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PubMed1988

The role of newer antiarrhythmic drugs in the management of patients with ventricular arrhythmias.

The purpose of this review is to discuss the role of mexiletine, tocainide, flecainide, and amiodarone in the treatment of patients with symptomatic ventricular ectopy or sustained ventricular tachycardia (VT) and fibrillation (VF). The pharmacologic properties, electrophysiologic effects, clinical efficacy, adverse reactions, and costs of these new agents are compared with those of procainamide, quinidine, and disopyramide. With the exception of more convenient dosing intervals, these new agents do not afford novel or advantageous pharmacologic properties. The incidences and severity of adverse reactions are similar to those reported with conventional antiarrhythmic drugs. Results of clinical studies demonstrate that these newer drugs are comparable to procainamide, quinidine, and disopyramide in suppressing ventricular ectopy. Accordingly, the choice of an antiarrhythmic agent for patients with symptomatic ventricular ectopy can be based on the side-effect profile. The propensity for developing certain adverse effects can be defined if patients are subgrouped by age and left ventricular function. The adverse effects of amiodarone preclude its use in patients manifesting only ventricular ectopy. Treatment of patients with sustained VT/VF is more complex. Mexiletine and tocainide are generally not effective. The efficacy of flecainide is similar to that of procainamide, quinidine, and disopyramide. The negative inotropic effects of flecainide and disopyramide preclude their use in patients with severe ventricular dysfunction. Amiodarone is the most effective of these drugs for preventing recurrences of sustained VT/VF. Its use should, however, be restricted to patients refractory or intolerant to other antiarrhythmic drugs.

Anti-Arrhythmia Agents↗
PubMed1986

Antiarrhythmic and hemodynamic effects of prifuroline.

The antiarrhythmic activity of 4-(2-benzofuranyl)-2-(dimethylamino)-1-pyrroline (prifuroline) has been evaluated in rats, guinea-pigs and dogs. Prifuroline dose-dependently antagonizes the arrhythmogenic action of aconitine in rats, when administered either intravenously (5, 10 or 20 mg/kg) or intraduodenally (10, 20 or 50 mg/kg); it exhibits effectiveness by the digestive route at doses only twice as greater as the active i.v. doses: its intravenous anti-aconitine activity is comparable to that of disopyramide, and superior to that of quinidine; lidocaine is inactive in this test. Prifuroline also diminishes ventricular susceptibility to electrical stimulation in open-chest rats; its effect is comparable to that of disopyramide and amiodarone at the same dose levels; quinidine and lidocaine are less effective. Only prifuroline and propranolol were able to antagonize ouabain toxicity in guinea-pigs, quinidine showing only borderline activity, and disopyramide, lidocaine and verapamil being ineffective. In a model of arrhythmias induced by anoxic stress in rats, all the tested compounds were found active, with prifuroline and disopyramide providing complete protection at high dose levels. The arrhythmias induced in dogs by coronary artery ligation were markedly antagonized by prifuroline after doses of 5 and 10 mg/kg i.v. or 30 mg/kg intraduodenally; the duration of its antiarrhythmic activity in this model of arrhythmias in conscious dogs was much longer after intraduodenal than after i.v. administration. Prifuroline was also able to restore sinus rhythm in guinea-pigs after intracardiac conduction blockade with acetylcholine, although being devoid of anticholinergic activity. It also diminishes the maximal frequency of guinea-pig atria electrically stimulated in viro (EC25 = 5 X 10(-6) g/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMed1987

Antiarrhythmic, electrophysiologic and hemodynamic effects of ACC-9358.

