Correlation of Antiarrhythmic Effects of Diphenylhydantoin with Digoxin-Induced Changes in Myocardial Contractility, Sodium-Potassium Adenosine Triphosphatase Activity, and Potassium Efflux

Abstract

To clarify the suppressant action of diphenylhydantoin (DPH) on digitalis-induced arrhythmias we studied effects of DPH and digoxin, 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+ efflux was greater (87 ± 20 µmoles/min), and Na ⁺ -K⁺ ATPase activity was lower (2.6 µmoles/mg hour^-1, P+-K⁺ ATPase activity (7.7 µmoles/mg hour^-1, PP+-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.