in vivo. QRS duration in signal-averaged electrocardiograms and standard electrocardiograms were measured as an index of intraventricular conduction time in 17 patients with implanted pacemakers at various pacing rates (100-180 ppm, VVI mode). Single intravenous administration of lidocaine, disopyramide or aprindine prolonged the QRS of signal-averaged electrocardiograms in a frequency-dependent manner. Lidocaine (n = 17) produced significant QRS prolongation from pre-drug control at rates > or = 120 ppm (6.2 +/- 1.4% at 180 ppm), whereas disopyramide (n = 17) and aprindine (n = 17) did so from the lowest rate (8.9 +/- 1.8% to 12.3 +/- 2.9% at 100-180 ppm with disopyramide; 14.7 +/- 1.3% to 19.3 +/- 2.2% at 100-180 ppm with aprindine). Addition of lidocaine to disopyramide (n = 17) showed an additive effect; QRS prolongation was enhanced significantly by 1.4-2.8% at rates > or = 150 ppm. In contrast, addition of lidocaine to aprindine (n = 17) showed a subtractive effect; the QRS prolongation was attenuated significantly by 1.6-2.4% at rates < 150 ppm. Combined intravenous administration of class-I antiarrhythmic drugs causes not only additive but also subtractive effects on the intraventricular conduction of the human heart, probably through their interaction on the sodium channel receptor.

Aged↗