The antiarrhythmic, electrophysiologic and hemodynamic effects of a new antiarrhythmic agent, ACC-9358, were evaluated. In anesthetized dogs, ACC-9358 converted ouabain-induced ventricular tachycardia to normal sinus rhythm at a cumulative dose equal to encainide or flecainide and less than disopyramide. In 24-hr coronary artery ligated dogs, ACC-9358 suppressed spontaneous ventricular arrhythmias for up to 6 hr after oral or i.v. administration. The antiarrhythmic effect and plasma concentrations of ACC-9358 correlated well for both oral (r = 0.88) and i.v. (r = 0.87) administration. ACC-9358, flecainide and disopyramide were equieffective in converting crush-stimulation-induced atrial flutter in anesthetized dogs to normal sinus rhythm. In alpha-chloralose-anesthetized, closed-chest dogs, ACC-9358 slowed impulse conduction through the atria, atrioventricular node, His-Purkinje system and ventricles and prolonged atrial functional refractory period. In conscious dogs, ACC-9358 increased heart rate, reduced stroke volume and had no effect on mean arterial pressure, systemic vascular resistance or cardiac output. In alpha-chloralose-anesthetized dogs, ACC-9358-induced sinus tachycardia was unaffected by propranolol but was blocked by hexamethonium or vagotomy. In isolated cat ventricular muscle, the IC50 for the negative inotropic effect of ACC-9358 was significantly greater than flecainide or disopyramide. These results indicate that ACC-9358 is a potent, broad-spectrum, long-acting, orally and intravenously active class Ic antiarrhythmic agent that 1) may be devoid of active metabolites, 2) exerts little or no vascular effects and 3) has less direct cardiodepressant activity than flecainide or disopyramide.

Animals↗
PubMed1986

Negative inotropic effects of tetrodotoxin and seven class 1 antiarrhythmic drugs in relation to sodium channel blockade.

The negative inotropic effect and the effect on action potential configuration were investigated for TTX and 7 class 1 antiarrhythmic drugs (aprindine, AR-LH 31, CCI 22277, disopyramide, mexiletine, quinidine and sparteine) in the isolated guinea-pig papillary muscle contracting at 1 Hz. The ratio of the molar concentration producing 50% reduction of Vmax to that reducing force of contraction by 50% ranged from 0.23 (sparteine) to 2.2 (disopyramide) showing that some of the drugs were more potent Na channel blockers than negative inotropic agents, while the reverse was true for others. With the exceptions of sparteine and AR-LH 31, all the drugs produced a larger negative inotropic effect than TTX at concentrations equieffective in reducing Vmax. Thus, blockade of Na channels can account for only part of the negative inotropic effect of aprindine, CCI 22277, disopyramide, mexiletine and quinidine. Even sparteine and AR-LH 31 showed a negative inotropic property independent of Na channel blockade because, unlike TTX and like all other agents, they retained their negative inotropic activity after inactivation of Na channels by elevated extracellular K concentration (24 mmol/l). Relative negative inotropic effects of lorcainide, Org 6001 and propafenone were similar at 5.9 and 24 mmol/l (K)o. In contrast, the -log molar IC50(Fc) of flecainide, prajmalium bitartrate and tocainide was significantly decreased (by 0.35 to 0.81 log units) if Na channels were inactivated by K depolarization. Ouabain-sensitive Na,K-ATPase was not inhibited by sparteine, while mexiletine and AR-LH 31 produced partial inhibition (each at 1 mmol/l). We conclude that the negative inotropic effect of class 1 antiarrhythmic drugs represents the sum of their Na channel blocking and additional drug-dependent inotropic properties. Quinidine, aprindine and mexiletine appear to be combined Na channel and Ca channel inhibiting agents thus causing a larger negative inotropic effect than TTX. However, a superimposed positive inotropic mechanism may also be operative in some antiarrhythmic drugs (sparteine, AR-LH 31, high concentrations of mexiletine).

Action Potentials↗
PubMed1980

Hemodynamic effects of newer antiarrhythmic drugs.

