Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Disopyramide”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,117 records · Page 62Linked to original sources
PubMed1998

Inhibition of delayed rectifier K+ current by dofetilide and E-4031 differentially affects electrical cardiac responses to vagus stimulation in anesthetized dogs.

Vagal activation influences various cardiac functions as well as occurrence of arrhythmias. Inhibition of a rapid type of delayed rectifier K+ current (I[Kr]) has been reported to be effective for the treatment of both ventricular and supraventricular arrhythmias. However, it is unknown how I[Kr] inhibition modulates the cardiac responses to vagal activation in situ. We analyzed the effects of I[Kr] inhibitors, dofetilide and E-4031, and a class I antiarrhythmic agent, disopyramide, on electrical cardiac responses to vagus stimulation in anesthetized dogs. Dofetilide (0.003-0.3 micromol/kg, i.v.), E-4031 (0.01-1 micromol/kg, i.v.) and disopyramide (2.9-29 micromol/kg, i.v.) prolonged sinus cycle length (SCL), right atrial effective refractory period (AERP) and ventricular effective refractory period (VERP) dose-dependently. During cervical vagus stimulation-induced prolongation of SCL, atrio-His (AH) interval and VERP and shortening of AERP, dofetilide and E-4031 inhibited the prolongation of SCL but potentiated the shortening of AERP. Dofetilide and E-4031 did not affect prolongations of AH interval and VERP. On the other hand, disopyramide inhibited all electrical cardiac responses to vagus stimulation. These results suggest that I(Kr) inhibition differentially modulate cardiac responses to vagus activation probably due to a different role of I(Kr) in each cardiac function in the heart in situ.

Animals↗
PubMed1982

Evaluation of EMIT adapted to the (Cobas) Bio centrifugal analyzer.

EMIT assays for the determination of phenytoin, methotrexate, disopyramide, digoxin and thyroxine were adapted to the Cobas Bio centrifugal analyzer and compared with the corresponding laboratory routine procedures. Evaluation of the data from the Cobas Bio by 5 different mathematical models showed that the four-parameter logit model correlated best with the comparison procedures and the originally recommended calculation model for the reagent lots used in our study. The precision of the EMIT phenytoin, methotrexate and disopyramide assays was in most cases very good (between-days coefficient) of variation 1.6-7.5%). A lower precision was observed with the EMIT digoxin assay (between-days coefficients of variation 9.2-16.8%) and at low concentrations also with the EMIT thyroxine assay (3.1-21.4%). Calibration curves of the EMIT phenytoin, methotrexate assays were stable for at least one hour. The results from the determination of phenytoin, methotrexate and disopyramide in patient samples by use of the Cobas Bio were in good agreement with those values obtained with the EMIT/LAB. The data determined with the EMIT digoxin assay adapted to the Cobas Bio correlated better with those of a radioimmunoassay than the values measured with the EMIT/LAB system. The results of thyroxin determinations with EMIT by use of the Cobas Bio and the original procedure with an ABA-100 were in good agreement and on average about 12% lower than those measured by radioimmunoassay. The Cobas Bio allows rapid determination with EMIT and a reduction in direct costs of up to 85%.

Centrifugation↗
PubMed1985

A comparative study of sinoatrial conduction time with therapeutic doses of antiarrhythmic agents in isolated cross-perfused canine atria.

The effects of therapeutic doses of antiarrhythmic drugs (12 mg/Kg of procainamide, 2 mg/Kg of disopyramide and 0.2 mg/Kg of propranolol) on sinus cycle length (SCL), sinoatrial conduction time (SACT) estimated by a constant atrial pacing technique, and atrial developed tension (DT) were measured in isolated canine atria cross-perfused with heparinized arterial blood from donor dogs as well as on mean systemic blood pressure (SBP) and on heart rate (HR) in those dogs. Procainamide, which produced hypotension and bradycardia in the donor dog, did not change SACT significantly, although it increased SCL and decreased DT in the isolated atrium. However, disopyramide raising SBP slightly (but not significantly) and decreasing HR in the donor dog produced a significant prolongation of SACT and SCL and reduction of DT in the isolated atrium. Propranolol caused slight but insignificant hypotension and long-lasting bradycardia in the donor dog, accompanied by a significant increase in SCL and SACT, and decrease in DT in the isolated canine atrium. We concluded that SACT was significantly increased by a therapeutic dose of propranolol and disopyramide but was not altered by that of procainamide.

