Identification of a cardiac sodium channel insensitive to synthetic modulators.
BACKGROUND
DPI 201-106 (DPI) was the first synthetic compound showing cardioselective modulation of voltage-gated sodium channels (VGSCs) resulting in a positive inotropic effect. Currently, the exact mode of action for this class of compounds is not known.


METHODS
Effects of different natural and synthetic sodium channel modulators were investigated in cardiac tissue of several species with conventional electrophysiologic methods.


RESULTS
In electrically driven cardiac tissues, all compounds investigated increased force of contraction (FC) and action potential duration (APD) with increasing concentrations except for DPI in cattle trabecular muscle, which demonstrated no effect. Interestingly, calculation of EC50 levels at 30% repolarization demonstrates that natural VGSC-ligands were highly potent in prolonging the APD in cattle whereas no positive trends could be obtained for DPI and SDZ 211-939 (SDZ) in cattle.


CONCLUSIONS
These results demonstrate that the binding site for DPI and SDZ is distinct from sites 2 or 3 of the VGSC alpha-subunit. Moreover, this is the first time that these compounds show no effect or even shortening of APD. This finding will enable the characterization of the mode of action and probably the binding site for synthetic VGSC-modulators.
Mevissen
M
M
Institute of Veterinary-Pharmacology, University of Berne, Switzerland.
Denac
H
H
Schaad
A
A
Portier
C J
CJ
Scholtysik
G
G
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006041:Goats; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006736:Horses; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D012756:Sheep; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013552:Swine; D013997:Time Factors; D014701:Veratridine / Q000494:pharmacology
D002316:Cardiotonic Agents; D010879:Piperazines; D015222:Sodium Channels; D014701:Veratridine; C046261:DPI 201-106