The aim of antiarrhythmic drug therapy is to terminate or suppress specific arrhythmias and improve cardiovascular function. Short-term studies of the new Class I drugs encainide, mexilitine, and tocainide have demonstrated only minor falls in cardiac index with modest rises in mean aortic pressure. In contrast, disopyramide has been shown to depress myocardial function in both animals and patient studies. Heart failure may be precipitated by therapy with disopyramide and electromechanical dissociation has been reported. Class II agents with beta-adrenergic blocking actions all produce a degree of myocardial depression. Atenolol resembles propranolol in patients with coronary artery disease in its hemodyanmic effects, whereas acebutolol is less of a depressant, resembling practolol. The Class III agent amiodarone has only a mild depressant effect associated with a reduction in afterload and an increase in coronary blood flow. The Class IV agent verapamil, which is a calcium channel blocker, has potent myocardial depressant actions and causes peripheral vasodilatation. Hypotension, heart failure, and shock have been precipitated particularly in patients receiving beta-blocking drugs concurrently. While all the new antiarrhythmic drugs currently studied will cause some degree of hemodyanmic depression in an appropriately high concentration, present investigations suggest that particular caution needs to be taken when disopyramide, aprindine, atenolol, and verampamil are administered either acutely by the intravenous route or chronically by the oral route.

Acebutolol↗
PubMed1990

Comparisons of efficacy and tolerance of moricizine with other antiarrhythmic agents in the treatment of chronic ventricular arrhythmias.

Comparative trials of a new drug with standard antiarrhythmic agents are important for establishing relative efficacy and tolerance. For moricizine, such trials have included comparisons with propranolol, disopyramide and quinidine. Furthermore, the Cardiac Arrhythmia Pilot Study compared moricizine in postinfarction patients with encainide and flecainide. These trials show moricizine to be superior in efficacy to a beta blocker (propranolol) and disopyramide and equivalent to quinidine. Although the class IC drugs (encainide and flecainide) showed somewhat greater efficacy in the Cardiac Arrhythmic Pilot Study, they are now known to increase the risk of mortality in postinfarction patients. Moricizine was also shown to be well tolerated in these trials and associated with fewer discontinuations than propranolol, disopyramide and quinidine. Thus, moricizine is a promising new agent when profiled against other drugs frequently used for therapy of chronic ventricular arrhythmias.

Anilides↗
PubMed1990

Relative efficacy and safety of intravenous drugs for termination of sustained ventricular tachycardia.

The relative safety and efficacy of intravenous administration of adenosine, lignocaine, disopyramide, flecainide, and sotalol for termination of stable, induced ventricular tachycardia was assessed in serial trials. Ventricular tachycardia was terminated by pacing if it persisted 10-15 min after the end of drug administration. 24 patients with recurrent ventricular tachycardia were studied. Ventricular tachycardia was terminated by a drug in 35 of 105 trials. In 6 patients no drug terminated the arrhythmia. Adenosine did not terminate tachycardia or have any serious adverse effect in any patient; both flecainide and disopyramide were significantly more effective than lignocaine, but flecainide had significantly more severe adverse effects than lignocaine. Lignocaine was the safest drug and should continue to be used as first-line drug therapy for stable ventricular tachycardia. Disopyramide should be considered as second-line treatment. DC cardioversion is necessary for unstable ventricular tachycardia, and its availability must be ensured before attempted pharmacological intervention.

Adenosine↗
PubMed2004

Human organic cation transporter 3 mediates the transport of antiarrhythmic drugs.

Antiarrhythmic drugs have been considered to be transported by the organic cation transport system. The purpose of this study was to elucidate the molecular mechanism underlying the transport of antiarrhythmic drugs using cells from the second segment of the proximal tubule (S2) cells of mice expressing human-organic cation transporter 3 (S2 human-OCT3). The antiarrhythmic drugs tested were cibenzoline, disopyramide, lidocaine, mexiletine, phenytoin, pilsicanide, procainamide and quinidine. Human-OCT3 mediated a time- and dose-dependent uptake of quinidine and lidocaine, with Km values of 216 and 139 microM, respectively. Human-OCT3 also mediated the uptake of disopyramide and procainamide but not that of phenytoin. All antiarrhythmic drugs tested inhibited histamine uptake mediated by human-OCT3 in a dose-dependent manner. The IC50 values of antiarrhythmic drugs for human-OCT3 ranged between 0.75 and 656 microM. Kinetic analysis revealed that disopyramide, lidocaine, procainamide and quinidine inhibited histamine uptake mediated by human-OCT3 in a competitive manner. In conclusion, these results suggest that human-OCT3 mediates the transport of antiarrhythmic drugs, which may be the mechanism underlying the distribution and the elimination of these drugs.

