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 b aseline contraction. In isolated normoxic rat hearts, Langendorff-perf used for 30 min with 11 mM glucose. 3% albumin, and 0.4 mM or 0.8 mM p almitate, 20 mu M ranolazine significantly increased active, dephospho rylated, 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 m ar but not 1.2 mM palmitate. PDHa was significantly increased with 1.2 mM palmitate by DCA plus ranolazine, and additive effects were also s een at 0.8 mM palmitate. Activation of PDH by ranolazine and promotion of glucose oxidation offers a plausible means by which the drug may b e anti-ischaemic non haemodynamically. Extensive studies with extracte d enzymes and isolated rat heart mitochondria failed to demonstrate an y effects of ranolazine on PDH kinase or phosphatase, or on PDH cataly tic activity, whereas effects of other known effectors (such as DCA) w ere readily demonstrable, suggesting that ranolazine activates PDH ind irectly. Further analyses of the hearts revealed that ranolazine reduc ed acetyl CoA content under all conditions where fatty acid was presen t, and +/-DCA which itself had little effect. In the absence of fatty acid, ranolazine and/or DCA raised acetyl CoA. In perfusions where oct anoate (+/-albumin) replaced palmitate, ranolazine still decreased ace tyl CoA, but not when acetate replaced palmitate. In octanoate-perfuse d hearts, the contents of the C-4, C-6 and C-8 CoA esters were all inc reased by ranolazine, This is consistent with ranolazine causing an in hibition of fatty acid beta-oxidation leading to decreased acetyl CoA and activation of PDH. (C) 1996 Academic Press Limited