Mode-dependent inhibition by quinidine of Na+-Ca2+ exchanger current from guinea-pig isolated ventricular myocytes

1. The aim of the present study was to determine whether or not the class Ia anti-arrhythmic agent quinidine modulates ionic current (INaCa) generated by the sarcolemmal Na+-Ca2+ exchanger of adult ventricular cardiac myocytes. 2. Selective whole-cell voltage-clamp recordings of INaCa were made from guinea-pig ventricular myocytes, with major interfering currents blocked. The INaCa was measured as the ionic current sensitive to 10 mmol/L external Ni2+ during a descending voltage ramp protocol. 3. The effects of quinidine concentrations in the range 10-100 micromol/L were studied. Quinidine produced a concentration-dependent partial blockade of outward INaCa, generated by reverse-mode exchange. At +60 mV, 100 micromol/L quinidine blocked INaCa by 33.0 +/- 4.1% (mean+/-SEM; n = 4). This was the maximal concentration that we were able to test, because concentrations of quinidine higher than 100 micromol/L were found to be toxic to cells under our conditions. The drug did not produce any significant inhibition of inward INaCa (generated by forward-mode exchange). 4. The Ni2+-insensitive residual current was not significantly altered by quinidine at any membrane potential, confirming that the inhibitory effects of quinidine we observed could be attributed to an action on the Na+-Ca2+ exchanger. 5. For the purpose of comparison, quinidine was tested against L-type Ca current (ICa,L). It blocked peak ICa,L at 0 mV, with an IC50 of 14.9 +/- 1.5 micromol/L. Thus, quinidine was less potent against the exchanger than against ICa,L. 6. Our data suggest that quinidine preferentially inhibits the Naout/Cain mode of exchanger function. We conclude that this drug is a weak inhibitor of ventricular INaCa and that the inhibitory effect is mode dependent.