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PubMed1999

Human atrial repolarization: effects of sinus rate, pacing and drugs on the surface electrocardiogram.

OBJECTIVES: We studied the effects of rate and some cardioactive drugs on the atrial surface electrocardiogram (ECG). BACKGROUND: In atrioventricular block, atrial surface ECG is unmasked. The effect of rate alone permits detection of the effect of other exogenous stimulations such as drugs in the presence of rate alterations. METHODS: High fidelity, high gain ECG leads I, II and III were recorded from 51 patients with heart block. Durations of P and Ta waves and the total PTa interval were measured from nonconducted atrial events. RESULTS: No relationship was found between sinus cycle length and PTa, P or Ta in 31 patients. In 20 patients, progressively decreasing the atrial pacing cycle length from 853 ms to 381 ms resulted in a linear reduction of the PTa interval from 444 to 291 ms (rho = 0.76, slope = 0.24). This was largely due to shortening of Ta. A linear rate correction formula was derived: corrected PTa = PTa - 0.24 (PP - 1000). Atropine (0.02 mg/kg) shortened the PP interval (p < 0.001) and the PTa interval (p < 0.01). Propranolol (0.1 mg/kg) prolonged the PP interval (p < 0.001) but did not alter the PTa interval. Neither disopyramide (2.0 mg/kg) nor flecainide acetate (2.0 mg/kg) altered the PP interval, but both prolonged the PTa interval (p < 0.001). This was largely due to P wave lengthening after flecainide (p < 0.001) and to Ta prolongation after disopyramide (p < 0.001). CONCLUSIONS: In heart block, PTa, P and Ta waves can be measured reliably. The effects of pacing and some antiarrhythmic drugs on the atrial myocardium are similar to those known at the ventricular level.

Adult↗
PubMed1999

Transverse conduction capabilities of the crista terminalis in patients with atrial flutter and atrial fibrillation.

OBJECTIVES: In this study, the transverse conduction capabilities of the crista terminalis (CT) were determined during pacing in sinus rhythm in patients with atrial flutter and atrial fibrillation. BACKGROUND: It has been demonstrated that the CT is a barrier to transverse conduction during typical atrial flutter. Mapping studies in animal models provide evidence that this is functional. The influence of transverse conduction capabilities of the CT on the development of atrial flutter remains unclear. METHODS: The CT was identified by intracardiac echocardiography. The atrial activation at the CT was determined during programmed stimulation with one extrastimulus at five pacing sites anteriorly to the CT in 10 patients with atrial flutter and 10 patients with atrial fibrillation before and after intravenous administration of 2 mg/kg disopyramide. Subsequently, atrial arrhythmias were reinduced. RESULTS: At baseline, pacing with longer coupling intervals resulted in a transverse pulse propagation across the CT. During shorter coupling intervals, split electrograms and a marked alteration of the activation sequence of its second component were found, indicating a functional conduction block. In patients with atrial flutter, the longest coupling interval that resulted in a complete transverse conduction block at the CT was significantly longer than that in patients with atrial fibrillation (285 +/- 49 ms vs. 221 +/- 28 ms; p < 0.05). After disopyramide administration, a transverse conduction block occurred at longer coupling intervals as compared with baseline (287 +/- 68 ms vs. 250 +/- 52 ms; p < 0.05). Subsequently, a sustained atrial arrhythmia was inducible in 15 of 20 patients. This was atrial flutter in three patients with previously documented atrial fibrillation and in eight patients with history of atrial flutter. Mapping revealed a conduction block at the CT in all of these patients. CONCLUSIONS: It was found that the CT provides transverse conduction capabilities and that the conduction block during atrial flutter is functional. Limited transverse conduction capabilities of the CT seem to contribute to the development of atrial flutter.

Aged↗
PubMed1979

Antiarrhythmic activity of some N-alkylbispidinebenzamides.

A series of aromatic ring substituted bispidinebenzamides, 2--10, was prepared by condensation of N-methyl- or N-n-butylbispidine with the appropriate acid chlorides. These compounds were initially evaluated in mice for acute toxicity and for their ability to protect against chloroform-induced ventricular fibrillation. All compounds had significant activity, which was optimized in 2, 3, and 5. These last compounds had potencies and LD50/ED50 ratios comparable to those of a standard antiarrhythmic, disopyramide. However, their potencies in increasing the effective refactory period in isolated rabbit atria were considerably less than that of disopyramide.

