The antianginal agent ranolazine is a weak inhibitor of the respiratory complex I, but with greater potency in broken or uncoupled than in coupled mitochondria.

@article{Wyatt1995TheAA,
  title={The antianginal agent ranolazine is a weak inhibitor of the respiratory complex I, but with greater potency in broken or uncoupled than in coupled mitochondria.},
  author={K M Wyatt and Christopher Skene and Keith Veitch and Le Thi Hue and James G. Mccormack},
  journal={Biochemical pharmacology},
  year={1995},
  volume={50 10},
  pages={
          1599-606
        }
}
Ranolazine (RS-43285) has shown antianginal effects in clinical trials and cardiac anti-ischaemic activity in several in vivo and in vitro animal models, but without affecting haemodynamics. Its mechanism is thought to mainly involve a switch in substrate utilisation from fatty acids to glucose to, thus, improve efficiency of O2 use; however, its precise molecular target(s) are unknown. In studies to investigate its action further, using isolated rat heart mitochondria, ranolazine was found to… 
Mechanism of inhibition of mitochondrial respiratory complex I by 6-hydroxydopamine and its prevention by desferrioxamine.
TLDR
The qualitative and quantitative differences between the behavior of the liver and brain enzyme complexes indicate that the assumption that thebehavior of liver mitochondria can be used as a model for the situation in brain should be reconsidered.
Effects of Ranolazine on Carbohydrate Metabolism in the Isolated Perfused Rat Liver
TLDR
It seems likely that ranolazine inhibits gluconeogenesis and increases glycolysis in consequence of its inhibitory actions on energy metabolism and fatty acid oxidation and by deviating reducing equivalents in favour of its own biotransformation.
Damage to mitochondrial complex I during cardiac ischemia reperfusion injury is reduced indirectly by anti-anginal drug ranolazine.
TLDR
Improvements in complex I structure and function with ranolazine were associated with improved cardiac function after IR and these protective effects are not mediated by a direct action on mitochondria, but rather indirectly via cytosolic mechanisms that lead to less oxidation and better structural integrity of complex I.
Effects of ranolazine on fatty acid transformation in the isolated perfused rat liver
TLDR
It was concluded that ranolazine inhibits fatty acid uptake and oxidation in the liver by at least two mechanisms: inhibition of cell membrane permeation and by an inhibition of the mitochondrial electron transfer via pyridine nucleotides.
Ranolazine reduces Ca2+ overload and oxidative stress and improves mitochondrial integrity to protect against ischemia reperfusion injury in isolated hearts.
TLDR
Ranolazine indirectly reduces O2·- emission, preserves bioenergetics, delays mPTP opening, and restricts loss of cytochrome c, thereby reducing necrosis and apoptosis, and may provide functional protection of the heart during IR injury.
Cardioprotection and mitochondrial S-nitrosation: effects of S-nitroso-2-mercaptopropionyl glycine (SNO-MPG) in cardiac ischemia-reperfusion injury.
TLDR
Data suggest that mitochondrial S-nitrosation and complex I inhibition constitute a protective signaling pathway that is amenable to pharmacologic augmentation.
Cardioprotection by metabolic shut-down and gradual wake-up.
TLDR
Evidence is reviewed in support of the hypothesis that the wash-out of inhibitors or reversal of endogenous inhibition at reperfusion may afford protection by facilitating a more gradual wake-up of mitochondrial function, thereby avoiding a burst of ROS and Ca(2+) overload.
Ranolazine, a partial fatty acid oxidation inhibitor, reduces myocardial infarct size and cardiac troponin T release in the rat.
TLDR
It is demonstrated for the first time that ranolazine significantly reduces (i) infarct size and (ii) cardiac troponin T release in rats subjected to left anterior descending coronary artery occlusion-reperfusion.
In vivo cardioprotection by S-nitroso-2-mercaptopropionyl glycine.
TLDR
Results are consistent with a role for mitochondrial S-nitrosation and complex I inhibition in the cardioprotective mechanism of IPC and SNO-MPG in vivo, and hearts from mice harboring a heterozygous mutation in the complex I NDUSF4 subunit were refractory to protection, suggesting that a fully functional complex I, capable of reversible inhibition is critical forCardioprotection.
Ranolazine: a potential new treatment for chronic stable angina.
TLDR
The clinical data with ranolazine focuses on its use in chronic stable angina, where it has been shown to increase exercise tolerance and decrease angina compared with placebo and in combination with beta-blockers and calcium-channel blockers.
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