acetylstrophanthidin and Arrhythmias--Cardiac

To detect delayed after depolarizations (DAD) in extracellular electrograms using signal averaging technique.. DAD were induced by acetylstrophanthidin (0.25 mumol.L-1, n = 9) and resibufogenin (0.52 mumol.L-1, n = 5) in sheep cardiac Purkinje fibers. Intracellular voltage was recorded with a conventional microelectrode, and simultaneous extracellular electrograms were recorded differentially from widely spaced electrodes placed in the tissue bath. Noise of electrograms was reduced using signal averaging technique.. Acetylstrophanthidin and resibufogenin both induced DAD in the intracellular recording and extracellular DAD (DAD-E) in the extracellular electrogram in sheep heart Purkinje fibers. Acetylstrophanthidin and resibufogenin induced typical changes in the action potential including decrease in action potential amplitude, resting potential, maximum diastolic potential, and action potential duration. Similar shortening occurred in the "Q-T interval" recorded by the extracellular electrogram. With either acetylstrophanthidin or resibufogenin, shortening of stimulation cycle length from 990 ms to 690 ms reduced the coupling interval between action potential upstroke and peak voltage of the DAD (P < 0.01), and the coupling interval between the "QRS" and DAD-E recorded extracellularly (P < 0.01).. DAD can be detected using the extracellular electrograms combined with the high resolution, signal averaging technique.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Bufanolides; Cardiotonic Agents; Electrophysiology; In Vitro Techniques; Purkinje Fibers; Sheep; Signal Processing, Computer-Assisted; Strophanthidin

The purpose of this study was to compare the electrotoxicological effects of resibufogenin (RBG) (n = 14) with acetylstrophanthidin (AS) (n = 14) to induce delayed afterdepolarization (DAD) and triggered activity (TA), and their alteration of the electrophysiological properties in sheep cardiac Purkinje fibers using the extracellular electrograms, signal averaging, and standard microelectrode techniques simultaneously. The results indicated: 1) Lower toxic dose of RBG (0.52 mumol.L-1) and AS (0.25 mumol.L-1) induced intracellular and extracellular DAD (DAD-I and DAD-E) at pacing cycle length of 990 and 690 ms. 2) Higher toxic dose of RBG (2.6 mumol.L-1) and AS (5.0 mumol.L-1) induced DAD and TA, nonsustained or sustained premature action potential and oscillatory potentials; 3) At the beginning period of superfusing the drugs, both RBG and AS caused changes of the electrophysiological characteristics. This study demonstrates that the electro-toxicological characteristics and electrophysiological properties of RBG are similar to that of AS and suggests that RBG belongs to the family of digitalis-like drugs.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Bufanolides; Cardiotonic Agents; Electrophysiology; In Vitro Techniques; Membrane Potentials; Purkinje Fibers; Sheep; Strophanthidin

Twenty-eight anesthetized mongrel dogs were studied 2 to 74 months after experimental myocardial infarction in order to examine the effects of procainamide, lidocaine and acetylstrophanthidin on conduction within the infarcted region and the way such effects relate to changes in body surface potentials and antiarrhythmic efficacy. In each animal, 100 to 200 QRS complexes in the X, Y, Z leads were signal averaged, vector summed and high pass filtered at 50 Hz. Susceptibility to ventricular arrhythmia was evaluated using routine programmed ventricular extrastimulation in the anesthetized open chest animal. Epicardial electrograms were sequentially recorded at 45 standard sites within the infarcted region and referenced to the beginning of the QRS complex. Of the three agents, only procainamide exhibited antiarrhythmic action whereas lidocaine and acetylstrophanthidin produced inconsistent effects. Procainamide prolonged the time at which activity in the epicardial electrographic recordings ended relative to the beginning of the body surface QRS complex. This effect was significantly greater in electrograms that ended late in the QRS complex in the control state than for those that ended earlier. Such preferential effect on more abnormal sites was reflected on the body surface as a greater effect of procainamide in prolonging the lower energy terminal portion of the signal-averaged QRS complex than the earlier high energy portion. In contrast, lidocaine significantly prolonged the time at which electrograms ended only for those relatively normal electrograms that ended early in the QRS complex in the control state. In the signal-averaged body surface QRS complex, lidocaine produced a small but significant prolongation of the early high energy portion of the QRS complex but no change in the late portion. Acetylstrophanthidin produced a significant prolongation in early-ending electrograms and, surprisingly, significantly shortened the end time of electrograms that ended late in the QRS complex in the control state. Such effects were not reflected, however, on the body surface because acetylstrophanthidin had no significant effect on either the early or the late portion of the QRS complex. It is concluded that procainamide's differential effect between early- and late-ending electrograms is detected on the body surface by a greater prolongation in the terminal portion of the QRS complex. The signal-averaged body surface QRS complex is less sensitive in detecti

