| Title | The late INa Inhibitor Ranolazine Attenuates Effects of Palmitoyl-L-Carnitine to Increase Late INa and Cause Ventricular Diastolic Dysfunction. | | Author(s) | Wu Y, Song Y, Belardinelli L, Shryock JC | | Institution | CV Therapeutics. | | Source | J Pharmacol Exp Ther 2009 Apr 29. | | Abstract | Palmitoyl-L-carnitine (PC), an ischemic metabolite, causes cellular Na(+) and Ca(2+) overload and cardiac dysfunction. This study determined if ranolazine attenuates PC-induced Na(+) current and ventricular contractile dysfunction of the isolated heart. PC (4 micromol/L, 30 minutes) increased late Na(+) current by 1,034 plus or minus 349% in guinea pig isolated ventricular myocytes; ranolazine (10 micromol/L) and tetrodotoxin (TTX, 3 micromol/L) 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 micromol/L) significantly reduced the PC-induced increase in LVEDP by 72 plus or minus 6 % (n=6, p<0.001), reduced left ventricular wall stiffness, and attenuated the PC-induced increase of CPP by 53 plus or minus 10% (n=6-7, p<0.05). Ranolazine (10 micromol/L) reduced the PC-induced increases of lactate and adenosine release by 70 plus or minus 8 and 81 plus or minus 5 %, respectively (n=6, p less than 0.05 for both). TTX (2 micromol/L) significantly (p<0.05) reduced PC- induced increases of CPP and LVEDP. Pretreatment of isolated myocytes or hearts with the free radical scavenger Tiron (1 mmol/L) 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19403851 |
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