DIGOXIN-INDUCED VENTRICULAR ARRHYTHMIAS IN THE GUINEA-PIG HEART IN-VIVO - EVIDENCE FOR A ROLE OF ENDOGENOUS CATECHOLAMINES IN THE GENESIS OF DELAYED AFTERDEPOLARIZATIONS AND TRIGGERED ACTIVITY

The mechanisms of digoxin-induced ventricular arrhythmias were studied in vivo using a novel experimental model. Anesthetized guinea pigs we re instrumented with custom-made electrode catheters which enabled the monitoring and recording of right atrial, right ventricular, and His bundle electrograms, midmyocardial monophasic action potentials (MAP), and systemic arterial blood pressure. Intravenous digoxin induced ven tricular arrhythmias ranging from ventricular premature contractions ( VPCs) to ventricular fibrillation (VF). These were associated with del ayed afterdepolarizations (DADs) observed on the MAP recordings. The s everity of the arrhythmias depended on the dose of digoxin. Short burs ts of ventricular pacing neither terminated nor suppressed episodes of ventricular tachycardias (VTs). A direct relationship existed between the paced ventricular cycle length and the coupling interval between the last paced beat and the first ectopic beat (r = 0.983, P < 0.001, n = 10) and between the amplitude of the DADs and the pacing rate (r = 0.972, P < 0.05, n = 7). The increased contractility (LV dp/dt) and h eart rate evoked by isoproterenol (0.1 mu g/kg) did not induce DADs in the absence of digoxin. Verapamil terminated the digoxin-induced VTs in 15 of 16 animals and abolished the associated DADs in 7 of 7 animal s. Adenosine terminated the VTs in 15 of 19 animals and abolished the DADs in 8 of 10 animals. Digoxin induced VT in only 1 of 6 animals tre ated with reserpine (5 + 5 mg/kg) 24 and 48 h prior to experimentaion. However, subsequent intravenous isoproterenol (0.2 mu g/kg) induced V T and DADs, both of which were abolished by verapamil, in all 6 animal s. It was concluded that digoxin-induced ventricular arrhythmias in th e guinea pig heart in vivo were due to DAD-dependent triggered activit y. In addition, it was shown that endogenous catecholamines play a mec hanistic role in digoxin-induced ventricular arrhythmias. The anti-arr hythmic action of adenosine in this setting is probably due to its ind irect antiadrenergic activity in the ventricular myocardium.