Animals↗
PubMed1990

Differences in plasma binding of drugs between Caucasians and Chinese subjects.

Interracial differences in drug responsiveness can be accounted for, at least in part, by differences in drug disposition. To investigate whether reversible interactions with plasma constituents may be a contributing factor in such differences, the binding of a number of model drugs was studied in plasma obtained from healthy Caucasian and Chinese subjects (n = 8 in each group). The unbound fractions of drugs binding to sites I and II on albumin (warfarin, diazepam, and salicylic acid) were similar in the two groups, and there was no difference in the plasma albumin concentration. By contrast, the percentages of unbound diphenhydramine (26.40% +/- 6.46% versus 18.30% +/- 4.31, mean +/- SD) and propranolol (13.81% +/- 1.33% versus 11.68% +/- 2.37) were significantly (p less than 0.05) higher in Chinese subjects compared to Caucasians. A 30% difference was also observed in the nonlinear binding of disopyramide. These basic drugs interact with both alpha 1-acid glycoprotein and albumin, and the lower binding was associated with a lower plasma concentration of the acute-phase reactant in Chinese subjects. Kinetic analysis of the disopyramide binding isotherm was also suggestive of reduced binding capacity with no change in binding affinity. The reason for the racial difference in the alpha 1-acid glycoprotein level is unknown; however, for drugs extensively bound to this glycoprotein the resulting difference in unbound fraction would be expected to have predictable pharmacokinetic consequences that may result in differences in responsiveness. Determination of plasma binding, especially of drugs interacting with alpha 1-acid glycoprotein, should therefore be an essential component of comparative studies in subjects of different races.

Asian People↗
PubMed1982

[The effect of anti-arrhythmic drugs on myocardial function (author's transl)].

In a randomized study the influence of anti-arrhythmic drugs on left ventricular myocardial function was tested. Propafenon, mexiletine, tocainide, disopyramide or placebo were given over seven days on top of basic treatment with digitalis, diuretics and nitrates. Propafenon, mexiletine, tocainide and disopyramide had negative inotropic effects of 16, 17, 19 to maximally 30%, respectively. Echocardiography was especially suitable for serial assessment of left ventricular failure. Propafenon, mexiletine and tocainide are the anti-arrhythmic drugs of choice in the treatment of cardiac arrhythmias. However, the at times marked decrease in contractility must be taken into account when the decision is made whether a given arrhythmia requires treatment or not.

Adult↗
PubMed1993

Comparison of cardiac pacing with drug therapy in the treatment of neurocardiogenic (vasovagal) syncope with bradycardia or asystole.

BACKGROUND: The efficacy of permanent cardiac pacing in patients with neurocardiogenic (or vasovagal) syncope associated with bradycardia or asystole is not clear. We compared the efficacy of cardiac pacing with that of oral drug therapy in the prevention of hypotension and syncope during head-up tilt testing. METHODS: Among 70 patients with a history of syncope in whom hypotension and syncope could be provoked during head-up tilt testing, 22 had bradycardia (a heart rate < 60 beats per minute, with a decline in the rate by at least 20 beats per minute) or asystole along with hypotension during testing. There were 9 men and 13 women, with a mean (+/- SD) age of 41 +/- 17 years. Head-up tilt testing was repeated during atrioventricular sequential pacing (in 20 patients with sinus rhythm) or ventricular pacing (in 2 patients with atrial fibrillation). Regardless of the results obtained during artificial pacing, all the patients subsequently had upright-tilt testing repeated during therapy with oral metoprolol, theophylline, or disopyramide. RESULTS: During the initial tilt test, 6 patients had asystole and 16 had bradycardia along with hypotension. Despite artificial pacing, the mean arterial pressure during head-up tilt testing still fell significantly, from 97 +/- 19 to 57 +/- 19 mm Hg (P < 0.001); 5 patients had syncope, and 15 had presyncope. By contrast, 19 patients who later received only medical therapy (metoprolol in 10, theophylline in 3, and disopyramide in 6), 2 patients who received both metoprolol and atrioventricular sequential pacing, and 1 patient who received only atrioventricular sequential pacing had negative head-up tilt tests. After a median follow-up of 16 months, 18 of the 19 patients who were treated with drugs alone (94 percent) remained free of recurrent syncope or presyncope, whereas the patient treated only with permanent dual-chamber pacemaker had recurrent syncope. CONCLUSIONS: In patients with neurocardiogenic syncope associated with bradycardia or asystole, drug therapy is often effective in preventing syncope, whereas artificial pacing is not.

