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 were 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 ventricular arrhythmias ranging from ventricular premature contractions (VPCs) to ventricular fibrillation (VF). These were associated with delayed afterdepolarizations (DADs) observed on the MAP recordings. The severity of the arrhythmias depended on the dose of digoxin. Short bursts 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 = 0.913, 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 heart rate evoked by isoproterenol (0.1 microgram/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 animals. 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 treated with reserpine (5 + 5 mg/kg) 24 and 48h prior to experimentation. However, subsequent intravenous isoproterenol (0.2 micrograms/kg) induced VT and DADs, both of which were abolished by verapamil, in all 6 animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Xu
J
J
Likoff Cardiovascular Institute, Medical College of Pennsylvania, Philadelphia, USA.
Hurt
C M
CM
Pelleg
A
A
D000241:Adenosine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology*; D002395:Catecholamines / Q000502:physiology*; D004077:Digoxin; D004195:Disease Models, Animal; D004562:Electrocardiography; D005260:Female; D006168:Guinea Pigs; D008297:Male; D011433:Propranolol / Q000494:pharmacology; D011897:Random Allocation; D012110:Reserpine / Q000494:pharmacology; D018754:Ventricular Dysfunction / Q000503:physiopathology*; D014700:Verapamil / Q000494:pharmacology
D002395:Catecholamines; D004077:Digoxin; D012110:Reserpine; D011433:Propranolol; D014700:Verapamil; D000241:Adenosine