Differential effects of amiodarone on Vmax and conduction velocity in anisotropic myocardium.

Despite its widespread clinical use, the precise mechanism of action of amiodarone (AMI) has not been completely defined. We examined the effects of AMI (20 micrograms/ml) on Vmax and on conduction velocity (theta) during longitudinal (LP) and transverse (TP) propagation with respect to fiber orientation, in 10 strips of uniform anisotropic epicardial muscle obtained from the left ventricle of adult canine hearts. Mean values +/- SEM (standard error of the mean) were calculated as normalized values (beat 50/beat 1) after 4 h of AMI superfusion at five different basic cycle lengths (BCL). Vmax decreased from 0.99 +/- 0.01 at a BCL of 5,000 ms to 0.43 +/- 0.03 at a BCL of 300 ms during LP. During TP, Vmax decreased from 0.99 +/- 0.01 at a BCL of 5,000 ms to 0.54 +/- 0.05 at a BCL of 300 ms. The differences in the relative changes between both directions at a BCL of 300 ms, as well as at intermediate values of 1,000, 500, and 400, were significant (p less than 0.01). theta during LP (theta L) was depressed from 0.99 +/- 0.01 at a BCL of 5,000 ms to 0.80 +/- 0.04 at a BCL of 300 ms. In contrast, theta during TP (theta T) did not change as the BCL was decreased. In consequence, theta L was significantly more depressed than theta T at BCLs shorter than 1,000 ms (p less than 0.05). Moreover, theta T after AMI was not statistically different from control at any BCL studied. The lack of depression of theta T associated with a marked depression of Vmax during either LP or TP suggests that in addition to its sodium channel blocking properties, AMI could produce a decrease in the effective axial resistivity.     

Effects of lidocaine on Vmax and conduction velocity in uniform anisotropic canine ventricular muscle: possible role of its binding-rate constants.

We evaluated the effect of lidocaine (5 micrograms/ml) on Vmax and conduction velocity during longitudinal and transverse propagation to fiber orientation in strips of uniform anisotropic ventricular muscle from adult canine hearts. Tissues were markedly anisotropic, with conduction velocities 3.2 times faster during longitudinal propagation than during transverse propagation to the long axis of the fibers, and with the greatest values of Vmax associated with the slowest conduction velocities. After addition of lidocaine, Vmax (normalized values with respect to control for each cycle length, expressed as mean +/- SEM) decreased from 0.99 +/- 0.02 at a cycle length of 1,000 ms to 0.86 +/- 0.02 at a cycle length of 300 ms during longitudinal propagation. During transverse propagation, Vmax decreased from 0.99 +/- 0.03 at a cycle length of 1,000 ms to 0.87 +/- 0.03 at a cycle length of 300 ms. The differences in the relative changes between both directions at these cycle lengths, as well as with intermediate values of 500, 400, and 350 ms, were not significant. Similar results were obtained for conduction velocity. We conclude from these findings that under these experimental conditions the effects of lidocaine are characterized by a relative change both in Vmax and conduction velocity that is almost the same during longitudinal and transverse propagation at all cycle lengths explored. Moreover, the rapid binding-rate constants reported for lidocaine may play a significant role in determining the characteristics of Vmax and conduction velocity depressions in both directions.     

Frequency-dependent effects of several class I antiarrhythmic drugs on Vmax of action potential upstroke in canine cardiac Purkinje fibers

Vmax of the action potential upstroke in canine cardiac Purkinje fibers was studied in the presence of seven class I antiarrhythmic drugs--lidocaine (4 micrograms/ml), mexiletine (4 micrograms/ml), propranolol (0.9 micrograms/ml), procainamide (30 micrograms/ml), quinidine (5 micrograms/ml), flecainide (4 micrograms/ml), and disopyramide (3.1 micrograms/ml)--at constant cycle lengths (CCL) and after abrupt changes in cycle length (ACCL). The time constant of Vmax recovery after ACCL at a basic cycle length of 500 ms was 0.09 +/- 0.01 s for lidocaine, 0.18 +/- 0.03 s for mexiletine, 1.35 +/- 0.20 s for propranolol, 4.4 +/- 0.8 s for procainamide, 8.3 +/- 1.2 s for quinidine, 11.0 +/- 0.9 s for flecainide, and 37.9 +/- 9.4 s for disopyramide. These values were similar to those reported by others in guinea pig papillary muscle, and, with the exception of flecainide, conformed to the scheme proposed by Courtney (J Mol Cell Cardiol 1980; 12:1273-86) based on the molecular weight and lipid solubility hypothesis. Each drug altered the Vmax differently at CCL from after ACCL at the same diastolic intervals. The magnitude of these differences and the range of diastolic intervals at which they were present varied among different drugs. These observations explain differences in the drug effects on the Vmax of the regularly and prematurely occurring depolarizations. In the presence of lidocaine and mexiletine, the recovery kinetics of Vmax were not altered by CCL within the 300-1,500-ms range, and the magnitude of Vmax depression was not influenced by action potential duration within the 200-270-ms range.     

