The Late Na+ Current (INa) Inhibitor Ranolazine Attenuates Effects of Palmitoyl-L-Carnitine to Increase Late INa and Cause Ventricular Diastolic Dysfunction

Abstract

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.