EFFECT OF EXTRACELLULAR ATP ON THE NA+ CURRENT IN RAT VENTRICULAR MYOCYTES

Extracellular ATP concentration can rise because of its release by nerve terminals and by damaged cells during ischemia. After the activation of P2-purinergic receptors, ATP induces a positive inotropic effect and increases the L-type Ca2+ current via activation of a G(s) protein but without cAMP production. In addition, ATP shifts the voltage characteristics of Ca2+ current toward hyperpolarized potentials. If ATP produced similar effects on the Na+ current (I(Na)), this compound should also affect cardiac excitability and conduction. Using the whole-cell patch-clamp to record I(Na) in rat ventricular cells, we show that extracellular application of ATP induced hyperpolarizing shifts in the current-voltage relation and the availability of I(Na). The ED50 for the shifts in both conductance and availability was obtained with 0.7 mumol/L ATP. Maximal shifts in conductance and availability were respectively 9.7+/-0.6 and 10.6+/-0.7 mV. The leftward shift of the availability curve is responsible for the decrease of I(Na) amplitude at less polarized holding potentials. These effects were not cholera toxin sensitive and thus cannot be attributed to activation of the G(s) protein. At 100 mumol/L, ATPgammaS and alpha,beta-methylene ATP could induce shift, whereas UTP and beta,gamma-methylene ATP as well as ADP and adenosine were without effect. Thus, depending on the resting membrane potential, ATP should either enhance excitability or favor slow conduction and weaken cardiac electrical homogeneity and consequently favor arrhythmia.