Electrophysiologic effects of flecainide relative to serum and tissue concentrations in rabbits after chronic drug administration

The effects of chronic treatment with flecainide on the cellular electrophysiology and the relationship of the electrophysiologic effects to serum and myocardial flecainide concentrations were determined in rabbit ventricular myocardium. Two groups of rabbits were administered flecainide at doses of 7.5 mg/kg body weight (dose I) and 20 mg/kg body weight (dose II) intraperitoneally (i.p.) twice daily for 12-14 days; a third group received saline. Serum and myocardial flecainide concentrations with dose II (0.44 +/- 0.15 micrograms/ml and 3.0 +/- 1.4 micrograms/g, respectively) were significantly (p less than 0.01) higher than with dose I (0.19 +/- 0.11 micrograms/ml and 0.81 +/- 0.15 micrograms/g, respectively). At 1.0-Hz stimulation, only the high dose produced significant changes in transmembrane action potentials of right ventricular myocardial fibers, which showed a 17.6% (n = 6, p less than 0.05) decrease in maximal upstroke velocity (Vmax) of phase 0 and 19.5% (n = 6, p less than 0.05) prolongation of effective refractory period (ERP). Repetitive stimuli led to an exponential decline in Vmax with both dosage regimens. The magnitude of Vmax decrease was frequently dependent and was greater with the higher dose. The rate of decrease of Vmax per action potential (AP) during train of stimuli in rabbits treated with dose II was 0.037 +/- 0.012 (n = 5) at 2.0-Hz stimulation, and the recovery time constant from use-dependent block at 4.0-Hz stimulation increased significantly from 12.6 +/- 3.6% decrease in Vmax with the low dose to 35.6 +/- 7.1% decrease with the high dose. The data show that sodium channel inhibition by chronic flecainide administration is a function of dose, serum, and myocardial flecainide concentrations.     

Use-dependent effects of amiodarone on Vmax in cardiac Purkinje and ventricular muscle fibers

Superfusion with 5 micrograms/ml amiodarone for 3-4 h induced use-dependent Vmax block in dog Purkinje and guinea pig ventricular muscle fibers. The recovery from block was exponential with tau of 289 +/- 30 ms in Purkinje (n = 7) and 282 +/- 47 ms in muscle (n = 6) fibers. The onset of frequency-dependent Vmax block was rapid, i.e. reached steady state after 4.2 +/- 0.5 beats (n = 5). The combination of rapid interaction with sodium channel and the reported action potential lengthening make amiodarone unique among Class I antiarrhythmic drugs.     

Comparative effects of tetrodotoxin, lidocaine, and amiodarone on Vmax in guinea pig cardiac Purkinje and papillary muscle fibers

1. Electrophysiological effects of three drugs (tetrodotoxin, lidocaine, and amiodarone), which are known to depress Na channels in cardiac tissues, were studied on isolated guinea pig Purkinje fibers, by means of microelectrode techniques, and compared the findings with their effects on the ventricular papillary muscle. 2. Special attention was paid with regard to their effects on the maximum upstroke velocity (Vmax) of action potentials. 3. In Purkinje fibers, tetrodotoxin was the most inhibitory for Vmax, then in descending order, amiodarone, and lidocaine. 4. That is, half maximal inhibition (IC50) of Vmax by tetrodotoxin, lidocaine and amiodarone was approximately 1.7 x 10(-5) M, 1.5 x 10(-4) M and 2.8 x 10(-4) M, respectively. 5. As for papillary muscle, higher concentrations of the three drugs were needed to get similar potency. 6. The relationships between the depression in the Vmax and action potential duration are discussed in conjunction with their antiarrhythmic activities.     