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chronic Disease; Dogs; Electrocardiography; Electrophysiology; Heart Conduction System; Lidocaine; Myocardial Infarction; Pericardium; Procainamide; Skin; Strophanthidin

Antiarrhythmic drugs frequently cause extracardiac side effects that limit their use. If intracoronary delivery of a lower dose of drug to an electrically unstable focus can control arrhythmias, systemic adverse effects of these agents might be avoided. We investigated whether intracoronary lidocaine can suppress ventricular arrhythmia induced by acetylstrophanthidin, a rapidly acting digitalislike agent. We isolated and then cannulated either the left anterior descending or the left circumflex coronary artery in 12 pentobarbital-anesthetized dogs. Sustained ventricular tachycardia that persisted for 11.4 +/- 8.6 minutes was reliably induced by the intracoronary infusion. In all of 24 trials, an intracoronary lidocaine bolus at 2% of the usual systemic dose (0.77 mg/30 sec) abolished digitalis-induced ventricular tachycardia for an average of 2.0 +/- 1.8 minutes. This effect was not observed after a saline bolus. We conclude that an intracoronary bolus of low-dose lidocaine can suppress acetylstrophanthidin-induced ventricular arrhythmia.

Topics: Animals; Arrhythmias, Cardiac; Dogs; Female; Infusions, Intravenous; Lidocaine; Male; Strophanthidin

Chronic treatment of dogs with digoxin alone, quinidine alone and digoxin in combination with quinidine was initiated in dogs to assess changes in arrhythmogenic potential associated with the quinidine-induced increase in serum digoxin concentration observed during combined digoxin and quinidine treatment. The arrhythmogenic potential of digoxin was evaluated through the use of the acetylstrophanthidin (AcS) tolerance test. AcS was infused at a rate of 5 micrograms/kg/min until ventricular arrhythmias occurred during a drug-free period and during chronic treatment with digoxin, quinidine and digoxin plus quinidine. The dose of AcS required to initiate ventricular arrhythmias is inversely related to the arrhythmogenic potential of digoxin present at the time of AcS infusion. Administration of quinidine alone in two different dosage regimens produced serum quinidine concentrations of 5.99 +/- 1.18 and 2.99 +/- 0.43 micrograms/ml and significantly increased AcS tolerance, whereas digoxin alone, over a wide range of serum digoxin concentrations, significantly decreased AcS tolerance. This decrease in AcS tolerance was linearly related to the serum digoxin concentration. The addition of quinidine treatment to animals receiving digoxin resulted in a significant elevation in the steady-state serum digoxin concentration. However, the AcS tolerance determined during the elevated serum digoxin concentration induced by quinidine was greater than that determined during treatment with the same dose of digoxin alone. Thus, quinidine administration to animals receiving digoxin resulted in a significant increase in the steady-state serum digoxin concentration but did not increase the arrhythmogenic potential of digoxin over that observed during treatment with the same dose of digoxin alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arrhythmias, Cardiac; Digoxin; Dogs; Drug Interactions; Quinidine; Strophanthidin

Oscillatory afterpotentials, or late afterdepolarizations, are one mechanism postulated to cause cardiac arrhythmias and possibly conduction disturbances. We studied excitability by determining strength-interval curves in Purkinje fibers under normal conditions and during the presence of oscillatory afterpotentials induced by cardiac glycoside toxicity. During exposure to acetylstrophanthidin (0.10-0.15 mg/l), the mean resting potential depolarized 5.6 mV and oscillatory afterpotentials of 3-17 mV appeared. Current threshold for evoking action potentials was reduced below control level (e.g., increased excitability) throughout electrical diastole. Associated with oscillatory afterpotentials was a marked biphasic variation in current threshold giving strength-interval curves a characteristic biphasic shape. During the rising phase of the oscillatory afterpotentials, excitability reached a maximum, whereas the minimum increase in excitability occurred during the falling phase of oscillatory afterpotentials. This biphasic change in excitability remained correlated with the oscillatory afterpotentials at different cycle lengths. Results show that during acetylstrophanthidin toxicity excitability is increased throughout electrical diastole, and characteristic time-dependent changes in excitability occur during oscillatory afterpotentials. Time-dependent changes in excitability were detected with both intra- and extracellular stimulation techniques.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Cardiac Glycosides; Diastole; Heart Conduction System; Membrane Potentials; Purkinje Fibers; Sheep; Strophanthidin; Time Factors

