Cardiac sodium channels as targets for new inotropic agents

Abstract

Congestive heart failure (CHF) is the most frequent cause of hospitalization in patients over 65. Hospitalized patients with severe CHF could benefit from new agents that directly support myocardial contractility and peripheral hemodynamics. The few classes of drugs available for short-term use (beta agonists, digoxin, and phosphodiesterase inhibitors) all act via cyclic AMP and have significant limitations, including tolerance, tachyarrhythmias, and excessive vasodilation, especially in late-stage disease. Newer agents are in development that increase contractility by novel mechanisms, including calcium sensitizers and ion channel modulators. Among the latter, sodium-channel modulators (e.g., DPI 201-106 and LY333612) interfere directly with inactivation of the rapid sodium channel. We review the structure and function of the human sodium channel and discuss the role of the sodium–calcium exchange mechanism in modulating the amount of calcium available for use in myocardial contraction. Sodium channel enhancers markedly increase contractility independent of cAMP in papillary muscle strips from patients with advanced CHF that are refractory to standard agents. Moreover, the unfavorable systolic and diastolic force–frequency relationships of isolated papillary muscle in advanced CHF are improved by some agents in this class. In ischemic CHF animal models, stroke volume and output are enhanced in the absence of positive chronotropic or arrhythmogenic activity. Additional studies are suggested to help determine the ultimate role for these agents in the therapy of end-stage CHF.