Modification of cardiac Na+ current by RWJ 24517 and its enantiomers in guinea pig ventricular myocytes

We examined the effects of the cardiotonic agent RWJ 24517 (Carsatrin, race mate) and its (S)- and (R)- enantiomers on action potential duration, Na+ c urrent (I-Na), and delayed rectifier K+ current (I-K) of guinea pig ventric ular myocytes. RWJ 24517 (0.1 and 1 mu M) prolongation of action potential duration could not be accounted for by suppression of either the rapid (I-K r) or slow (I-Ks) component of I-K, although RWJ 24517 did reduce I-Kr at c oncentrations of 1 mM. A more dramatic effect of RWJ 24517 (0.1-1 mu M) and the (S)-enantiomer of RWJ 24517 (0.1-3 mu M) was an increase in peak I-Na and slowing of the rate of I-Na decay, eliciting a large steady-state curre nt. Neither RWJ 24517 nor the (S)-enantiomer affected the fast time constan t for I-Na decay, but both significantly increased the slow time constant, in addition to increasing the proportion of I-Na decaying at the slow rate. Both agents elicited a use-dependent decrease of peak I-Na (3-10 mu M), wh ich probably resulted from a slowing of both fast and slow rates of recover y from inactivation. In contrast, the (R)-enantiomer of RWJ 24517 did not i nduce a steady-state component I-Na or increase peak I-Na up to 10 mu M, bu t it decreased peak I-Na at 30 mu M. The (R)-enantiomer displayed little us e-dependent reduction of I-Na during trains of repetitive pulses and had no effect on rates of inactivation or recovery from inactivation. These actio ns of the racemate and the (S) stereoisomer to slow inactivation and to pro long both Na+ influx and action potential duration may contribute to the po sitive inotropic actions of these agents because the resulting accumulation of intracellular Na+ would increase intracellular Ca2+ via Na+/Ca2+ exchan ge.