Adolescent↗
PubMed1992

Combined class I antiarrhythmic agents have differential effects on tonic and use dependent block of maximum rate of depolarisation of action potentials in guinea pig cardiac muscle.

OBJECTIVE: The aim was to study the difference between tonic and use dependent block of the cardiac sodium channel produced by the combined application of the same subclass of antiarrhythmic agents (class Ia or Ib). METHODS: Conventional glass microelectrode technique was used to record the maximum rate of depolarisation (dV/dtmax) of action potentials reflecting sodium channel availability, before and after the combined application of quinidine plus disopyramide, aprindine plus lignocaine, aprindine plus mexiletine, and lignocaine plus mexiletine. Guinea pig papillary muscles (n = 4-8 per experiment) were used for the study. RESULTS: All combinations increased tonic block additively compared to use of a single drug. On the other hand, use dependent block was increased by the combination of quinidine 10 microM plus disopyramide 30 microM compared to a single drug, and was not changed by lignocaine 50 microM plus mexiletine 20 microM, whereas it was decreased by aprindine 3 microM plus lignocaine 50 microM or mexiletine 20 microM. When concentrations of mexiletine and lignocaine were increased, both tonic and use dependent block in a single drug were increased dose dependently, whereas the combination produced an additive increase in tonic block but no change in use dependent block compared to a single drug. CONCLUSIONS: The results suggested that the binding and unbinding process of the drug to produce tonic block was different from that to produce use dependent block, and that combination of different drugs produced diverse effects on use dependent block even though state dependent affinity of individual drugs seemed similar. These two factors must be born in mind in evaluating the combination therapy.

Action Potentials↗
PubMed1988

Randomized controlled trial of prophylactic antiarrhythmic therapy in patients with inducible ventricular tachyarrhythmias after recent myocardial infarction.

Survivors of acute myocardial infarction who had inducible sustained ventricular tachyarrhythmias at programmed stimulation 1-4 weeks after infarction were recruited to a randomized pilot trial of Class I antiarrhythmic drugs, in an attempt to determine whether their mortality and risk of spontaneous ventricular tachycardia and fibrillation could be reduced by treatment. Of 136 eligible patients, 96 (71%) joined the trial and 47 were randomized to 'no treatment' and 49 were randomized to 'treatment' (quinidine, disopyramide or mexiletine given to attain 'therapeutic' serum levels). During follow-up, the two groups fared similarly. For the 'treatment' and 'no treatment' groups, the respective 3-year probabilities of remaining incident-free were:cardiac death, 0.91 vs 0.89; instantaneous death + non-fatal ventricular tachyarrhythmias, 0.87 vs 0.87; cardiac death + non-fatal ventricular tachyarrhythmias, 0.83 vs 0.85. The highest risk patients with inducible ventricular tachycardia fared similarly in the 'treatment' and 'no treatment' groups. The respective probabilities of remaining incident-free were: cardiac death, 0.89 vs 0.88; instantaneous death + non-fatal ventricular tachyarrhythmias, 0.79 vs 0.84; cardiac death + non-fatal ventricular tachyarrhythmias, 0.76 vs 0.77. We conclude that prophylactic Class I antiarrhythmic drug therapy with quinidine, disopyramide or mexiletine given to achieve a 'therapeutic' serum level does not appear to alter the prognosis of patients with inducible ventricular tachyarrhythmias after myocardial infarction.

Actuarial Analysis↗
PubMedDate not supplied

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.

Action Potentials↗
PubMed1995

Prolongation of intraventricular conduction time associated with fatal [correction of fetal] impairment of defibrillation efficiency during treatment with class I antiarrhythmic agents.