Animals↗
PubMed2001

Cardiovascular action of a cardioselective Ca(2+)channel blocker AH-1058 in conscious dogs assessed by telemetry.

AH-1058, 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-propenyl]piperidine hydrochloride, is a novel Ca(2+)channel blocker exerting cardioselective action in isolated or anesthetized canine heart preparations. To clarify the cardiac and hemodynamic action of AH-1058 in conscious dogs, we assessed the effects of the drug on the hemodynamic parameters continuously recorded by telemetry in conscious unrestrained beagle dogs, and its cardiovascular effects were compared with those of verapamil, disopyramide and atenolol. Oral administration of AH-1058 (0.15, 0.3 and 0.6 mg/kg) reduced the systolic blood pressure and maximal upstroke velocity of the left ventricular pressure (LVdP/dt(max)), increased heart rate and prolonged the QA interval in a dose-dependent manner whereas the drug did not affect diastolic blood pressure. Verapamil at 10 mg/kg reduced systolic and diastolic blood pressure with little effect on heart rate, LVdP/dt(max) and QA interval. Disopyramide at 20 mg/kg increased systolic and diastolic blood pressure, decreased LVdP/dt(max) and prolonged the QA interval with little changes in heart rate. Atenolol at 10 mg/kg decreased LVdP/dt(max) and prolonged the QA interval with little changes in systolic blood pressure, diastolic blood pressure and heart rate. The time course of the cardiohemodynamic action of AH-1058 was longer than those of the other drugs. These results suggest that AH-1058 is a long-acting cardiodepressive drug, and its hemodynamic profile is obviously different from that of disopyramide and atenolol. This unique cardiovascular profile may be beneficial for the treatment of certain pathological processes in which selective inhibition of the ventricular Ca(2+)channels would be the target of drug therapy.

Animals↗
PubMed1998

The genetic variant A of human alpha 1-acid glycoprotein limits the blood to brain transfer of drugs it binds.

The objective of this work was to check the effects of alpha-1 acid glycoprotein (AAG) and of its components, A and F1/S genetic variants, on the brain transfer of drugs they bind in plasma. The relevant extractions of six basic drugs, highly bound to AAG, were measured. We chose three drugs selectively bound to the A variant, disopyramide, imipramine and methadone, one drug mainly bound to the mixture F1/S, mifepristone, and two drugs which were simultaneously bound to the variant A and the mixture F1/S, propranolol and chlorpromazine. Their brain extraction were investigated in rats using the carotid injection technique and the capillary depletion method. Injected drugs were dissolved either in buffer, either in native AAG containing the three variants (A, F1 and S), either in variant A or in variant F1/S solutions. Brain extractions of disopyramide, imipramine and methadone were significantly reduced by native AAG and by variant A. Drug's plasma retention was related to their preferential and almost exclusive binding to A variant, both of them exhibiting the same decrease in brain transfer as compared to a buffered solution. At the opposite, there were no significative differences between the extraction either in buffer, either in AAG or in F1/S solutions, of drugs both bound to A variant and F1/S mixture (chlorpromazine and propranolol) or to the F1/S mixture (mifepristone). In serum, the retentional effect of the A variant on the extraction of disopyramide and imipramine was counteracted by the presence of albumin and lipoproteins, which simultaneously bind these two drugs at a high extent and act as permissive binders. We conclude that AAG binding decreases brain drug transfer when the A variant is mainly and almost exclusively involved in the binding. On the contrary, the entire fraction of the tested drugs when bound exclusively or partly to the mixture F1/S is available for transfer into the brain.

Animals↗
PubMed1983

Concordance and discordance of drug responses in atrioventricular reentrant tachycardia.