Effect of phenytoin on the clinical pharmacokinetics of amiodarone

Five healthy male volunteers were given oral amiodarone hydrochloride, 200 mg per day for 6 1/2 weeks, to determine its effects on the pharmacokinetics of both intravenous and oral phenytoin. Predose amiodarone and N-desethylamiodarone serum concentrations were obtained weekly during weeks 2-6. Amiodarone serum concentrations (ASC) increased during weeks 2-4 and then decreased sharply during weeks 5-6 when oral phenytoin, 2-4 mg/kg/day, was co-administered. In addition, N-desethylamiodarone serum concentrations (DEASC) exceeded corresponding ASC during weeks 5-6 whereas during weeks 2-4, DEASC were less than ASC. Because of the long elimination half-life for amiodarone previously reported in healthy volunteers after single doses of amiodarone and the frequent administration of amiodarone associated with this half-life, a modified equation for a continuous infusion was used to describe each subject's ASC versus time data. Pre-phenytoin ASC were fitted to an appropriate function to predict ASC during weeks 5-6 assuming no interaction. Observed versus predicted ASC were compared for weeks 5 and 6. Observed ASC during weeks 5 and 6 were (mean +/- SD) 0.25 +/- 0.09 micrograms/mL and 0.19 +/- 0.07 micrograms/mL, respectively. Corresponding predicted ASC were 0.36 +/- 0.12 micrograms/mL (P = .011) and 0.38 +/- 0.13 micrograms/mL (P = .004). These represented percent differences of 32.2 +/- 12.5% and 49.3 +/- 5.6% for weeks 5 and 6, respectively. Assuming there were no changes in the bioavailability of amiodarone during continuous administration, these findings strongly suggest induction of amiodarone metabolism by phenytoin. The clinical significance of this interaction remains to be determined.     

A comparison of the electrophysiologic effects of acute and chronic amiodarone administration on canine Purkinje fibers

The electrophysiologic effects of acutely and chronically administered amiodarone on canine Purkinje fibers were assessed using microelectrode techniques to record intracellular action potentials. Chronically treated dogs received amiodarone for 3 weeks (serum levels, 0.91 +/- 0.09 microgram/ml or 1.42 X 10(-6) M). Acute studies were performed using fibers from untreated dogs superfused for 1 h with 5 X 10(-5) M amiodarone (32 micrograms/ml) in Tyrode's solution (KCl = 4 mM). Acute superfusion shortened the action potential duration to 50 and 90% repolarization by 41 and 8%, respectively (p less than 0.01), and decreased Vmax of phase 0 from 418 +/- 20 to 309 +/- 23 V/s (p less than 0.01) (paced cycle length of 500 ms). Prominent use-dependent depression of Vmax was noted. Acute exposure of fibers from untreated dogs to blood from dogs chronically treated with amiodarone using the blood cross-perfusion technique decreased the action potential duration to 50% repolarization and Vmax, similar to acute exposure in Tyrode's solution. Blood cross-perfusion was used to study fibers from treated dogs superfused with blood from another amiodarone-treated dog. Chronic amiodarone prolonged the action potential duration to 90% repolarization by 13% (p less than 0.02) and did not change Vmax when compared to control studies using fibers obtained from untreated dogs superfused with blood from untreated dogs. Thus, the effects of acutely superfused amiodarone on action potentials of canine Purkinje fibers differ from the effects of chronically administered amiodarone.     

Effects of long-term oral administration of amiodarone on the electromechanical performance of rabbit ventricular muscle.

