Cardiac Na+ channel activation as a positive inotropic principle.

This article reviews the relation of cardiac cellular Na+ load and increased force of contraction. Digitalis glycosides and naturally occurring Na+ channel activators are considered. DPI201-106 was described as the first synthetic organic molecule with cardioselective Na+ channel-activating properties and investigated in clinical studies. Its pharmacology is reviewed. DPI 201-106 prolongs the open state of cardiac Na+ channels. This effect represents the primary mechanism of its positive inotropic effect. The involvement of cAMP is excluded. Ca2+ antagonistic and local anaesthetic effects are assumed to contribute advantageously to the pharmacodynamic profile of DPI 201-106. Chemically and pharmacologically related to DPI 201-106 is the new compound SDZ 210-921 for which original results are presented. It is concluded that DPI 201-106 represents the lead structure of a new class of cardiotonics with selective cardiac Na+ channel activation. DPI 201-106 and related compounds may serve as promising tools in the investigation of cardiac Na+ channel-gating dynamics, in addition to their therapeutic potential.