Whether the results of some drug studies could be used to predict the results of other drug studies was examined during serial electrophysiologic drug testing in patients with sustained atrioventricular reentrant tachycardia. The drugs studied were intravenous propranolol, 0.1 mg/kg; intravenous ouabain, 0.01 mg/kg; the combination of propranolol plus ouabain; intravenous procainamide, 0.75 to 1.5 g; oral quinidine, 1.2 to 2.4 g/day; and oral disopyramide, 0.8 to 1.6 g/day. Response was inability to induce sustained tachycardia after administration of a drug. Responses due to increased anterograde limb refractoriness. Six of 10 patients with response to propranolol plus ouabain versus 0 of 9 patients without response to this combination had response to propranolol alone (p less than 0.01). Seven of 14 patients with response to the combination versus 0 of 9 patients without response to the combination had response to ouabain alone (p less than 0.05). Responses due to increased retrograde limb refractoriness. Eight of 9 patients with response to procainamide versus 2 of 17 patients without response to this drug had response to quinidine (p less than 0.01). There was not a significant relation between response to procainamide and response to disopyramide, or between response to quinidine and response to disopyramide. Anterograde limb versus retrograde limb. There was not a significant relation between response to propranolol plus ouabain and response to any class I drug. In conclusion, there are relations between drug responses during electrophysiologic studies in patients with atrioventricular reentrant tachycardia. Thus, it should be possible to simplify these studies.

Adolescent↗
PubMed1997

Ischaemia-induced loss or reversal of the effects of the class I antiarrhythmic drugs on vulnerability to fibrillation.

1. In the last decade, a number of clinical observations have questioned the efficacy of certain class I antiarrhythmic drugs against ischaemia-induced ventricular fibrillation. The effects of three drugs of this class, disopyramide (Ia), lignocaine (Ib) and flecainide (Ic) on the vulnerability to fibrillation during experimental ischaemia were investigated. 2. The study was carried out in anaesthetized, open-chest pigs (n = 8 for each of the drugs, in addition to the control group, n = 6). Vulnerability to fibrillation was evaluated by measuring electrical fibrillation threshold (EFT) by means of stepwise increased intensity of wide (100 ms) diastolic impulses applied to the ischaemic tissue at a 180 beats min-1 rate. Monophasic action potential (MAP) duration and conduction time in the ischaemic region were also measured. 3. EFT determinations were performed before and during periods of ischaemia induced by complete occlusion of the left anterior descending coronary artery near its origin. Ischaemic periods of increasing duration (30, 60, 90, 120, 150 s) were induced to determine the electrophysiological changes, of EFT especially, leading to fibrillation. 4. In the absence of ischaemia, all three drugs, administered by intravenous route (1 mg kg-1 plus 0.04 mg kg-1 min-1) increased EFT to a similar extent (from approximately 7 to 10 mA), despite a 25% prolongation of conduction time. 5. During ischaemia, none of the drugs prevented the fall in EFT towards 0 mA, resulting in spontaneous fibrillation. After 30 s of ischaemia, they no longer had any capacity for raising EFT and, after 60, 90 and 120 s of ischaemia, the decrease in EFT was exacerbated. This accelerated reduction in EFT shortened the time to onset of fibrillation (after 120 s of ischaemia, 62.5% of fibrillations with flecainide instead of 12.5 under control conditions, 75% instead of 25 with lignocaine and 50% instead of 25 with disopyramide). The reduction in MAP duration due to ischaemia was also significantly accelerated (at 60 s, 178 +/- 5 ms instead of 192 +/- 4 with flecainide, 175 +/- 3 ms instead of 194 +/- 5 with lignocaine and 180 +/- 5 ms instead of 196 +/- 3 with disopyramide) and the slowing of conduction was made worse (prolongation of conduction time by 70% instead of 50). 6. In conclusion, the antifibrillatory properties normally manifested by these drugs are first suppressed, then inverted by ischaemia, depending on oxygen debt varying with severity and duration of ischaemia.