To test whether fatal deterioration of defibrillation efficiency during antiarrhythmic therapy can be prevented by avoiding extreme decrease in ventricular prevented by avoiding extreme decrease in ventricular conduction or toxic plasma drug levels, we determined the defibrillation threshold (DFT) before and during infusion of incremental doses of disopyramide (n = 8), mexiletine (n = 9), or flecainide (n = 9) in anesthetized dogs. Disopyramide did not alter DFT [from 4.4 +/- 1.5 to 4.4 +/- 1.6 J (3.1 +/- 1.2 micrograms/ml)]. Mexiletine tended to increase DFT [from 4.6 +/- 1.2 to 6.1 +/- 2.0 J (1.8 +/- 0.6 micrograms/ml); p < 0.05], and defibrillation eventually was unsuccessful in 3 of the 9 dogs. Although the plasma mexiletine level before refractory fibrillation was far beyond the human therapeutic range, prolongation of intraventricular conduction time (CT) was moderate (16 +/- 3%). Flecainide increased DFT from 4.2 +/- 1.3 to 6.1 +/- 1.5 J at a plasma level of 1.04 +/- 0.37 micrograms/ml (p < 0.0005). In 3 of 5 dogs that developed refractory fibrillation, plasma flecainide level before terminal ventricular fibrillation (VF) was not toxic, but prolongation of CT in the 5 dogs was remarkable (30 +/- 9%). Thus, VF resistant to defibrillation is not necessarily associated with both toxic plasma drug level and remarkably decreased conduction. Reliability of these valuables as indicators of fatally deteriorated defibrillation efficiency may vary among antiarrhythmic agents.

Analysis of Variance↗
PubMed1995

Kinetics of frequency-dependent conduction delay by class I antiarrhythmic drugs in human atrium.

We investigated use-dependent prolongation of interatrial conduction time (IACT) by class I antiarrhythmic drugs in 16 patients. Changes in IACT at the initiation of atrial pacing were used to evaluate the onset kinetics. We examined recovery kinetics by giving a single extra stimulus with a varying coupling interval after discontinuing train stimulation. Time constants of the onset kinetics were 1.52 +/- 0.15/n(fast) and 0.087 +/- 0.031/n(slow) for mexiletine, 0.075 +/- 0.015/n for aprindine, 0.078 +/- 0.019/n for disopyramide, and 0.050 +/- 0.006/n for pilsicainide. The recovery time constants were 203 +/- 66 ms for mexiletine, 1,021 +/- 162 ms for aprindine, 993 +/- 101 ms for disopyramide, and 2,930 +/- 569 ms for pilsicainide. Class I antiarrhythmic drugs produced use-dependent IACT prolongation in humans, with characteristic kinetics for each agent similar to that of depression of the maximum upstroke velocity of cardiac action potential (Vmax) reported in in vitro studies.

Anti-Arrhythmia Agents↗
PubMed1995

Is the ECG measure RSh a promising technique for detecting class I antiarrhythmic drug action in men?

Previous animal experiments suggest that the increase in the amplitude from the R-wave to the S-wave (RSh) may be more sensitive than other ECG measures to sodium channel blocking drug actions. We measured RSh of three orthogonal leads at baseline and during intravenous pharmacologic stimulation with adenosine, ajmaline, atropine, disopyramide, isoproterenol, lidocaine, norepinephrine (NE), propranolol, and verapamil in an observer-blinded placebo-controlled study in healthy young men. The short-term reproducibility of RSh was high. Ajmaline increased RSh in the anteroposterior lead, disopyramide in the anteroposterior and vertical lead, and lidocaine in the vertical and horizontal lead, respectively. Isoproterenol increased RSh in the anteroposterior lead; atropine decreased RSh in the vertical lead. The other drugs did not affect RSh significantly. Our data do not support the concept that RSh measure is a more sensitive technique for assessing class I antiarrhythmic drug action in humans, at least in healthy subjects. In addition, our results indicate that changes in autonomic tone may influence RSh measurements.

Adenosine↗
PubMed1991

Cytochrome P-450 isozyme pattern is related to individual susceptibility to diethylnitrosamine-induced liver cancer in rats.

Differences in susceptibility to chemical carcinogenesis between rodent strains and species have been linked to variations in genetically-determined mixed function oxidase activities. In order to verify whether such variations also determine the susceptibility of individual animals of the same strain to a chemical carcinogen, outbred male Wistar rats were administered diethylnitrosamine (DEN) (1, 2, or 3 mg/kg) five times a week for 20 weeks. The relationship was examined between the outcome (i.e., presence or absence of liver tumors, and latency period) and the hepatic activities of mixed function oxidases and conjugating enzymes, as well as of O6-methylguanine-DNA-methyltransferase, measured before the carcinogen treatment. In addition, the metabolic profiles of two model drugs, antipyrine and disopyramide, in the urine were analyzed and correlated with the carcinogen susceptibility. The length of the latency period of hepatocellular tumors in individual rats was negatively related to the activities of hepatic dimethylnitrosamine N-demethylase, aryl hydrocarbon hydroxylase and epoxide hydrolase and positively related to the amount of microsomal protein. Consistent relationships between the other 10 measured parameters and the susceptibility to DEN-induced carcinogenesis were not detected. Long-term treatment with DEN slightly decreased the proportion of metabolism of antipyrine into norantipyrine, and increased the share of 4-hydroxyantipyrine; a decrease in the metabolism of disopyramide to N-deisopropyldisopyramide was also detected. It is concluded that the pattern of cytochrome P-450 isoenzymes is related to differences in individual susceptibility to nitrosamine-induced carcinogenesis. The relationship was most marked at low dose levels, which are the levels at which nitrosamine exposures of humans are known to occur.