1. The effects of long-term administration of oral amiodarone on transmembrane action potential and contraction of ventricular muscle were investigated in rabbits. 2. ECGs of rabbits that received oral amiodarone 50 mg or 100 mg kg-1 daily for 4 weeks, showed a significant prolongation of RR, QT and corrected QT (QTc) intervals, whereas PQ and QRS were unaffected. Serum and myocardial tissue amiodarone concentrations were 0.14-0.18 micrograms ml-1 and 1.47-3.63 micrograms g-1 wet wt. respectively. 3. Right ventricular papillary muscles isolated from treated rabbits were characterized by a moderate prolongation of action potential duration (APD) compared with controls. A slight decrease of the maximum upstroke velocity (Vmax) was also observed at the higher dose. The APD prolongation by chronic amiodarone, unlike acute effects of sotalol, E-4031, Cs+ and 4-aminopyridine, did not show marked reverse use-dependence. 4. APD and Vmax restitution following slow basic stimuli (0.03 Hz) were unaffected by chronic treatment with amiodarone. 5. Acute application of amiodarone (10 microM) caused a significant decrease in APD and developed tension, as well as a marked use-dependent Vmax inhibition with fast recovery kinetics. 6. These findings suggest that a major and consistent electro-physiological effect of chronic amiodarone is repolarization delay (Class-III action) showing minimal frequency-dependence. However, when amiodarone above a certain concentration is present in the extracellular space, a fast kinetic Class-I action would be added as an acute effect.     

Chronic and acute effects of dronedarone on the action potential of rabbit atrial muscle preparations: comparison with amiodarone

Dronedarone, a noniodinated derivative of amiodarone, is under evaluation as a potentially less toxic anti-arrhythmic alternative to amiodarone. The acute and chronic electrophysiologic effects of dronedarone and amiodarone were compared in isolated rabbit atrial muscle by microelectrode techniques. Four-week PO treatment with dronedarone or amiodarone increased action potential duration (APD90) (58 +/- 4 ms control versus 69 +/- 2 ms dronedarone, p < 0.01; 68 +/- 3 ms amiodarone, p < 0.01 for a 100-mg/kg/d dose) and effective refractory period (49 +/- 6 ms control versus 68 +/- 4 ms dronedarone, p < 0.01; 63 +/- 3 ms amiodarone, p < 0.01). The APD90 prolonged reverse rate-dependency. In contrast, acute superfusion with 10 microM dronedarone or amiodarone decreased APD90 (61 +/- 6 ms control versus 53 +/- 4 ms dronedarone, p < 0.05; 52 +/- 6 ms amiodarone, p < 0.05), effective refractory period (50 +/- 5 ms control versus 44 +/- 4 ms dronedarone, p < 0.05; 43 +/- 6 ms amiodarone, p < 0.05), and the maximum upstroke slope of the action potential (Vmax) (188 +/- 9 V/s control versus 182 +/- 11 V/s dronedarone p < 0.05; 182 +/- 11 V/s amiodarone, p < 0.05). Thus, chronic and acute electrophysiologic effects of dronedarone on rabbit atrial muscle are similar to those of amiodarone, suggesting a similar potential against atrial arrhythmias.     

Cytotoxic effects of amiodarone and desethylamiodarone on human thyrocytes

Since recent in vivo evidence suggests that the benzofuran antiarrhythmic drug amiodarone has a direct toxic effect on the human thyroid gland, we have investigated the effects of both amiodarone and its metabolite desethylamiodarone on a novel immortalized functional human thyrocyte line (SGHTL-34 cells). Desethylamiodarone markedly reduced cell number as assessed from both DNA and protein content. Few cells were left after 24 hr exposure to 12.5 micrograms/ml; the concentration producing death of 50% of cells (EC50) was 6.8 +/- 1.1 micrograms/ml (mean +/- SE, N = 15). Amiodarone was much less potent, producing a maximum decrease in cell number of approximately 25% at concentrations up to 50 micrograms/ml. The effect of desethylamiodarone was seen within 24 hr of culture. T3 in concentrations up to 0.75 micrograms/ml had no effect on the action of amiodarone or desethylamiodarone on SGHTL-34 cells. Light microscopy demonstrated vacuolation of SGHTL-34 cells after 4-day culture with either the drug or its metabolite. Studies using primary cultures of human retroorbital fibroblasts demonstrated that the greater cytotoxicity of desethylamiodarone was not confined to thyrocytes. When SGHTL-34 cells were incubated with 2.5 micrograms/ml desethylamiodarone for 4 days, 71.7 +/- 0.9% was taken up by the cells; there was no detectable conversion to amiodarone. Incubation of thyrocytes with 50 micrograms/ml amiodarone for 4 days resulted in the uptake of 80.1 +/- 2.1% by the cells. In addition, 5.0 +/- 0.1% of the amiodarone was converted to material with the same retention time as desethylamiodarone standard; of this material, 72.9 +/- 2.8% was taken up by the cells. We conclude that desethylamiodarone, at concentrations near those found in the plasma of patients on long-term amiodarone therapy, exerts a direct cytotoxic effect on human thyroid cells in short-term culture. This effect may play a role in the aetiology of clinical thyroid disease during amiodarone therapy. We suggest that, since the effect is not restricted to thyrocytes, desethylamiodarone may play a role in the aetiology of amiodarone toxicity which occurs clinically in many tissues.     

