Inhibition of the persistent or late Na current (INa) using ranolazine (Ranexa) 
represents a novel mechanism of action that was approved in the United States in 
2006 and only recently in the European Union for use in patients with stable 
angina pectoris. In general, myocardial ischemia is associated with reduced 
adenosine triphosphate fluxes and decreased energy supply, resulting in severe 
disturbances of intracellular ion homeostasis in cardiac myocytes. In the recent 
years, increased late INa was suggested to contribute to this phenomenon by 
elevating intracellular Na concentration with subsequent rise in diastolic Ca 
levels by means of the sarcolemmal Na-Ca exchange system. Ranolazine, a specific 
inhibitor of late INa, reduces Na influx and hence ameliorates disturbed Na and 
Ca homeostasis. This is associated with a symptomatic improvement of angina in 
patients unlike other antianginal drugs without affecting heart rate or systemic 
blood pressure as shown in placebo-controlled studies. Therefore, ranolazine is 
a useful new option for patients with chronic stable angina not only as an 
add-on therapy. New clinical and experimental studies even point to potential 
antiarrhythmic effects, beneficial effects in diastolic heart failure, and under 
hyperglycemic conditions. In the present article, the relevant 
pathophysiological concepts for the role of late INa inhibition are reviewed and 
the most recent data from basic studies and clinical trials are summarized.