7-Alkoxycoumarin O-Dealkylase↗
PubMedDate not supplied

Frequency-independent blockade of cardiac Na+ channels by riluzole: comparison with established anticonvulsants and class I anti-arrhythmics.

The Na+ channel blocking activity and the antiarrhythmic effects of riluzole, and established anticonvulsants (lamotrigine and lifarizine) and class I antiarrhythmics (lidocaine, flecainide and disopyramide) were studied under in vitro and in vivo conditions. Guinea-pig cardiac Purkinje fibres were superfused with Tyrode solution and electrically driven for recording action potentials with intracellular microelectrodes. In these preparations paced at 1 Hz, all compounds tested produced concentration-dependent (0.3-100 microM) reductions in the maximum rate of depolarization of the action potential (Vmax). For riluzole, phenytoin and carbamazepine this effect was frequency-independent (0.5-6 Hz) but for lamotrigine, lifarizine, lidocaine, flecainide and disopyramide it was frequency-dependent. In anaesthetized rats, riluzole, in contrast to flecainide, did not delay the appearance of aconitine-induced arrhythmias. Riluzole (0.3-3.9 mg/kg, i.v.) also lacked notable cardiac electrophysiological effects in anaesthetized dogs. At an i.v. dose of 3.0 mg/kg riluzole failed to restore a normal sinus rhythm in conscious dogs with polymorphic arrhythmias produced by ligation of the left anterior descending coronary artery 24 h earlier. These results indicate that riluzole, phenytoin and carbamazepine, unlike lamotrigine, lifarizine and flecainide, block cardiac Na+ channels in a frequency-independent manner. This property may account for the lack of antiarrhythmic activity of riluzole, phenytoin and carbamazepine in animal models of arrhythmias that respond to class I antiarrhythmic drugs. It may also account for the clinical observation that riluzole does not seem to cause the unfavourable electrocardiographic changes characteristic of drugs that block cardiac Na+ channels in a frequency-dependent manner.

Aconitine↗
PubMed1992

Induction of TU abnormalities in patients with torsades de pointes.

1. TU abnormalities could be induced by the specific interventions in the majority of the patients with TDP in chronic stage: isoproterenol in congenital long QT patients, disopyramide in Ia-related TDP patients, and slow heart rate in bradycardia-related TDP patients. 2. Humps in MAP could be recorded in all patients with congenital long QT syndrome by isoproterenol, in half of the patients with Ia-related TDP by disopyramide, but in none of the control patients by these agents. 3. The results suggested that TU abnormalities and the occurrence of hump in MAP were hypersensitive reactions. 4. The results also suggested that specific intervention was not enough for the appearance of marked TU abnormalities in some TDP patients, especially in Ia-related TDP patients. Additional aggravating factors were probably required for marked TU abnormalities and the occurrence of TDP in these patients.

Action Potentials↗
PubMed1996

Drug-induced narrowing of the width of the zone of entrainment as a predictor of the subsequent non-inducibility of reentrant ventricular tachycardia after an additional dose of an antiarrhythmic drug.