The aim of this study was to determine if "ischemia" and/or reperfusion potentiate digitalis toxicity through effects on oscillatory afterpotentials. Isolated canine Purkinje tissue-papillary muscle preparations were studied using standard microelectrode techniques. Tissues were superfused for 10 min with an "ischemic" solution that mimicked hypoxia, acidosis, elevated lactate, zero substrate and normo- or hyperkalemia. Reperfusion with "normal" Tyrode's solution was then reinstated for 60 min. Next, subthreshold oscillatory after potentials were induced with acetylstrophanthidin (ACS) and the protocol was repeated with ACS in all solutions. Without ACS, ischemic conditions with 4 mM KCl caused depolarization of Purkinje and muscle tissues. Reperfusion resulted in hyperpolarization of Purkinje tissue followed by mild depolarization, and then recovery. Purkinje tissue exposed to ischemic conditions with hyperkalemia responded similarly, except that hyperpolarization upon reperfusion was absent. In the presence of ACS, ischemic conditions with 4 mM KCl abolished oscillatory afterpotentials and caused marked depolarization of Purkinje tissue. Reperfusion decreased the coupling intervals and increased the amplitude of oscillatory afterpotentials relative to pre-ischemic levels, and frequently elicited arrhythmic activity. Arrhythmias ceased and tissues recovered by 60 min of reperfusion. Ischemic conditions incorporating hyperkalemia also abolished ACS-induced oscillatory afterpotentials and delayed their reappearance upon reperfusion. All other reperfusion responses were similar. This study demonstrates that "ischemic" suppresses oscillatory afterpotential-mediated effects of digitalis in canine Purkinje tissue, whereas reperfusion potentiates oscillatory afterpotential-induced arrhythmias.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Calcium; Coronary Disease; Dogs; In Vitro Techniques; Male; Perfusion; Potassium; Purkinje Fibers; Sodium-Potassium-Exchanging ATPase; Strophanthidin

A possible role for endogenous prostaglandins in the toxic electrophysiological effects of the aglycone acetylstrophanthidin was studied in isolated canine Purkinje fiber papillary muscle preparations by standard microelectrode techniques. Acetylstrophanthidin (5 X 10(-8) g/ml) caused a significant increase in 6-keto-prostaglandin F1 alpha release from these preparations. A significant loss of membrane potential and the development of oscillatory afterpotentials was observed, as well. Administration of either of two nonsteroidal antiinflammatory agents, indomethacin (3 X 10(-5) g/ml) or aspirin (5 X 10(-5) g/ml), in the presence of acetylstrophanthidin, abolished the stimulation of 6-keto-prostaglandin F1 alpha release and delayed and attenuated the loss of membrane potential and the development of oscillatory afterpotentials. In addition, indomethacin and aspirin appeared to preserve the electrogenic pumping capacity of Purkinje fiber cells exposed to acetylstrophanthidin. Exposure of Purkinje tissues to acetylstrophanthidin inhibited post-pacing hyperpolarization normally exhibited by these tissues. Both indomethacin and aspirin decreased this inhibition. Addition of prostacyclin (1 ng/ml) after 30 minutes of exposure to acetylstrophanthidin to preparations in which endogenous prostaglandin synthesis had been inhibited, resulted in a significant increase in the amplitude of oscillatory afterpotentials within 2 minutes. These results suggest that the presence of endogenous prostaglandins may play a role in the development of the toxic electrophysiological effects associated with acetylstrophanthidin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arrhythmias, Cardiac; Aspirin; Cardiac Pacing, Artificial; Dogs; Female; Heart Conduction System; Heart Ventricles; In Vitro Techniques; Indomethacin; Male; Membrane Potentials; Papillary Muscles; Purkinje Fibers; Strophanthidin; Time Factors; Ventricular Function