Animals↗
PubMed2000

Effect of sodium channel blockers on ST segment, QRS duration, and corrected QT interval in patients with Brugada syndrome.

INTRODUCTION: Brugada syndrome is characterized by an ST segment elevation in leads V1-V3 and a high incidence of ventricular fibrillation (VF). A mutation in a cardiac Na+ channel gene, SCN5A, has been linked to Brugada syndrome, and sodium channel blockers have been shown to be effective in unmasking the syndrome when concealed. The aim of this study was to examine the effects of Na+ channel blockers on ST segment elevation, QRS, corrected QT (QTc) interval, and ventricular arrhythmias in patients with Brugada syndrome. METHODS AND RESULTS: We examined the effects of three different Na+ channel blockers (flecainide, disopyramide, and mexiletine) on the amplitude of the ST segment 20 msec after the end of QRS (ST20), QRS duration, QTc interval measured from 12-lead ECG, and ventricular arrhythmias in 12 Brugada and 10 control patients. Maximum ST20 observed in the V2 or V3 leads under baseline conditions was greater in the Brugada patients than in control patients, whereas QRS duration and maximum QTc interval were no different between the two groups. Flecainide and disopyramide, but not mexiletine, significantly increased maximum ST20 and QRS duration in both groups, although these effects were much more pronounced in the Brugada patients. The increases in ST20 and QRS duration with flecainide were significantly larger than those with disopyramide. An increase of 0.15 mV in ST20 with flecainide separated the two groups without overlap. Ventricular premature complexes developed only with flecainide in Brugada patients (3/12) displaying a marked ST elevation but not widening of QRS. CONCLUSION: Our findings suggest that Na+ channel blockers amplify existing I(Na) and possibly other ion channel defects, with a potency inversely proportional to the rate of dissociation of the drug from the Na+ channel, thus causing a prominent elevation of the ST segment and, in some cases, prolongation of QRS duration in patients with Brugada syndrome.

Adult↗
PubMed1990

Combined application of class I antiarrhythmic drugs causes "additive", "reductive", or "synergistic" sodium channel block in cardiac muscles.

STUDY OBJECTIVE: The aim was to study the differences in cardiac sodium channel block among combinations of class I antiarrhythmic drugs. DESIGN: Conventional glass microelectrode techniques were used to record transmembrane action potentials and their maximum upstroke velocity (dV/dtmax) reflecting the sodium channel availability, during treatment of the preparations with mexiletine (20, 40 microM) in combination with aprindine (5 microM), disopyramide (40 microM), and flecainide (5 microM). EXPERIMENTAL MATERIAL: Guinea pig papillary muscles (n = 6.8 per experiment) were used for the study. MEASUREMENTS AND MAIN RESULTS: In preparations constantly stimulated at 1 Hz, a shortening of action potential duration by aprindine was further enhanced, while prolongation by disopyramide or flecainide was reduced, after additional application of mexiletine. Trains of stimuli (0.5-2.0 Hz) were applied following a long quiescent period to evaluate "tonic" and "use dependent" decrease (block) of dV/dtmax. Additional application of mexiletine to the other three drugs resulted in an enhancement of tonic block. Use dependent block by aprindine at 0.5-1.0 Hz was reduced by 8-9% after admixture of mexiletine, reflected in net increase in dV/dtmax at steady states (reductive effect). Dual exponential components of dV/dtmax recovery from use dependent block in presence of both drugs suggest their competitive interaction on a common receptor site associated with sodium channels. Use dependent block by flecainide at 0.5-2.0 Hz was increased (p less than 0.01) after admixture of mexiletine. Steady state dV/dtmax was therefore largely inhibited by the drug combination (synergistic effect). Use dependent block in the presence of both disopyramide and mexiletine was similar to that predicted from the algebraic sum of each treatment. CONCLUSION: Combined application of class I antiarrhythmic drugs causes not only additive but also reductive or synergistic effects on dV/dtmax through modulation of use dependent block.

Action Potentials↗
PubMed1992

Blockade of 2,4-dinitrophenol induced ATP sensitive potassium current in guinea pig ventricular myocytes by class I antiarrhythmic drugs.