BACKGROUND: The efficacy of drugs used to treat inducible monomorphic sustained ventricular tachycardia (VT) has been assessed by investigating their ability to suppress inducibility, but the mechanism of the drug action remains to be determined. OBJECTIVES: To determine electrophysiological variables that predict inducibility, divided doses of class I antiarrhythmic drugs were given and their effects were analysed, particularly the ability of the final dose to suppress inducibility. METHODS: The excitable gap was estimated by the zone of entrainment, which was defined as the difference between the cycle length of VT and the longest paced cycle length that interrupted VT during entrainment of VT with rapid pacing at paced cycle lengths in decrements of 10 ms. The cycle length of VT, the block cycle length, and the zone of entrainment were measured in the drug free state and after intermediate and final doses of procainamide, disopyramide, cibenzoline, and mexiletine. RESULTS: Sustained monomorphic VT with a mean (SD) cycle length of 285 (43) ms was induced in 8 patients. It was entrained and interrupted at the block cycle length of 231 (31) ms. The width of the zone of entrainment was 54 (23) ms. In 8 studies VT was not inducible at final doses of procainamide in 4, cibenzoline in 1, and mexiletine in 3. In another 10 studies (procainamide in 4, disopyramide in 1, cibenzoline in 2, and mexiletine in 3), VT remained inducible at the intermediate dose and at the final dose. The cycle length of VT was prolonged to a similar degree in studies of effective and ineffective drugs, but the cycle length that blocked VT was longer at the intermediate dose of the effective drugs. Consequently, the width of the zone of entrainment was significantly narrowed at the intermediate dose of effective drugs and the width of the zone of entrainment was narrower than when ineffective drugs were given (22 (13) ms v 76 (18) or 75 (37) ms at the intermediate and final doses respectively (P < 0.02). CONCLUSION: Drugs that narrowed the zone of entrainment were associated with non-inducibility of VT after the final dose of the drug was given. The baseline variables did not predict the responses to class I antiarrhythmic drugs.

Adult↗
PubMed2002

Effects of HNS-32, a novel antiarrhythmic agent, on guinea-pig myocardium.

The electrophysiological and mechanical effects of HNS-32, a novel azulene-1-carboxamidine derivative with antiarrhythmic activity, were studied in isolated guinea-pig myocardial preparations. HNS-32 (10(-6)-10(-4) mol/l) concentration-dependently decreased the maximum rate of rise (V(max)) of action potential in isolated papillary muscle; the potency was the same or slightly higher than that of disopyramide. At 10(-4) mol/l, HNS-32 also shortened the action potential duration (APD) and depolarized the resting membrane potential; these effects were similar to those of 10(-5) mol/l verapamil. HNS-32 (10(-7)-10(-4) mol/l), as well as verapamil (10(-8)-10(-5) mol/l) and disopyramide (10(-6)-10(-3) mol/l), had concentration-dependent negative chronotropic and negative inotropic effects on isolated right atrial and right ventricular papillary muscle preparations, respectively. The concentration-response relationship for the positive chronotropic effect of isoproterenol was not affected by HNS-32 (10(-5) mol/l). In isolated ventricular myocytes, HNS-32 (10(-6)-10(-4) mol/l) concentration-dependently inhibited the peak amplitude of the L-type Ca(2+) current. These results suggest that NHS-32 has V(max) reducing activity on myocardial tissue, which may be responsible for antiarrhythmic effect. The drug may also have additional effect on the Ca(2+) channel at higher concentrations.

Action Potentials↗
PubMed1978

Recurrent sustained ventricular tachycardia 3. Role of the electrophysiologic study in selection of antiarrhythmic regimens.

Twenty patients with recurrent sustained ventricular tachycardia (VT) underwent serial electrophysiological studies (EPS) 1) to determine the predictive value of the EPS in the selection of antiarrhythmic therapy, and 2) to establish the therapeutic efficacy of available antiarrhythmic agents. In each patient VT could be reproducibly initiated by programmed stimulation. After control EPS, the effects of several drugs (lidocaine, procainamide, quinidine, disopyramide and diphenylhydantoin) on the ability to initiate VT were assessed. An oral regimen was chosen on the basis of acute EPS and its effectiveness was evaluated by repeat EPS in 24--72 hours. Blood levels achieved acutely were used as guidelines to chronic therapy. In 14 patients the initiation of VT was prevented by the acute administration of one or more agents. In 13 of these patients, a chronic oral regimen based on these results prevented recurrence of VT with a three- to 27-month follow-up. In the remaining patient, oral therapy could not achieve blood levels of procainamide shown to be effective intravenously, and VT recurred. In six patients no single drug or drug combination was effective during acute EPS, and VT recurred in all while on therapy with the agent shown to make initiation of VT most difficult. Procainamide prevented VT in nine patients; quinidine in three patients; lidocaine in three patients; diphenylhydantoin in two patients; and disopyramide in one patient. The mean duration of EPS studies was 4.5 days. This study suggests that serial EPS provides rapid identification of successful antiarrhythmic therapy and can predict in which patients conventional therapy would be ineffective, thereby identifying patients requiring more aggressive modes of therapy.

Administration, Oral↗