Influence of amiodarone on oral digoxin bioavailability in healthy volunteers

The aim of the present work was to evaluate the possible influence of amiodarone on some basic parameters of acute oral digoxin kinetics. A single oral dose of digoxin (0.50 mg) was administered to six healthy volunteers both before and at the end of a 7-day treatment with with amiodarone. This treatment caused a clear-cut rise in peak serum digoxin levels (Cmax) from 2.92 +/- 1.09 to 5.87 +/- 1.68 ng/ml (p less than 0.005) and a decrease of the peak time (Tmax) in four out of the six subjects. The area under the serum concentration-time curve (AUC) was increased by amiodarone with a high individual variability (30.71 +/- 6.15 vs 40.63 +/- 10.04 ng X h X ml-1). Also the 72-hour recovery of the glycoside in the urine was higher (258.77 +/- 68.41 vs 357.62 +/- 62.98 micrograms; p less than 0.01), while renal clearance (Clr) was not altered. These results show that amiodarone increases digoxin bioavailability by a mechanism which appears to be independent of changes in drug elimination.     

Antiarrhythmic effect of chronic oral amiodarone treatment in dogs with myocardial infarction and reproducibly inducible sustained ventricular arrhythmias.

The antiarrhythmic effect of an 8-week oral amiodarone regimen was studied in dogs with 1-week-old myocardial infarction and reproducibly inducible sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Eighteen dogs were randomly assigned to receive either amiodarone, 40 mg/kg/day for 10 days, followed by 30 mg/kg/day for 4 days and then 20 mg/kg/day for 6 weeks (N = 9), or placebo (N = 9). Programmed electrical stimulation was conducted weekly in the two treatment groups. Plasma concentrations of amiodarone and desethylamiodarone were determined weekly, and their myocardial concentrations in the noninfarcted and infarcted regions of the left ventricle were measured at the end of the study. Suppression of inducible arrhythmias was observed at weeks 1,3-7, and 8 in the amiodarone-treated dogs, whereas no suppression occurred in the placebo-treated group. Plasma amiodarone concentration was maximal at 2.5 +/- 1.4 micrograms/ml at week 2, decreased to 1.9 +/- 1.1 micrograms/ml at week 3, and remained steady thereafter. Plasma desethylamiodarone concentrations were in the range of 0.2 +/- 0.1 to 0.4 +/- 0.2 microgram/ml from weeks 1 through 8. Myocardial amiodarone and desethylamiodarone concentrations in the noninfarcted region of the left ventricle were 34.0 +/- 15.8 and 20.8 +/- 7.8 micrograms/g, respectively, at the end of the study. The lack of antiarrhythmic effect of amiodarone at week 2 coincided with the highest plasma amiodarone concentration. The data indicate that this dog model of ventricular arrhythmias is useful for studying the antiarrhythmic action of amiodarone.     

Amiodarone does not affect digoxin kinetics in the rabbit

It has been reported that amiodarone may interact with digoxin in man. We investigated the effects of amiodarone pretreatment (35 mg kg-1 day-1) on the pharmacokinetics of a single dose of digoxin (50 micrograms kg-1) in 6 rabbits. Total body clearance of digoxin was 138.84 +/- 44.67 and 147.99 +/- 29.17 ml min-1, serum half life 187.9 +/- 60.9 and 181.34 +/- 25.57 min and volume of distribution 35.4 +/- 8.54 and 37.8 +/- 3.9 litres before and after amiodarone treatment, respectively. None of these changes were statistically significant. We conclude that the presence of an amiodarone-induced change in digoxin pharmacokinetics in the rabbit was not evident and that other animal models will be necessary for studying this interaction.     

