Effects of the calcium sensitizer [+]-EMD 60263 and its enantiomer [-]-EMD 60264 on cardiac ionic currents of guinea pig and rat ventricular myocytes

The thiadiazinone enantiomers [+]-EMD 60263 and [-]-EMD 60264 ((+)-5-(1-(alpha-ethylimino-3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroquinoline-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazine-2-on) exhibit distinct stereoselectivity for Ca2+-sensitizing action ([+]-enantiomer) and phosphodiesterase inhibition ([-]-enantiomer). However, in isolated guinea pig papillary muscle, both compounds cause an action-potential prolongation that has been related to a nonselective depression of the delayed rectifier potassium current. Because [-]-EMD 60264 did not increase force of contraction despite phosphodiesterase inhibition, we postulated that one or several additional actions may oppose the anticipated positive inotropic effect. Therefore we investigated whether other membrane currents were also affected in volt age-clamped ventricular cardiomyocytes. Both [+]-EMD 60263 and [-]-EMD 60264 reduced sodium current as well as L-type calcium current in guinea pig ventricular myocytes, but steady-state inactivation or conductance curves of I-Na and I-Ca were not shifted along the voltage axis. Inward rectifier and transient outward current were studied in rat myocytes, but neither current was affected. We conclude that the positive inotropic action of [+]-EMD 60263 can be explained by prevalence of the Ca2+-sensitizing effect over its inhibitory actions on Na+ and Ca2+ current, whereas the negative inotropic effect of [-]-EMD 60264 may be caused by inhibition of I-Ca predominating over PDE inhibition.