Stereoselectivity of actions of the calcium sensitizer [+]-EMD 60263 and its enantiomer [-]-EMD 60264.
The thiadiazinone derivative [+]-EMD 60263 ((+)-5-(l-(alpha-ethylimino-3,4-dimethoxybenzyl)-1,2,3,4-tetrah ydroquinoline -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 microM) shifted the EC50 of Ca2+ for contractile activation of skinned fibers of pig heart from 2.41 microM to 0.73 microM, whereas [-]-EMD 60264 (30 microM) 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.
Ravens
U
U
Institut für Pharmakologie, Universitätsklinikum Essen, Germany.
Flüss
O M
OM
Li
Q
Q
Himmel
H M
HM
Wettwer
E
E
Klockow
M
M
Lues
I
I
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D016275:Atrial Function; D002118:Calcium / Q000502:physiology*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D004558:Electric Stimulation; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006352:Heart Ventricles / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000502:physiology; D018408:Patch-Clamp Techniques; D013237:Stereoisomerism; D013552:Swine; D013829:Thiadiazines / Q000494:pharmacology*; D016276:Ventricular Function
D013829:Thiadiazines; C088204:EMD 60263; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D002118:Calcium