Stereoselectivity of actions of the calcium sensitizer [+]-EMD 60263 and its enantiomer [-]-EMD 60264

The thiadiazinone derivative [+]-EMD 60263 ((+)-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) is a Ca2+-sensitizing agent with only minor phosphodiesterase inhibitory activity. Our aim was to characterize the inotropic and electrophysiological effects of [+]-EMD 60263 and its enantiomer [-]-EMD 60264 in several cardiac muscle preparations. The Ca2+-sensitizing activity resided in the [+]-enantiomer only. [+]EMD 60263 (3 mu M) shifted the ECS, of Ca2+ for contractile activation of skinned fibers of pig heart from 2.41 mu M to 0.73 mu M, whereas [-]-EMD 60264 (30 mu M) was ineffective. In Langendorff-perfused guinea pig hearts, [+]-EMD 60263 and [-]-EMD 60264 induced concentration-dependent positive and negative inotropic effects, respectively; both enantiomers reduced spontaneous heart rate but did not influence perfusion pressure. The maximum increase in force of human atrial trabeculae was 35 % of pre-drug control with [+]-EMD 60263 in comparison to 113 % with forskolin. In guineapig papillary muscles, [+]-EMD 60263 and [-]-EMD 60264 had opposite inotropic responses, however, both agents similarly prolonged action potential duration. Both enantiomers concentration-dependently blocked the rapidly activating component IK, Of the delayed rectifier in guinea-pig myocytes. The block saturated at potentials positive to +30 mV, closely resembling the effects of the antiarrhythmic agent E-4031 which had been originally used to define I-Kr. It is concluded, that the positive inotropic action of [+]-EMD 60263 can be explained by prevalence of the Ca2+-sensitizing effect. The accompanying prolongation in action potential duration is caused by block of the I-Kr component of the delayed rectifier. While the inotropic effects are stereoselective, most of the electrophysiological actions are clearly independent of sterical configuration. The combination of Ca2+-sensitizing with class-III antiarrhythmic action may provide an interesting pharmacological profile of potential therapeutic use.