Ranolazine attenuates palmitoyl-L-carnitine-induced mechanical and metabolic derangement in the isolated, perfused rat heart

The effect of ranolazine, a novel anti-ischaemic drug that stimulates the a ctivity of pyruvate dehydrogenase, on palmitoyl-L-carnitine-induced mechani cal dysfunction and metabolic derangement in isolated perfused rat hearts h as been studied and compared with the effect of dichloroacetate, an activat or of pyruvate dehydrogenase. Rat hearts paced electrically were perfused aerobically at constant flow by the Langendorff technique. Palmitoyl-L-carnitine (4 mu M) increased left v entricular end-diastolic pressure and reduced left ventricular developed pr essure (i.e. induced mechanical dysfunction); it also reduced tissue levels of adenosine triphospbate and increased tissue levels of adenosine monopho sphate (i.e. induced metabolic derangement). These functional and metabolic alterations induced by palmitoyl-L-carnitine were attenuated by ranolazine (5, 10, and 20 mu M) in a concentration-dependent manner. In contrast, dic hloroacetate (1 and 10mM) did not attenuate palmitoyl-L-carnitine-induced m echanical and metabolic derangement. In the normal (palmitoyl-L-carnitine-u ntreated) heart, however, ranolazine did not modify mechanical function and energy metabolism. These results suggest that ranolazine attenuates palmitoyl-L-carnitine-indu ced mechanical and metabolic derangement in the rat heart, and that the ben eficial action of ranolazine is not because of the energy-sparing effect or activation of pyruvate dehydrogenase.