Although coadministration of verapamil and digoxin results in significant increases in plasma glycoside concentrations, evidence of digitalis toxicity appears to be infrequent with this combination. To evaluate the effect of verapamil on electrophysiologic toxicity from digitalis, 5 anesthetized dogs were instrumented for physiologic recording and given acetylstrophanthidin by intravenous infusion until evidence of toxicity appeared. Each animal was then treated with verapamil intravenously, with mean steady-state plasma levels of 177 +/- 30 ng/ml, and acetylstrophanthidin infusion repeated; after return of sinus rhythm, the verapamil infusion was increased (producing mean levels of 379 +/- 50 ng/ml) and acetylstrophanthidin given a third time. Prior to verapamil dosing, ventricular ectopy was the manifestation of glycoside toxicity; following the first verapamil infusion, only 20% of the dogs developed ectopy, the remainder having second- or third-degree atrioventricular (AV) block, or AV junctional tachycardia. With the higher verapamil dose, AV block or junctional tachycardia occurred in all animals during acetylstrophanthidin infusion. In addition, the dose of glycoside required to produce electrophysiologic toxicity was significantly increased by verapamil. Therefore, verapamil appears to exert a protective effect against the development of digitalis-induced arrhythmia, possibly by suppressing delayed afterpotential generation, and significantly increases the dose of digitalis required to produce AV block.

Topics: Animals; Arrhythmias, Cardiac; Dogs; Dose-Response Relationship, Drug; Heart Block; Hemodynamics; Male; Strophanthidin; Verapamil

Digitalis drugs can suppress ventricular arrhythmias. It is uncertain whether this effect results from improved left ventricular (LV) function. We utilized radionuclide scanning techniques to evaluate changes in LV ejection fraction (EF) after an infusion of acetyl-strophanthidin in 43 patients with frequent ventricular premature beats (VPBs) (44 to 2400/hr). Acetyl-strophanthidin suppressed ventricular arrhythmia in 17 patients, but LVEF increased in only six of these patients (57% to 67%), while it was unaltered in 11 patients (28% to 30%). In 26 patients ventricular arrhythmia was not suppressed. Fifteen of these patients had an increase in LVEF (60% vs 71%), while this was unchanged in 11 patients (27% vs 29%). Thus no correlation was observed between the positive inotropic and antiarrhythmic action of acetyl-strophanthidin on ventricular arrhythmia and LVEF. We conclude that the suppression of VPBs by acetyl-strophanthidin is independent of the drug's effects on LV function. Evidence is reviewed suggesting that the antiarrhythmic effect of acetyl-strophanthidin on ventricular ectopic activity is due to its vagotonic action.

Topics: Adult; Aged; Arrhythmias, Cardiac; Female; Heart; Humans; Male; Middle Aged; Myocardial Contraction; Radionuclide Imaging; Stroke Volume; Strophanthidin; Vagus Nerve

Digitalis toxicity in vivo generally is recognized by the appearance of cardiac arrhythmias but in vitro by a decline in myocardial performance. To determine whether concentrations of digitoxin producing cardiac arrhythmias in intact animals also produce a decline in myocardial performance directly, three groups of adult cats were studied. One received digitoxin daily until arrhythmias developed (toxic group), the second sufficient digitoxin to produce an inotropic effect without arrhythmias (nontoxic group), and the third was untreated. Peak isometric force and maximal dF/dt of isolated right ventricular papillary muscles were significantly greater in nontoxic muscles (3.9 +/- 0.4 gm/mm2 and 21.3 +/- 1.7 gm/mm2 . sec-1). Values in toxic muscles were similar to untreated ones (2.8 +/- -.6 gm/mm2 and 19.0 +/- 3.2 gm/mm2 . sec-1). Acetylstrophanthidin (2 X 10(-8) M) resulted in an increase in peak force and max dF/dt in nontoxic muscles, whereas myocardial performance changed minimally in untreated muscles and declined in 8 of 10 toxic muscles. We conclude that electrical and mechanical toxicity induced by digitoxin frequently coexist.

Topics: Animals; Arrhythmias, Cardiac; Cats; Digitoxin; Myocardial Contraction; Papillary Muscles; Stimulation, Chemical; Strophanthidin

Topics: Adrenergic Agents; Animals; Arrhythmia, Sinus; Arrhythmias, Cardiac; Dogs; Epinephrine; Heart Arrest; Heart Conduction System; Norepinephrine; Pharmacology; Research; Sinoatrial Node; Stellate Ganglion; Strophanthidin; Strophanthins

Topics: Arrhythmias, Cardiac; Ouabain; Strophanthidin; Strophanthins; Sympathomimetics

Topics: Arrhythmias, Cardiac; Brugada Syndrome; Cardiac Conduction System Disease; Heart Conduction System; Humans; Strophanthidin; Strophanthins

Topics: Arrhythmias, Cardiac; Humans; Strophanthidin; Strophanthus