Release of adenine nucleotide metabolites by toxic concentrations of cardiac glycosides

Summary In isolated perfused guinea-pig hearts the effect of toxic concentrations of cardiac glycosides on the release of the adenine nucleotide metabolites adenosine, inosine, hypoxanthine, xanthine, and uric acid was investigated. Digoxin concentrations of 0.03–1 mol · l^–1 produced moderate to severe tachyarrhythmias. Large amounts of metabolites were released by concentrations of 0.1 mol · l^–1, and higher. Occurrence of glycoside-induced ventricular fibrillation was associated with a particularly high release. Metabolite release was also obtained when fibrillation was elicited electrically in normal control hearts, or in hearts receiving simultaneously a marginally toxic digoxin concentration (0.03 mol · l^–1). Digoxin-induced tachyarrhythmias and metabolite release were almost completely prevented by a high potassium concentration in the coronary perfusion fluid (8.1 mmol · l^–1). The antiarrhythmic effect was also obtained with lidocaine (60 mol · l^–1), but the release was only partially antagonized. Similar results concerning arrhythmias and metabolite release as with digoxin were obtained with ouabain. The findings suggest that the decrease in myocardial ATP observed in glycoside-intoxicated heart preparations is partly due to the loss of nucleotide precursor substances. Moreover, it appears likely that liberated adenosine in the interstitium of severely intoxicated heart preparations reaches pharmacologically effective concentrations.