Effects of the calcium sensitizer [+]-EMD 60263 and its enantiomer [-]-EMD60264 on cardiac ionic currents of guinea pig and rat ventricular myocytes

The thiadiazinone enantiomers [+]-EMD 60263 and [-]-EMD 60264 ((+)-5-(1-(al pha-ethylimino-3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroquinoline-6-yl)-6-met hyl-3,6-dihydro-2H-1,3,4-thiadiazine-2-on) exhibit distinct stereoselectivi ty for Ca2+-sensitizing action ([+]-enantiomer) and phosphodiesterase inhib ition ([-]-enantiomer). However, in isolated guinea pig papillary muscle, b oth compounds cause an action-potential prolongation that has been related to a nonselective depression of the delayed rectifier potassium current. Be cause [-]-EMD 60264 did not increase force of contraction despite phosphodi esterase inhibition, we postulated that one or several additional actions m ay oppose the anticipated positive inotropic effect. Therefore we investiga ted whether other membrane currents were also affected in volt age-clamped ventricular cardiomyocytes. Both [+]-EMD 60263 and [-]-EMD 60264 reduced so dium current as well as L-type calcium current in guinea pig ventricular my ocytes, but steady-state inactivation or conductance curves of I-Na and I-C a were not shifted along the voltage axis. Inward rectifier and transient o utward current were studied in rat myocytes, but neither current was affect ed. 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 inh ibition.