OBJECTIVE: The aim was to assess the effects of various antiarrhythmic drugs on 2,4-dinitrophenol (DNP) induced outward current (IDNP), presumably the ATP sensitive K+ current (IK,ATP) of isolated cardiac cells and to discuss mechanisms involved in the hypoglycaemia which occurs in patients on these drugs. METHODS: The quasi-steady state current-voltage relationship from the isolated guinea pig ventricular cells was measured using whole cell voltage clamp techniques with a ramp pulse programme. The effects of seven different antiarrhythmic drugs on IDNP were examined. Action potentials were elicited at a rate of 0.2 Hz by an intracellular current injection. RESULTS: DNP (50 mumol.litre-1) increased the quasi-steady state outward current at potentials positive to about -60 mV. This current (IDNP) was completely inhibited by the subsequent application of glibenclamide (1 mumol.litre-1), thereby suggesting that the IDNP is probably IK,ATP. Cibenzoline (10 mumol.litre-1, class Ia), disopyramide (30 mumol.litre-1, class Ia), and procainamide (100 mumol.litre-1, class Ia) significantly inhibited the IDNP by 95.5(SD 11.3)%, 77.8(21.2)%, and 76.4(23.9)% respectively. Flecainide (class 1c) inhibited the IDNP by 66.9(23.9)% at 10 mumol.litre-1 but not at 2 mumol.litre-1. Mexiletine (30 mumol.litre-1, class Ib), pilsicainide (50 mumol.litre-1, class Ic), and E4031 (10 mumol.litre-1, class III) at concentrations as high as approximately fivefold the clinically effective blood levels, did not suppress IDNP. Except for 10 mumol.litre-1 flecainide, all the concentrations listed above which blocked IDNP were within twofold of the clinical blood concentrations documented to be effective for suppression of arrhythmias. Cibenzoline, disopyramide, and procainamide, but not flecainide, belong to class Ia antiarrhythmic drugs. All these class Ia antiarrhythmic drugs "shortened" the action potential duration of guinea pig ventricular cells, an opposite change to that noted for multicellular preparations, eg, guinea pig papillary muscles. CONCLUSIONS: Class Ia antiarrhythmic drugs (cibenzoline, disopyramide, and procainamide) inhibit IDNP (presumably IK,ATP) in guinea pig ventricular cells within a range of therapeutic concentrations. This inhibitory effect of IK,ATP can probably explain the hypoglycaemia which occurs in some patients receiving these drugs, and the prolongation of the action potential duration alleged to occur in "superfused" papillary muscles.

2,4-Dinitrophenol↗
PubMed2002

Attenuation of aortic banding-induced cardiac hypertrophy by propranolol is independent of beta-adrenoceptor blockade.

OBJECTIVE: Racemic propranolol attenuates cardiac hypertrophy secondary to abdominal aortic banding-induced pressure overload by a mechanism independent of its effect on cardiac work load. This was only observed, however, using doses of propranolol that were much higher than those needed to induce beta-adrenoceptor blockade. Thus, the question remains as to whether the antihypertrophic effect of propranolol depends on its ability to antagonize cardiac beta-adrenoceptor-mediated action (positive chronotropic effect, trophic effect) or on beta-adrenoceptor-independent action. METHODS: In a rat model of chronic pressure overload induced by abdominal aortic banding, we evaluated the effects on left ventricular hypertrophy (LVH) of the propranolol isomers, L-propranolol and D-propranolol, which compared to L-isomer is approximately 50-fold less potent as a beta-adrenoceptor antagonist, but is similarly potent as a membrane-stabilizer, as well as of timolol, a non-selective beta-adrenergic antagonist devoid of membrane stabilizing activity, and disopyramide, which is a membrane stabilizer, but not a beta-adrenoceptor blocker. RESULTS: Compared to sham-operated rats, banded rats had 30% greater left ventricular to body weight (LVW/BW) ratio (P < 0.01). The increase in LVW/BW ratio was significantly attenuated by treatment with 40 and 80 (but not 10) mg/kg per day of L-propranolol. Left ventricular hypertrophy was also prevented by D-propranolol, 40 and 80 mg/kg per day, and disopyramide, 50 mg/kg per day, whereas timolol, 30 and 60 mg/kg per day, showed no antihypertrophic effect. In separate groups of banded rats in which the reduction in heart rate induced by propranolol (80 mg/kg per day) was prevented by chronic cardiac pacing at 375 b.p.m., hypertrophy was again prevented, indicating that the effects of L-propranolol on LVH are not related to a reduction in cardiac work load. CONCLUSIONS: In the aortic banding-induced model of LVH: (i) the antihypertrophic effect of propranolol is independent of its beta-adrenergic blocking activity; and Iii) since disopyramide and D-propranolol also proved to be able to antagonize banding-induced LVH, the hypothesis is proposed that membrane-stabilizing activity, among the ancillary properties of propranolol, most likely accounts for the antihypertrophic effect of this drug.

