Vol. 291, Issue 2, 845-855, November 1999

Modification of Cardiac Na⁺ Current by RWJ 24517 and Its Enantiomers in Guinea Pig Ventricular Myocytes¹

Robert G. Tsushima² , James E. Kelly, Joseph J. Salata³ , Kristine N. Liberty and J. Andrew Wasserstrom

Departments of Medicine (Cardiology) and Molecular Pharmacology and Medicinal Chemistry and the Feinberg Cardiovascular Research Institute, Northwestern University Medical School, Chicago, Illinois (R.G.T., J.E.K., K.N.L., J.A.W.); and R.W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania (J.J.S.)

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_Na up 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.