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 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"M) altered Na + -K ATPase activity or produced K loss; DPH alone depressed contractile force. Digoxin alone (10~M) 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 ^tmoles/min and a decrease in Na-K + ATPase activity from 13.8 to 5.2 /^moles phosphorus/mg protein hour" (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 ± 2 0 fimoles/ min), and Na + -K ATPase activity was lower (2.6 ju.moles/mg hour-, 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 /xmoles/mg hour, 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 antiarrhytbmic 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.