Table 1.

A summary of the possible mechanisms of ranolazine as an anti-anginal drug.

Mechanism	Details	Notes
Effects on metabolism	Ranolazine increases the amount of active dephosphorylated pyruvate dehydrogenase Ranolazine stimulates glucose oxidation at the expense of fatty acid oxidation	Concentration >10 μM (higher than used in clinical settings) This mechanism suggests an intra-mitochondrial effect
Effects on late Na+ current (INaL)	Ranolazine inhibits INaL and therefore reduces Na+ overload during ischemia This reduces cytosolic Ca2+ overload that occurs by activation of Na+/Ca2+ exchanger in the reverse mode This also reduces mitochondrial Ca2+ overload	Ranolazine inhibits INaL with an IC50 = 5.9 μM (within the clinical range) Ranolazine inhibits INaL possibly by inhibiting the mechano-sensitivity of Nav1.5
Effects on mitochondrial complex I	Ranolazine inhibits mitochondrial complex I Ranolazine reduces electron flow to complex III during ischemia Ranolazine reduces mitochondrial free radical generation	Ranolazine is a weak inhibitor of complex I in coupled mitochondria Ranolazine becomes more potent as a complex I blocker in uncoupled or broken mitochondria
Effects on myofilaments Ca2+ sensitivity	Ranolazine modulates myofilament cross-bridge kinetics and sensitivity to Ca2+ Ranolazine improves diastolic function at the cardiomyocyte level	The effects on myofilaments are achieved with concentrations of ranolazine within the clinical range