BACKGROUND: Ranolazine (Ran), an antianginal agent, inhibits late Na(+) current. 
The purpose of this study was to determine whether there was an added benefit of 
adding Ran to cardioplegia (CP) in a model of global ischemia/reperfusion.
METHODS AND RESULTS: Isolated rat hearts were Langendorff-perfused and exposed 
to 40-minute normothermic, cardioplegic global ischemia and 30 minutes of 
reperfusion. Before ischemia and during reperfusion, hearts were treated with no 
drug (control) or with the late Na(+) current inhibitors Ran (5 micromol/L) or 
tetrodotoxin (1 micromol/L). Ischemic cardioplegic arrest led to an increase of 
left ventricular end-diastolic pressure (LVEDP) by > or =20 mm Hg (ie, cardiac 
contracture). Ten out of 11 hearts treated with CP alone developed contracture, 
whereas 6 out of 11 hearts treated with CP plus Ran developed contracture. Ran 
added to CP reduced LVEDP at the end of ischemia from 41+/-5 mm Hg in CP alone 
to 26+/-3 mm Hg in CP plus Ran (P=0.024). Area under the curve for LVEDP during 
the entire ischemic period was also smaller in CP plus Ran versus CP alone. The 
percent increase (from baseline) of LVEDP measured at the end of 30-minute 
reperfusion was smaller for CP plus Ran (66+/-18%) versus CP alone (287+/-90%; 
P=0.035). The area under the curve for LVEDP during reperfusion was smaller in 
CP plus Ran versus CP alone. Tetrodotoxin (1 micromol/L) also reduced cardiac 
contracture during ischemia/reperfusion, compared to CP alone.
CONCLUSIONS: Our results suggest that Ran may have therapeutic potential as an 
adjunct to CP and further support a protective role of Na(+) current inhibition 
during ischemia/reperfusion.