Electrophysiological properties of a new antiarrhythmic agent,bisaramil on guinea-pig,rabbit and canine cardiac preparations

Electrophysiological effects of bisaramil, a novel antiarrhythmic agent, were examined using the conventional microelectrode technique applied to cardiac multicellular preparations from guinea-pigs, rabbits and dogs and the whole-cell patch-clamp technique applied to guinea-pig ventricular myocytes. Bisaramil at 10(-6) M or higher concentrations produced a dose-dependent decrease in the maximum rate of rise (Vmax) of action potentials of guinea-pig papillary muscles without changes in resting membrane potentials. In the presence of bisaramil, trains of stimuli at rates greater than 0.1 Hz led to the use-dependent block of Vmax, which was enhanced at higher frequencies. At a concentration of 3 x 10(-6) M, the degree of use-dependent block was about 35% at 3.3 Hz, of which degree was comparable to those of 10(-4) M disopyramide and lidocaine. The development of Vmax block by bisaramil was expressed by a single exponential function in the same manner as flecainide, whereas the time courses of the block development by disopyramide and lidocaine were described by two exponentials. Recovery time constants from Vmax block were 44.1 +/- 3.4 s and 20.3 +/- 2.3 s for bisaramil and flecainide, respectively. Bisaramil at 10(-6) and 3 x 10(6) M did not change the action potential duration of guinea-pig papillary muscles and rabbit atrial muscles with a significant reduction of Vmax. No change in action potential duration can be explained by depression of both the Ca2+ and the delayed outward K+ currents by bisaramil. On the other hand, 10(-6) M bisaramil shortened action potential duration of canine Purkinje fibers at 50% and 90% of repolarization.(ABSTRACT TRUNCATED AT 250 WORDS)     

Amiodarone and desethylamiodarone concentrations in plasma and tissues of surgically treated patients on long-term oral amiodarone treatment

The tissue disposition of amiodarone and its metabolite desethylamiodarone was studied in 12 surgical patients with various types of arrhythmias after chronic oral treatment with amiodarone. Amiodarone and desethylamiodarone concentrations in plasma and tissues were determined using a simple and sensitive high performance liquid chromatographic method. The mean plasma level of amiodarone and desethylamiodarone was found to increase from 0.55 microgram/ml to 1.40 microgram/ml and 0.68 microgram/ml to 1.80 microgram/ml for the respective components following the increase of the daily oral dose from 200 mg to 600 mg of amiodarone and indicates a linear relationship between plasma concentrations and dose. The mean levels of both drugs in different parts of the heart varied for amiodarone from 15 to 48 micrograms/g and for desethylamiodarone from 48 to 71 micrograms/g, with the highest values present in the epicardially resected ventricular myocardium. The mean cardiac tissue/plasma ratios ranged for amiodarone from 12 to 35 and for desethylamiodarone from 35 to 61 and show an extensive tissue uptake in the different parts of the heart for both drugs, with the metabolite accumulation 2 to 5 times higher than the parent compound. Relatively low levels, ranging for amiodarone from 2 to 15 micrograms/g and for desethylamiodarone from 5 to 25 micrograms/g, were observed in skeletal muscle, epidermis, skin and femoral artery. By far the largest content of the drugs was found in adipose tissue with mean concentrations of 207 +/- 98 micrograms/g and 82 +/- 43 g/g respectively for the parent compound and its metabolite, which suggests that fat constitutes the main depot of the drugs.(ABSTRACT TRUNCATED AT 250 WORDS)     

SELECTIVE DEPRESSION OF MAXIMUM RATE OF DEPOLARIZATION OF GUINEA-PIG VENTRICULAR ACTION POTENTIALS BY AMIODARONE AND LIGNOCAINE IN SIMULATED ISCHAEMIA: COMPARISON WITH ENCAINIDE

1. Standard microelectrode techniques were used to record intracellular action potentials from guinea-pig ventricular myocardium superfused with either control physiological saline (pH 7.5; pO2 500 mmHg; [K+] 5.6 mmol/L) or 'simulated ischaemic' solution (pH 6.4; pO2 90 mmHg; [K+] 11.2 mmol/L). 2. The effects on action potential parameters of therapeutic concentrations of lignocaine, amiodarone and encainide were studied under both conditions. 3. Simulated ischaemia, in the absence of drugs, produced marked reductions in resting potential (-86.6 +/- 2.3 to -64.7 +/- 3.5 mV), maximum rate of depolarization (Vmax; 263 +/- 66 to 106 +/- 36 V/s) and action potential duration (164 +/- 24 to 97 +/- 26 ms). No drug produced any additional effect on resting potential. 4. All three drugs produced enhanced depression of Vmax in ischaemia compared to control conditions (class I effect). This was much more marked for lignocaine and amiodarone (inactivated channel blockers) than for encainide (open channel blocker). 5. In addition the prolongation of action potential duration seen with acute exposure to amiodarone (174 +/- 12 to 192 +/- 17 ms; class III effect) was abolished under simulated ischaemic conditions. 6. It is concluded that lignocaine and amiodarone exert greater selectivity for ischaemic tissue than does encainide and that amiodarone may function primarily as a class I agent under ischaemic conditions.     

