Inhibitory effects of diprafenone stereoenantiomers on cardiac Na+ channels.

The potency of (-)- and (+)-diprafenone to depress the Vmax of Na+-dependent action potentials and to block single cardiac Na+ channels was analyzed in microelectrode experiments with guinea pig papillary muscles and in patch clamp experiments with DPI-modified Na+ channels using neonatal cardiocytes. Within 20-30 min, both optical enantiomers caused a Vmax depression which occurred predominantly as a phasic blockade at a low dosage (10 mumol/l). (-)- and (+)-diprafenone were equally effective in evoking a tonic and phasic depression of Vmax. Exposing the cytoplasmic side of inside-out patches to 10 mumol/l of (-)- or (+)-diprafenone evoked a flicker block of DPI-modified Na+ channels within 1-2 s. Kinetic analysis of the latter revealed a KD value for the blocking action of 6.3 X 10(-5) mol for the (-) enantiomer and 7.1 X 10(-5) mol for the (+) enantiomer. Nevertheless, larger association and dissociation rate constants were obtained with (+)-diprafenone than with (-)-diprafenone. This indicates that there are stereoselective reaction kinetics in blocking open modified Na+ channels.