Animals↗
PubMed1999

Direct effects of class I antiarrhythmic drugs on epicardial electrograms in dogs.

The effects of class I antiarrhythmic drugs on epicardial electrograms during regular atrial pacing were investigated in anesthetized, open-chest dogs. Lidocaine, flecainide or disopyramide was infused selectively into the distal site of the left-anterior descending artery. Lidocaine produced a dose-dependent elevation of ST segment without changing the amplitude of R wave. Flecainide produced a dose-dependent increase of R-wave amplitude accompanied by the augmentation of negative T. The ST segment was elevated at the high dose. The QRST area did not change at the low dose but significantly increased at the high dose, indicating that the ST-T change at the low dose was secondary to changes in ventricular depolarization. The effects of disopyramide on R wave and ST segment were between those of lidocaine and flecainide. The major action of lidocaine was the acceleration of ventricular repolarization while that of flecainide was the deceleration of ventricular conduction. Disopyramide had an action that was intermediate between the two drugs.

Animals↗
PubMed1991

Binding of alfentanil to human alpha 1-acid glycoprotein, albumin and serum.

The variability of the serum binding of the short-acting narcotic analgesic alfentanil was studied. Binding of alfentanil was measured in human alpha 1-acid glycoprotein (AAG) and human albumin solutions, and in serum from 6 groups of individuals: control subjects, patients with renal failure, cirrhosis, rheumatoid arthritis and myocardial infarction, and intensive care patients. Alfentanil is mainly bound to AAG and the influence of a change of the AAG concentration on its binding is much more marked than that of a change of the albumin concentration. In patients with renal failure, myocardial infarction and rheumatoid arthritis and in intensive care patients, AAG concentrations are increased, but alfentanil binding is significantly increased only in patients with myocardial infarction. In patients with cirrhosis, AAG, albumin concentrations, and alfentanil binding are decreased. In vitro addition of lidocaine, disopyramide, bupivacaine and quinidine, in concentrations that are observed clinically, lead only with disopyramide to an important increase in free fraction of alfentanil (from 7 to 19%). This latter finding was confirmed in 2 volunteers, treated chronically with disopyramide.

Adult↗
PubMed1989

Circulatory and myocardial effects of different sodium antagonistic drugs in comparison to the calcium antagonist verapamil.

The hemodynamic effects of intravenous class I and class IV antiarrhythmic drugs were investigated at different doses in comparison. In open-chest rats hemodynamic measurements in the intact circulation and isovolumic registrations 5 min after infusion of flecainide (2, 4, 8 mg/kg), disopyramide (1, 2, 4, 8 mg/kg), quinidine (5 and 10 mg/kg) and verapamil (0.35, 0.7, 1.5 mg/kg) were compared to saline controls. After clinically usual doses all investigated drugs had no effects on stroke volume, cardiac output, dp/dtmax and systemic resistance. The isovolumic pressure generating capacity of the left ventricle was not decreased at these doses. High intravenous doses of the drugs, however, caused a significant depression of myocardial performance (pressure generating capacity). Furthermore, flecainide decreased mean aortic pressure and heart rate, while disopyramide had no significant effect on the peripheral circulation. Blocking of the autonomic system (1 mg/kg propranolol and 0.1 mg/kg atropine) did not change significantly the action of disopyramide. Quinidine lowered heart rate and pressures. Verapamil reduced the heart rate and tended to decrease the mean aortic pressure. Besides the negative inotropic action of high doses the different hemodynamic profiles of class I and class IV antiarrhythmic drugs might be of importance for intravenous application in patients with left ventricular dysfunction.

Animals↗
PubMed1987

Assessment of drug effects on spontaneous and induced ventricular arrhythmias in a 24-h canine infarction model.

The antiarrhythmic efficacy of encainide, sotalol, flecainide and disopyramide was evaluated in anesthetized dogs subjected to 2-stage total occlusion of the left anterior descending coronary artery. Utilization of this canine model, while anesthetized, permitted the assessment of drug effects not only on uni- and/or multi-focal ectopic ventricular arrhythmias, but also on dysrhythmias associated with aberrant conduction or reentrant excitation pathways. The former was assessed by quantification of ectopic-to-total beat ratios while the later was determined by subjecting the animal to provocative stimuli which produced repetitive ventricular responses. At the cumulative i.v. doses studied, encainide (0.5-4 mg/kg), flecainide (1-8 mg/kg) and disopyramide (0.3-10 mg/kg), but not sotalol (2-8 mg/kg), effectively suppressed ventricular ectopic activity in a dose-related manner. In contrast, sotalol was highly effective in preventing the induction of reentrant ventricular tachyarrhythmias. Disopyramide was only modestly active, while flecainide and encainide had the least favorable profiles of effect in suppressing re-entry arrhythmias in this model. Based on these observations, the anesthetized Harris dog appears to represent a useful two-faceted in vivo model for use in the evaluation of potential antiarrhythmic agents.

