Stereoselectivity of actions of the calcium sensitizer [+]-EMD 60263 and its enantiomer [-]-EMD 60264 |
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Authors: | U Ravens Michael O Flüß Q Li Herbert M Himmel Erich Wettwer Michael Klockow Inge Lues |
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Affiliation: | Institut für Pharmakologie, Universit?tsklinikum Essen, Hufelandstrasse 55, D-45122 Essen, Germany, DE Department of Physiology, Queen’s University, Kingston, Ontario, K7L 3N6, Canada, CA Biomedizinische Forschung, Merck KGaA, D-64271 Darmstadt, Germany, DE
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Abstract: | 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 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 μM) shifted the EC50 of Ca2+ 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 IKr 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 IKr. 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 IKr 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.
Received: 7 January 1997 / Accepted: 25 February 1997 |
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Keywords: | Ca2+-sensitizing action Stereoselectivity Positive inotropic effect Action potential prolongation Delayed rectifier current IKr block Guinea pig cardiac myocytes |
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