Comparison of digoxin-induced cardiac toxicity in resistant and sensitive species

We have examined the species-specific arrhythmogenic effects of digoxin in the rat (resistant species) and in the guinea-pig (sensitive species). 26 adult rats and 23 adult guinea-pigs were anaesthetized with pentobarbitone and injected subcutaneously with varying doses of digoxin. Electrocardiograms were monitored continuously for 4 1/2 h following digoxin administration. The arrhythmogenic dose (AD50) and lethal dose 50 under anaesthesia (LD50) were determined using the method of Litchfield & Wilcoxin. AD50 in rats was 13.0 +/- 1.0 mg kg-1 (mean +/- s.d.) compared with 0.60 +/- 0.04 (P less than 0.01) in the guinea-pig and LD50 was 30.0 +/- 1.9 mg kg-1 in the rat compared with 0.60 +/- 0.04 (P less than 0.01) in the guinea-pig. The onset of arrhythmias was not dose-dependent in the rat but was clearly so in the guinea-pig; for example 102 +/- 15 min (mean +/- s.e.m.) following 0.5 mg kg-1, and 43 +/- 2 min following 1 mg kg-1. In the rat the onset of arrhythmias was 54.0 +/- 11.5 min. Supraventricular arrhythmias (paroxysmal atrial tachycardia) appeared in 73% of rats compared with only 18% of guinea-pigs whereas ventricular arrhythmias (ventricular tachycardia), multiple premature ventricular contractions and or multifocal PVC's occurred in 100% of guinea-pigs compared with only 32% of rats. All guinea-pigs that developed arrhythmias died whereas several rats recovered from supraventricular tachycardias. In conclusion, the guinea-pig is much more sensitive to digoxin toxicity than the rat, develops arrhythmias at much lower doses and these arrhythmias are much more likely to be ventricular in origin and cause fatality.