title: The antianginal agent trimetazidine does not exert its functional benefit via inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.
abstract: Trimetazidine acts as an effective antianginal clinical agent by modulating cardiac energy metabolism. Recent published data support the hypothesis that trimetazidine selectively inhibits long-chain 3-ketoacyl CoA thiolase (LC 3-KAT), thereby reducing fatty acid oxidation resulting in clinical benefit. The aim of this study was to assess whether trimetazidine and ranolazine, which may also act as a metabolic modulator, are specific inhibitors of LC 3-KAT. We have demonstrated that trimetazidine and ranolazine do not inhibit crude and purified rat heart or recombinant human LC 3-KAT by methods that both assess the ability of LC 3-KAT to turnover specific substrate, and LC 3-KAT activity as a functional component of intact cellular beta-oxidation. Furthermore, we have demonstrated that trimetazidine does not inhibit any component of beta-oxidation in an isolated human cardiomyocyte cell line. Ranolazine, however, did demonstrate a partial inhibition of beta-oxidation in a dose-dependent manner (12% at 100 micromol/L and 30% at 300 micromol/L). Both trimetazidine (10 micromol/L) and ranolazine (20 micromol/L) improved the recovery of cardiac function after a period of no flow ischemia in the isolated working rat heart perfused with a buffer containing a relatively high concentration (1.2 mmol/L) of free fatty acid. In summary, both trimetazidine and ranolazine were able to improve ischemic cardiac function but inhibition of LC 3-KAT is not part of their mechanism of action. The full text of this article is available online at http://www.circresaha.org.
authors.affiliation: Discovery Biology (IPC351), Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK. Alan_MacInnes@sandwich.pfizer.com
authors.forename: Alan
authors.initials: A
authors.lastname: MacInnes
authors.forename: David A
authors.initials: DA
authors.lastname: Fairman
authors.forename: Peter
authors.initials: P
authors.lastname: Binding
authors.forename: Jo ann
authors.initials: Ja
authors.lastname: Rhodes
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wyatt
authors.forename: Anne
authors.initials: A
authors.lastname: Phelan
authors.forename: Peter S
authors.initials: PS
authors.lastname: Haddock
authors.forename: Eric H
authors.initials: EH
authors.lastname: Karran
mesh_terms: D000083:Acetanilides; D000102:Acetyl-CoA C-Acyltransferase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008929:Mitochondria, Heart / Q000737:chemistry / Q000201:enzymology*; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D000069458:Ranolazine; D051381:Rats; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism; D014292:Trimetazidine / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000083:Acetanilides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011994:Recombinant Proteins; D014665:Vasodilator Agents; D000069458:Ranolazine; D000102:Acetyl-CoA C-Acyltransferase; D014292:Trimetazidine