Anilides↗
PubMedDate not supplied

Effects of the novel class Ia and class III antiarrhythmic agent RS-87337 on myocardial conduction in the anaesthetised dog.

The effects of the novel Class Ia/III antiarrhythmic compound RS-87337 on canine myocardial conduction were compared with those of the Class I antiarrhythmic disopyramide. RS-87337 had no effects on intra-atrial (I-A) or intra-ventricular (I-V) conduction parameters up to 10 mg.kg-1 i.v. (n = 6). Only one incidence of atrioventricular (A-V) block occurred at 10 mg.kg-1 at a pacing frequency of 261 beat.min-1. Disopyramide (5-10 mg.kg-1 i.v., n = 6) produced a frequency-dependent I-A conduction block and also significantly increased resting and paced A-V conduction times. Overall, disopyramide exhibited atrioselectivity while RS-87337 appeared more selective for ventricular conduction, possibly produced by a balance of its mixed Class Ia/III properties. RS-87337 was not cardiodepressant in the normal canine myocardium and produced no adverse effects on conduction parameters at doses up to 10 mg.kg-1 i.v.

Animals↗
PubMed1978

[The effect of some antiarrhythmic drugs on systolic time intervals in normal subjects (author's transl)].

Eleven healthy volunteers (mean age 30.1 +/- 4.3 yrs.) were repeatedly studied by measurement of systolic time intervals (QS2c, PEPc, LVETc, PEP/LVET) and arterial blood pressure (cuff method) before and after 24-hour oral application of four antiarrhythmic drugs (quinidine, disopyramide, prajmaliumbitartrate, propafenone) and two beta-blocking agents (propranolol, atenolol). The studies were repeated in the same group of volunteers with a different drug after an interval of one week. PEPc significantly increased after all antiarrhythmic agents at therapeutic doses by 6.1 to 9.4 ms (p less than 0.05 and p less than 0.01 resp.), whereas LVETc did not change significantly. PEP/LVET increased on an average by 0.033 +/- 0.006 (p less than 0.01). QS2c increased by 7.5 and 7.6 ms resp. (p less than 0.05) after prajmaliumbitartrate and propafenone. Heart rate remained unchanged after disopyramide and propafenone whereas it increased significantly (p less than 0.05) after quinidine and prajmaliumbitartrate. Blood pressure did not change significantly after any of these antiarrhythmic drugs. After application of the two beta-blocking agents propranolol and atenolol, no significant changes in STI could be observed. Mean arterial blood pressure significantly dropped after both, propranolol (minus 2.8 mm Hg) and atenolol (minus 9.7 mm Hg; p less than 0.05 and p less than 0.01, resp.). Heart rate decreased by minus 8.1 b.p.m. after propranolol (p less than 0.01) and minus 11.5 b.p.m. after atenolol (p less than 0.01). The results clearly indicate that at the dosage used, the four antiarrhythmic agents (quinidine, disopyramide, prajmaliumbitartrate, propafenone) exert a negative inotropic effect on left ventricular function as far as it can be judged from the measurement of STI. The lack of a significant negative inotropic effect of an oral treatment with beta-blocking agents on the STI can be explained by opposing effects of a decrease in blood pressure and a negative inotropic action.

Adult↗
PubMed1984

Effect of gastric pH on antidotal efficacy of activated charcoal in man.

Environmental pH is important for the adsorption capacity of activated charcoal: in our experiments the unadsorbed fractions of aspirin and disopyramide were increased by 10-20-fold as the pH was altered from 1.2 to 7.0 or vice versa. In order to study the effect of pH in vivo, six subjects were given 500 mg aspirin, 200 mg disopyramide and 200 mg tolfenamic acid on an empty stomach with 20 ml of 8.5% magnesium hydroxide or without it. A small dose of charcoal, 2.5 g, administered immediately after the drugs, reduced the absorption of aspirin by 30-40%, whereas the absorption of disopyramide and tolfenamic acid was reduced by 70-80%. The inhibition of absorption was irrespective of whether the drugs were taken with the antacid or without it. Thus, in vivo other factors than the gastric pH must be more important in controlling the adsorption to activated charcoal. Accordingly, the simultaneous administration of antacids cannot be recommended to enhance the adsorptive capacity of charcoal in humans.

