The thiadiazinone derivative [+]-EMD 60263 ((+)-5-(1-(α-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 Ca
2+-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 Ca
2+-sensitizing activity resided in the [+]-enantiomer only. [+]-EMD 60263 (3 μM) shifted the EC
50 of Ca
2+ for contractile activation of skinned fibers of pig heart from 2.41 μM to 0.73 μM, whereas [-]-EMD 60264 (30 μM) 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 guinea-pig 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 I
Kr 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 Ca
2+-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 Ca
2+-sensitizing with class-III antiarrhythmic action may provide an interesting pharmacological profile of potential therapeutic
use.
Received: 7 January 1997 / Accepted: 25 February 1997
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