The shortening of the action potential by DNP in guinea-pig ventricular myocytes is mediated by an increase of a time-independent K conductance.

Abstract

1. The mechanism of the well known shortening of the cardiac action potential by 2,4-dinitrophenol (DNP, a classical uncoupler of oxidative phosphorylation) was studied in single ventricular myocytes using a two microelectrode voltage clamp technique. 2. Single ventricular cells were isolated from the heart of adult guinea-pigs. These cells were superfused with Tyrode solution containing 1.8 or 3.6 mM Ca. 3. After application of 0.1 mM DNP initially a small depolarization and a prolongation of the action potential is observed. This effect is most likely related to an inhibition of the electrogenic sodium pump caused by ATP depletion. 4. The marked shortening of the action potential which follows the initial prolongation is accompanied by a very pronounced increase of the outward current. This DNP-induced outward current component is time-independent. This current shows a reversal potential negative to the resting potential indicating that it is mainly carried by potassium ions. 5. The DNP-induced current attenuates and abolishes the N-shape of the steady-state current-voltage relationship. When the inward-rectifying potassium current is blocked by pretreatment with 20 mM Cs or 1 mM Ba, large DNP-induced currents which show outward rectification can be seen. The increase in outward-rectifying potassium current by DNP is responsible for the shortening of the action potential and the loss of plateau. 6. In addition, DNP also seems to cause an increase of inward-rectifying potassium current. This effect appears later than the increase in outward rectifier; it does not contribute to the shortening of the action potential but causes a hyperpolarization of the cell. 7. In the latest phase of the DNP effect, which occurs only after the action potential has completely lost its plateau, changes of the amplitude and time constant of inactivation of the slow inward current can sometimes be observed. 8. The effect of DNP on the potassium conductance is discussed in terms of increased cytosolic calcium activity.