Absorption↗
PubMed1996

Effects of the new class I antiarrhythmic agent Ro 22-9194, (2R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propionamide D-tartrate, on ischemia- and reperfusion-induced arrhythmias in dogs: involvement of thromboxane A2 synthase inhibitory activity.

We investigated the effects of (2R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propionamide D-tartrate (Ro 22-9194), a novel class I antiarrhythmic agent, on myocardial ischemia- and reperfusion-induced arrhythmias in dogs. The incidence of ventricular fibrillation induced by reperfusion after a 30-min coronary ligation was significantly reduced by an i.v. infusion of Ro 22-9194 (10 mg/kg for 5 min before and an additional 20 mg/kg for 30 min during coronary ligation: total, 30 mg/kg) from 73% in the vehicle-treated group to 13%. Ro 22-9194 (20 and 30 mg/kg) also dose-dependently reduced the incidence of ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, after coronary reperfusion. Other class I antiarrhythmic agents, mexiletine (15 mg/kg) and disopyramide (7.5 mg/kg), did not inhibit the development of ventricular fibrillation. In in vitro studies, Ro 22-9194, but neither mexiletine nor disopyramide (approximately 10(-3) M), inhibited thromboxane A2 synthase and arachidonic acid-induced aggregation of human platelets (IC50: 1.2 x 10(-5) M and 3.4 x 10(-5) M, respectively). Furthermore, Ro 22-9194 (30 mg/kg) attenuated the increase in venous thromboxane B2 concentrations in the local coronary vein during coronary ligation in dogs. A thromboxane A2 synthase inhibitor, OKY-046 (2.5 mg/kg administered for 5 min before coronary ligation) also showed no evident increases in thromboxane B2 concentrations as well as an antifibrillatory effect. Venous 6-keto-prostaglandin F1 alpha concentrations were not affected by either Ro 22-9194 or OKY-046. These results demonstrate that, unlike mexiletine and disopyramide, Ro 22-9194 protects against reperfusion-induced fatal ventricular arrhythmias in dogs. They also suggest that, in addition to the class I antiarrhythmic effect, the thromboxane A2 synthase inhibitory activity may contribute to the antiarrhythmic properties of Ro 22-9194.

6-Ketoprostaglandin F1 alpha↗
PubMed1997

Mechanisms of the atrium-specific positive inotropic activities of quinidine- and atropine-like agents in rats.

This study investigated the mechanism of the positive inotropic effects of class 1 antiarrhythmic agents using electrically stimulated right atria (sinoatrial node excised), left atria and right ventricles of rats. Quinidine, disopyramide and procainamide produced concentration-dependent positive inotropic effects on right and left atria; effects on the right atria were greater than on left atria. At concentration producing positive inotropic effects on atria, the contractions of right ventricles were slightly increased by quinidine, unaffected by disopyramide and decreased by procainamide. The positive inotropic effects of quinidine were inhibited by propranolol, reserpine and mecamylamine but not by cocaine, hexamethonium and d-tubocurarine; propranolol also antagonized the positive inotropic effects of disopyramide and procainamide. Bupivacaine, which like quinidine blocks transient outward potassium current, slightly increased the contractions of right atria but not of left atria and ventricles. The atrium-specific positive inotropic effects of quinidine were mimicked by atropine, pirenzepine and dimethylphenylpiperazinium but not by nicotine, cytisine and butyrylcholine; the effects of atropine, dimethylphenylpiperazinium and pirenzepine were also blocked by propranolol. Quinidine increased the release of norepinephrine from atria but not from the ventricles; this release was greater from the right than from the left atria. It is concluded that quinidine- and atropine-like agents exert atrium-specific positive inotropic effects by blocking muscarinic receptors and permitting a dominance of acetylcholine effects via a release of norepinephrine from sympathetic nerve terminals.

Animals↗
PubMed2003

Effects of orthostatic self-training on head-up tilt testing for the prevention of tilt-induced neurocardiogenic syncope: comparison of pharmacological therapy.

