Correlation of antiarrhythmic effects of diphenylhydantoin with digoxin induced changes in myocardial contractility, sodium potassium adenosine triphosphatase activity, and potassium efflux

To clarify the suppressant action of diphenylhydantoin (DPH) on digitalis induced arrhythmias the effects of DPH and digoxin were studied alone and in combination, on contractile force, sodium potassium adenosinetriphosphatase (Na⁺ K⁺ ATPase) activity, and potassium (K⁺) balance in dog hearts perfused with Krebs Ringer's solution. Neither control perfusion nor DPH alone (3 x 10^-5M) altered Na⁺ K⁺ ATPase activity or produced K⁺ loss; DPH alone depressed contractile force. Digoxin alone (10^-6M) caused a 59% rise in contractile force at the onset of arrhythmia along with a net rate of K⁺ loss (K⁺ efflux) of 50 ± 12 μmoles/min and a decrease in Na⁺ K⁺ ATPase activity from 13.8 to 5.2 μmoles phosphorus/mg protein hour^-1 (P<0.001). Perfusion with combined DPH and digoxin delayed toxicity by 13 minutes (or 82%), at which time contractile force was higher (92% above base line, P<0.05), K⁺ efflux was greater (87 ± 20 μmoles/min), and Na⁺ K⁺ ATPase activity was lower (2.6 μmoles/mg hour^-1, P<0.05) than they were with digoxin alone. Combined DPH and digoxin perfusion lasting only until the time toxicity appeared with digoxin alone, however, yielded higher Na⁺ K⁺ ATPase activity (7.7 μmoles/mg hour^-1, P<0.02) and less rise in contractile force (25% above base line, P<0.05). Thus, DPH appeared to retard digoxin induced inhibition of Na⁺ K⁺ ATPase activity. Nevertheless, digoxin in the presence of DPH ultimately produced greater inhibition of Na⁺ K⁺ ATPase activity, greater increase in contractile force, and greater K⁺ efflux prior to toxicity than did digoxin without DPH. These findings suggest that the antiarrhythmic effects of DPH cannot be attributed solely to prevention of inhibition of Na⁺ K⁺ ATPase activity or to diminution of K⁺ efflux, two changes characteristically accompanying digoxin administration.