Alterations to the electrical activity of atrial muscle isolated from the rat heart, produced by exposure in vitro to amiodarone.

Glass microelectrodes were used to record transmembrane electrical activity from cells located just beneath the endocardial surface of the left atrial free wall of rat hearts during superfusion and electrical stimulation in vitro at 37 degrees C. Availability of the fast sodium channel for current flow was inferred from the maximum rate of rise of membrane potential during phase O of the action potential (Vmax). Muscle exposed to polysorbate 80 (10 to 80 micrograms ml-1) showed a concentration-dependent lengthening of action potential duration (APD) but no detectable change in Vmax. Amiodarone (1 to 20 micrograms ml-1) was dissolved in physiological salt solution with the aid of polysorbate 80 (50 micrograms ml-1) and caused a concentration-dependent prolongation of APD and a decrease in Vmax, both of which were slow to develop and extremely slow to wash-out. The speed of onset of action of amiodarone varied with drug concentration and ranged from a few minutes with high concentrations to many hours with low concentrations.     

Effects of the new cardiotonic agent loprinone hydrochloride (E-1020) on left ventricular diameter in normal and experimental heart failure dogs and its action potential characteristics in isolated guinea pig cardiac muscles and sinus nodes]

In anesthetized dogs, loprinone hydrochloride (LP, 10 approximately 100 micrograms/kg, i.v.) dose-relatedly increased cardiac contractility (LV dP/dt max), enhanced cardiac index and decreased systemic vascular resistance with relatively small reduction in mean aortic pressure (MAP) and a mild increase in heart rate (HR). LP also decreased left ventricular internal diameter (ID), increased fractional shortening (LVFS) and caused a leftward shift and an increase in the slope of the LV end-systolic pressure-ID relation. In the heart failure models induced by propranolol, LP rapidly reversed the cardiac depression and the enlargement in cardiac size. The extent of changes in MAP and HR by LP was smaller than those observed with several other cardiotonic agents. In guinea pig cardiac muscles, LP (10(-6)-10(-4) M) produced a concentration-related increase in contractile force and the maximum rate of rise of Ca(2+)-action potential. In the sinus nodes, LP induced a concentration-related decrease in action potential duration and increase in the slope of slow diastolic depolarization, resulting in an increase in beating rate. These influences of LP on sinus nodes were smaller than those of milrinone. These results indicate that LP increases LVFS, reduces cardiac size and improves the heart failure due to its cardiotonic and vasodilating properties. Moreover, electrophysiological studies suggest that at least a part of the lower chronotropic effects of LP may be due to the mildness of its direct stimulating effects on sinus nodes.     

Electrophysiological interactions between quinidine-lidocaine and quinidine-phenytoin in guinea-pig papillary muscle

The interactions between quinidine and lidocaine or phenytoin at the sodium channel level have been studied in the present work. The maximum upstroke velocity (Vmax) of the guinea-pig papillary muscle action potential has been used as a measure of the sodium current. Lidocaine interfered with the use-dependent blocking effects on Vmax of quinidine, by decreasing the fraction of sodium channels blocked by quinidine during the conditioning action potential, in an apparently competitive way. These results strongly suggest that quinidine and lidocaine bind to a common receptor site. Alternatively, it has been suggested that lidocaine and quinidine bind to different but related receptor sites, since lidocaine may induce allosteric changes in quinidine's receptor. Phenytoin increased the use-dependent blocking effects on Vmax of quinidine by slowing the time course of the slow component of reactivation of Vmax induced by quinidine. Phenytoin did not change the fraction of sodium channels blocked by quinidine during the conditioning action potential. These results suggest that phenytoin binds to a different receptor site than quinidine.