Abstract

We examined the effects of the cardiotonic agent RWJ 24517 (Carsatrin, racemate) and its (S)- and (R)-enantiomers on action potential duration, Na⁺ current (I_Na), and delayed rectifier K⁺ current (I_K) of guinea pig ventricular myocytes. RWJ 24517 (0.1 and 1 μM) prolongation of action potential duration could not be accounted for by suppression of either the rapid (I_Kr) or slow (I_Ks,) component of I_K, although RWJ 24517 did reduce I_Kr at concentrations of 1 μM. A more dramatic effect of RWJ 24517 (0.1–1 μM) and the (S)-enantiomer of RWJ 24517 (0.1–3 μM) was an increase in peak I_Na and slowing of the rate of I_Na decay, eliciting a large steady-state current. Neither RWJ 24517 nor the (S)-enantiomer affected the fast time constant 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 μM), which probably resulted from a slowing of both fast and slow rates of recovery from inactivation. In contrast, the (R)-enantiomer of RWJ 24517 did not induce a steady-state component I_Na or increase peak I_Naup to 10 μM, but it decreased peak I_Na at 30 μM. The (R)-enantiomer displayed little use-dependent reduction of I_Na during trains of repetitive pulses and had no effect on rates of inactivation or recovery from inactivation. These actions of the racemate and the (S)-stereoisomer to slow inactivation and to prolong both Na⁺ influx and action potential duration may contribute to the positive inotropic actions of these agents because the resulting accumulation of intracellular Na⁺ would increase intracellular Ca²⁺ via Na⁺/Ca²⁺ exchange.