The antianginal agent trimetazidine does not exert its functional benefit via inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.

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MacInnes A, Fairman DA, Binding P, Rhodes Ja, Wyatt MJ, Phelan A, Haddock PS, Karran EH

The antianginal agent trimetazidine does not exert its functional benefit via inhibition of mitochondrial long-chain 3-ketoacyl coenzyme A thiolase.

Circ Res. 2003 Aug 8;93(3):e26-32. doi: 10.1161/01.RES.0000086943.72932.71. Epub 2003 Jul 17.

PubMed ID

12869391 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drugs

Trimetazidine

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Trimetazidine	3-ketoacyl-CoA thiolase, mitochondrial	Protein	Humans	Unknown	Inhibitor	Details