Palmitoyl-L-carnitine (PC), an ischemic metabolite, causes cellular Na(+) and 
Ca(2+) overload and cardiac dysfunction. This study determined whether 
ranolazine [(+/-)-1-piperazineacetamide, 
N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-] attenuates 
PC-induced Na(+) current and ventricular contractile dysfunction of the isolated 
heart. PC (4 microM, 30 min) increased late Na(+) current by 1034 +/- 349% in 
guinea pig isolated ventricular myocytes; ranolazine (10 microM) and 
tetrodotoxin (TTX, 3 microM) significantly attenuated this effect of PC. PC 
increased left ventricular end-diastolic pressure (LVEDP), coronary perfusion 
pressure (CPP), wall stiffness, and cardiac lactate and adenosine release from 
the isolated heart. Ranolazine (10 microM) significantly reduced the PC-induced 
increase in LVEDP by 72 +/- 6% (n = 6, p < 0.001), reduced left ventricular wall 
stiffness, and attenuated the PC-induced increase of CPP by 53 +/- 10% (n = 6-7, 
p < 0.05). Ranolazine (10 microM) reduced the PC-induced increases of lactate 
and adenosine release by 70 +/- 8 and 81 +/- 5%, respectively (n = 6, p <or= 
0.05 for both). TTX (2 microM) significantly (p < 0.05) reduced PC-induced 
increases of CPP and LVEDP. Pretreatment of isolated myocytes or hearts with the 
free radical scavenger tiron (4,5-dihydroxy-1,3-benzenedisulfonic acid, disodium 
salt) (1 mM) significantly reduced the effects of PC to cause increases of late 
Na(+) current and LVEDP, respectively, but unlike ranolazine or TTX, tiron did 
not reverse increases of late Na(+) current and LVEDP caused by PC. In summary, 
ranolazine and TTX, inhibitors of the late Na(+) current, attenuated the 
PC-induced ventricular contractile dysfunction and increase of coronary 
resistance in the guinea pig isolated heart.