Adrenergic beta-Antagonists↗
PubMed1994

Shock-induced refractory period extension and pharmacologic modulation of defibrillation threshold.

Shock-induced refractory period extension (RPE) has been suggested as a mechanism of electrical defibrillation. We measured RPE caused by localized field stimulation measured before and during infusion of disopyramide (n = 5), flecainide (n = 5), or E-4031 (n = 5) in anesthetized dogs and determined the effect of the drugs on the internal defibrillation threshold (DFT). In the baseline state (n = 15), 16 V/cm S2 field stimulation prolonged the effective RP by 36 +/- 15 ms (22 +/- 12% of RP without S2), whereas 4 and 8 V/cm S2 stimuli did not cause marked RPE. The RPE normalized by the RP without S2 was not significantly influenced by any drug (16 V/cm: disopyramide 30 +/- 11 vs. 27 +/- 11, flecainide 25 +/- 5 vs. 19 +/- 12, and E-4031 18 +/- 13 vs. 22 +/- 14%). Disopyramide did not alter the defibrillation threshold (4.2 +/- 0.6-4.4 +/- 0.6 J). In 2 dogs given flecainide, ventricular fibrillation became refractory to defibrillation. In contrast, E-4031 lowered the threshold from 4.5 +/- 2.4 to 2.2 +/- 1.2 J (p < 0.01). The results suggest that flecainide and E-4031 do not modulate defibrillation efficiency through their effects on RPE.

Animals↗
PubMed1994

Effects of E-4031 on atrial fibrillation threshold in guinea pig atria: comparative study with class I antiarrhythmic drugs.

The effects of E-4031, a new class III antiarrhythmic agent, on atrial fibrillation threshold (AFT), atrial effective refractory period (ERP), and interatrial conduction time (ACT) were investigated in Langendorff-perfused guinea pig hearts; the results were then compared with those of the class I agents disopyramide, procainamide, lidocaine, and flecainide. Whole guinea pig hearts were perfused with Tyrode's solution containing acetylcholine (ACh 3 x 10(-7) M). The three indexes were measured before and after administration of the test drugs, using right atrial extrastimulus and 50-Hz continuous stimulation. Disopyramide, procainamide, and flecainide (> or = 10(-6) M) significantly increased AFT. Although E-4031 (> or = 3 x 10(-6) M) also increased AFT, this effect was less potent than that observed with the other drugs. E-4031 (> or = 10(-6) M) significantly prolonged ERP, and this prolongation was less pronounced than that observed with disopyramide but similar to that observed with procainamide or flecainide. E-4031 did not affect ACT, and the greatest prolongation of ACT was observed with flecainide. Lidocaine had no effect on any of the indexes. These findings suggest that in guinea pig hearts E-4031 exerts an antifibrillatory effect by prolonging atrial ERP alone, but this effect is less pronounced than that observed with class I drugs, because AFT measured by 50-Hz continuous stimulation is influenced by both ERP and ACT.

Acetylcholine↗