title: 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.
authors.affiliation: CV Therapeutics Inc, Palo Alto, California, USA.
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Wu
authors.forename: Yejia
authors.initials: Y
authors.lastname: Song
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.forename: John C
authors.initials: JC
authors.lastname: Shryock
mesh_terms: D000083:Acetanilides / Q000494:pharmacology*; D000818:Animals; D005260:Female; D006168:Guinea Pigs; D054144:Heart Failure, Diastolic / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*; D066298:In Vitro Techniques; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010172:Palmitoylcarnitine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010879:Piperazines / Q000494:pharmacology*; D000069458:Ranolazine; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000502:physiology; D018754:Ventricular Dysfunction / Q000139:chemically induced / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D000083:Acetanilides; D010879:Piperazines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D010172:Palmitoylcarnitine; D000069458:Ranolazine