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Identification of a Cardiac Sodium Channel Insensitive to Synthetic Modulators

Helena Denac, PhD

Andreas Schaad

Christopher J. Portier, PhD

Guenter Scholtysik, PhD

Institute of Veterinary-Pharmacology, University of Berne Berne, Switzerland; and National Institute of Environmental Health Sciences (NIEHS), Laboratory of Computational Biology and Risk Analysis, Research Triangle Park, NC

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 ox-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.

Key Words: DPI 201-106 • SDZ 211-939 • species differences • VGSC (voltage-gated sodium channel)

Journal of Cardiovascular Pharmacology and Therapeutics, Vol. 6, No. 2, 201-212 (2001)
DOI: 10.1177/107424840100600212


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