Although a wide variety of medical treatments for neurocardiogenic syncope have been proposed, therapy has largely been emperic based on the mechanisms commonly believed to lead to neurocardiogenic fainting. To determine the utility and efficacy of drug therapy and an orthostatic self-training program in the prevention of tilt-induced neurocardiogenic syncope, we investigated 43 consecutive patients who had shown syncope and were induced by head-up tilt test reproducibly, with either traditional medical treatments or orthostatic self-training at home. The initial 19 of 43 patients were treated with either oral propranolol or disopyramide therapies. The remaining 24 patients were treated with an orthostatic self-training program alone. Effects of these therapies on head-up tilt test were reevaluated in all patients. Propranolol prevented syncope in only six (32%) and disopyramide in five (26%) of the 19 patients. There was no significant difference in the effectiveness between them. Syncope was prevented in nine (47%) patients with either propanolol or disopyramide therapy alone, while in the remaining 10 patients it was not. On the other hand, orthostatic self-training program prevented syncope in 22 (92%) of 24 patients. We concluded that orthostatic self-training program is far more effective than traditional drug therapies. Orthostatic self-training is an effective, safe and well accepted therapy in the prevention of tilt-induced neurocardiogenic syncope.

Adult↗
PubMed1980

Antidysrhythmic and electrophysiological effects of a new antianginal agent, bepridil.

The antidysrhythmic effects of a new antianginal agent, bepridil, were compared with those of disopyramide, a known antidysrhythmic drug. Bepridil (20, 50, and 100 mg/kg, i.p.) conferred little protection against aconitine-induced dysrhythmias in mice, whereas similar doses of disopyramide exerted a marked dose-dependent antidysrhythmic effect. Intravenous administration of either bepridil (2 mg/kg) or disopyramide (10 mg/kg) significantly reduced the number of ventricular extrasystoles and completely abolished the occurrence of ventricular fibrillation following coronary artery ligation in the rat. Local anesthetic and electrophysiological effects in vitro of bepridil were also investigated. A marked but slowly developing reduction in action potential height of desheathed frog sciatic nerves was observed at concentrations of 0.01-0.05 mM. In sheep Purkinje fibres, a similar decrease in action potential height, associated with a pronounced reduction in the maximum rate of depolarization of phase zero of the action potential (MRD) was seen with bepridil (0.5-2 X 10(-5) M). Higher concentrations (2-8 X 10(-5) M) were required to reduce MRD of guinea pig ventricular muscle. The antidysrhythmic actions of bepridil may at least in part be explained by the electrophysiological effects observed.

Aconitine↗
PubMedDate not supplied

Effects of antiarrhythmic drugs on AV nodal and intraventricular conduction as assessed in the isolated, blood-perfused AV node preparation of the dog.

The effects of seven antiarrhythmic drugs on atrioventricular (AV) nodal and intraventricular (His-Purkinje-ventricular muscle) conduction were investigated in the isolated, blood-perfused AV node preparation of the dog. When injected into the posterior septal artery (PSA), which supplies mainly the AV node, quinidine, ajmaline, disopyramide, lidocaine, mexiletine, phenytoin, and procainamide increased AV nodal conduction time; and in high doses, these drugs produced second- or third-degree AV conduction block. However, quinidine, ajmaline, disopyramide, and lidocaine had less propensity to induce second- or third-degree AV conduction block than did phenytoin, mexiletine, and procainamide. When injected into the anterior septal artery (ASA), which supplies the His-Purkinje-ventricular muscle, all seven drugs prolonged intraventricular conduction time. The relative suppressant effects of these drugs on AV nodal and intraventricular conduction varied. Quinidine, disopyramide, and ajmaline suppressed AV nodal conduction as much as intraventricular conduction. Lidocaine and mexiletine suppressed AV nodal conduction more than intraventricular conduction, and phenytoin suppressed AV nodal conduction much more than intraventricular conduction. In contrast, procainamide suppressed intraventricular conduction rather than AV nodal conduction. All drugs increased blood flow in the ASA and the PSA.

Animals↗
PubMedDate not supplied

Electrophysiological and cardiovascular effects of pirmenol, a new class 1 antiarrhythmic drug.

Pirmenol, a new antiarrhythmic agent, has been studied in the pithed rat and in the sinoatrial (SA) node, atrium, atrioventricular (AV) node, Purkinje cells, and ventricular muscle of the isolated rabbit heart. It resembles disopyramide chemically and in its electrophysiologic effects. Pirmenol decreased the maximum rate of depolarization (MRD) and overshoot potential in isolated rabbit atrium, Purkinje cells, and ventricle. Pirmenol caused bradycardia in pithed rats and isolated rabbit SA nodes. In the latter, repolarization was delayed, but there was little change in MRD or in the slope of the slow diastolic depolarization. Like disopyramide, but unlike lidocaine, pirmenol lengthened APD in all cardiac tissues studied. The above effects were dose-related and were reversed on washout. Pirmenol did not lengthen conduction time within the AV node. Unlike disopyramide, pirmenol had no negative inotropic action, and did not alter the relation between contractile force and extracellular calcium concentration. This suggests, as does the absence of effect on sinoatrial MRD or AV conduction, that pirmenol does not block calcium channels.

