Ranolazine increases active pyruvate dehydrogenase in perfused normoxic rat hearts: evidence for an indirect mechanism.
Ranolazine has shown anti-anginal efficacy in humans and cardiac anti-ischaemic activity in models, but without affecting haemodynamics or baseline contraction. In isolated normoxic rat hearts, Langendorff-perfused for 30 min with 11 mM glucose, 3% albumin, and 0.4 mM or 0.8 mM palmitate, 20 microM ranolazine significantly increased active, dephosphorylated, pyruvate dehydrogenase (PDHa), but not with no palmitate or 1.2 mM palmitate. Dichloroactetate (DCA, 1 mM), a PDHa kinase inhibitor, significantly increased PDHa in hearts perfused with 0, 0.4 or 0.8 mM but not 1.2 mM palmitate. PDHa was significantly increased with 1.2 mM palmitate by DCA plus ranolazine, and additive effects were also seen at 0.8 mM palmitate. Activation of PDH by ranolazine and promotion of glucose oxidation offers a plausible means by which the drug may be anti-ischaemic nonhaemodynamically. Extensive studies with extracted enzymes and isolated rat heart mitochondria failed to demonstrate any effects of ranolazine on PDH kinase or phosphatase, or on PDH catalytic activity, whereas effects of other known effectors (such as DCA) were readily demonstrable, suggesting that ranolazine activates PDH indirectly. Further analyses of the hearts revealed that ranolazine reduced acetyl CoA content under all conditions where fatty acid was present, and +/- DCA which itself had little effect. In the absence of fatty acid, ranolazine and/or DCA raised acetyl CoA. In perfusions where octanoate (+/- albumin) replaced palmitate, ranolazine still decreased acetyl CoA, but not when acetate replaced palmitate. In octanoate-perfused hearts, the contents of the C4, C6 and C8 CoA esters were all increased by ranolazine. This is consistent with ranolazine causing an inhibition of fatty acid beta-oxidation leading to decreased acetyl CoA and activation of PDH.
Clarke
B
B
Department of Pharmacology, Heriot-Watt University Research Park, Edinburgh, Scotland, UK.
Wyatt
K M
KM
McCormack
J G
JG
D000083:Acetanilides; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000818:Animals; D003065:Coenzyme A / Q000378:metabolism; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D010477:Perfusion; D010879:Piperazines / Q000494:pharmacology*; D011768:Pyruvate Dehydrogenase Complex / Q000819:agonists*; D000069458:Ranolazine; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values
D000083:Acetanilides; D010879:Piperazines; D011768:Pyruvate Dehydrogenase Complex; D000105:Acetyl Coenzyme A; D003999:Dichloroacetic Acid; D000069458:Ranolazine; D003065:Coenzyme A