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 activity of pyruvate dehydrogenase, on palmitoyl-L-carnitine-induced mechanical dysfunction and metabolic derangement in isolated perfused rat hearts has been studied and compared with the effect of dichloroacetate, an activator of pyruvate dehydrogenase. Rat hearts paced electrically were perfused aerobically at constant flow by the Langendorff technique. Palmitoyl-L-carnitine (4 microM) increased left ventricular end-diastolic pressure and reduced left ventricular developed pressure (i.e. induced mechanical dysfunction); it also reduced tissue levels of adenosine triphosphate and increased tissue levels of adenosine monophosphate (i.e. induced metabolic derangement). These functional and metabolic alterations induced by palmitoyl-L-carnitine were attenuated by ranolazine (5, 10, and 20 microM) in a concentration-dependent manner. In contrast, dichloroacetate (1 and 10 mM) did not attenuate palmitoyl-L-carnitine-induced mechanical and metabolic derangement. In the normal (palmitoyl-L-carnitine-untreated) heart, however, ranolazine did not modify mechanical function and energy metabolism. These results suggest that ranolazine attenuates palmitoyl-L-carnitine-induced mechanical and metabolic derangement in the rat heart, and that the beneficial action of ranolazine is not because of the energy-sparing effect or activation of pyruvate dehydrogenase.
Maruyama
K
K
Department of Pharmacology, Asahikawa Medical College, Japan.
Hara
A
A
Hashizume
H
H
Ushikubi
F
F
Abiko
Y
Y
D000083:Acetanilides; D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D010879:Piperazines / Q000494:pharmacology*; D011768:Pyruvate Dehydrogenase Complex / Q000187:drug effects* / Q000378:metabolism; D000069458:Ranolazine; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left
D000083:Acetanilides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011768:Pyruvate Dehydrogenase Complex; D000255:Adenosine Triphosphate; D000069458:Ranolazine; D002331:Carnitine