Action Potentials↗
PubMed1993

Comparative study on the proarrhythmic effects of some antiarrhythmic agents.

BACKGROUND: A main side effect of antiarrhythmic drug therapy is the tendency of these drugs to promote arrhythmia within the therapeutic concentration range, i.e., the proarrhythmic activity of these drugs. However, a model for in vitro assessment, quantification, and comparison of proarrhythmic drug activities was still lacking, and only sparse data were available. METHODS AND RESULTS: To analyze the arrhythmogenic risk of common antiarrhythmic drugs in a quantitative and comparative manner, isolated perfused rabbit hearts were treated with increasing concentrations of antiarrhythmic drugs corresponding to low, medium, and high therapeutic concentrations. For analysis of the epicardial activation process, an epicardial mapping (256 unipolar leads) was performed. For each electrode, the activation time was determined. From these data, the origins of epicardial activation ("breakthrough points" [BTP]) were determined. At each electrode, an activation vector (VEC) was calculated giving direction and velocity of the local excitation wave. The beat similarity of various heartbeats (under treatment) compared with control was evaluated by determination of the percentage of identical BTPs (deviation < or = 1 mm) and of similar VECs (deviation < or = 5 degrees). BTP and VEC were reduced by all antiarrhythmic agents tested (propafenone = flecainide > quinidine > ajmaline > procainamide > disopyramide > mexiletine = lidocaine > sotalol), indicating a more or less pronounced disturbance of the epicardial activation process. Treatment with propafenone, quinidine, and disopyramide and to a lesser extent sotalol prolonged the activation-recovery interval (ARI). ARI dispersion was greatly enhanced by flecainide and was reduced by sotalol. In addition, it could be shown that propranolol is able to reduce the proarrhythmic action of flecainide. This effect seemed to be due to a reduction of the flecainide-induced increase in ARI dispersion. CONCLUSIONS: From the results of our study, we propose the following rank order of the arrhythmogenic risk: flecainide > propafenone > quinidine > ajmaline > disopyramide > procainamide > mexiletine, lidocaine > sotalol. Moreover, we conclude that propranolol given additionally may be helpful in reducing the proarrhythmic risk of flecainide.

Animals↗
PubMed1996

Relative role of alkalosis and sodium ions in reversal of class I antiarrhythmic drug-induced sodium channel blockade by sodium bicarbonate.

BACKGROUND: Hypertonic sodium salts are used to treat sodium channel-blocking drug cardiotoxicity. The relative roles of alkalinization and increased sodium concentration ([Na+]o) for various drugs are incompletely known. METHODS AND RESULTS: The effects of four class I drugs on action potential characteristics of canine Purkinje fibers at equieffective concentrations (disopyramide 30 mumol/L, mexiletine 80 mumol/L, flecainide 7 mumol/L, imipramine 5 mumol/L) were studied in the presence of normal Tyrode solution and one altered solution (increased [Na+]o, increased bicarbonate concentration, or both) in each experiment. Combined increases in sodium and bicarbonate concentration significantly reduced the depressant effects of flecainide, imipramine, and mexiletine on phase 0 upstroke (Vmax) but did not alter the effects of disopyramide. The effects of sodium bicarbonate were entirely due to alkalinization in the case of imipramine, but both alkalinization and increased [Na+]o contributed to the interaction with flecainide and mexiletine. The reversal of Vmax depression by increased [Na+]o and pH was due in part to hyperpolarization. In addition, alkalosis directly reversed the hyperpolarizing shift in Vmax inactivation caused by flecainide and imipramine without altering the shift caused by disopyramide and mexiletine. CONCLUSIONS: Increases in sodium bicarbonate concentration reverse the effects of class I antiarrhythmic drugs to a varying extent, with drug-specific contributions of the sodium and bicarbonate moiety. The molecular basis for this drug specificity remains to be elucidated, but it has important potential implications for the use of hypertonic sodium salts to treat cardiotoxicity caused by sodium channel-blocking drugs.

Alkalosis↗