Abstract

1. 2,4-Dinitrophenol in concentrations of the order of 10^-4 molar causes a reduction of 80 to 90 per cent in the amplitude of contraction and almost complete disappearance of phosphocreatine in the excised and continuously reperfused heart of the adult guinea pig. The ATP content is not significantly changed. The automaticity is not depressed even during the development of contracture induced by dinitrophenol.

2. The positive inotropic action of ouabain is greatly weakened or completely blocked by pretreatment with 10^-4 molar dinitrophenol. Moreover, small amounts of the cardiac glycoside, which normally are non-toxic and leave the energy-rich phosphate content of the heart unchanged, become highly toxic, producing arrhythmias and precipitating contracture, and cause a 50 per cent decrease in labile nucleotide phosphate. The phosphocreatine levels remain low. Coronary flow rates at this stage are within the normal range. In contrast to dinitrophenol, ouabain has no effect on aerobic phosphorylation in guinea pig heart tissue.

3. These results can be considered to provide further support for the previously proposed hypothesis that acceleration of dephosphorylation in the heart may be an effect not only of large, toxic, but also of small, ordinarily therapeutic doses of cardiac glycosides, and that the advanced stage of cardiac glycoside poisoning is characterized biochemically by an increase in the rate of breakdown of energyrich phosphate in the myocardium not matched by a corresponding increase in synthesis. They also suggest that the primary site of attack of the cardiac glycoside in the cardiac muscle fiber is probably the same both during the therapeutic and the toxic phase of their action.