Cardiac late sodium current (late INa, Nav1.5)

Class

Anti-anginal (late sodium current inhibitor, piperazine derivative; ranolazine)

Pathway

Inhibits the late inward sodium current in cardiac myocytes, reducing intracellular sodium/calcium overload and myocardial ischemia-related electrical and mechanical dysfunction

Nav1.5 is the main voltage-gated sodium channel in heart muscle cells, responsible for the rapid upstroke of the cardiac electrical signal that triggers each heartbeat. Normally these channels open briefly and then close (inactivate). In settings such as myocardial ischemia (reduced blood flow) or heart failure, a small fraction of channels fails to close properly, allowing a persistent, low-level 'late' sodium current to leak into the cell. This extra sodium buildup forces the cell to import more calcium through a companion transporter, producing calcium overload. Excess intracellular calcium stiffens the heart muscle during relaxation, raises oxygen demand, and can trigger abnormal electrical activity. Selectively blocking this late sodium current, while leaving the initial rapid current largely intact, reduces the downstream sodium and calcium overload without significantly slowing normal cardiac conduction or weakening contraction. This approach is relevant in chronic stable angina, where ischemia-driven late current contributes to symptoms even without an acute change in coronary blood flow, and has broader relevance to conditions where sodium channel dysfunction disturbs the heart's electrical stability. The rationale is to correct a pathological ionic consequence of ischemia rather than to change heart rate, blood pressure, or overall cardiac workload, which sets this mechanism apart from conventional anti-anginal strategies.