Protective effects of ranolazine in guinea-pig hearts during low-flow ischaemia and their association with increases in active pyruvate dehydrogenase.
1. In isolated Langendorff-perfused, electrically-paced, hearts of guinea-pigs, global low-flow-ischaemia (LFI; at 0.7 ml min-1) resulted in marked increases in the rates of release of lactate, lactate dehydrogenase (LDH) and creatine kinase (CK) over a 30 min period. At the end of the LFI period, tissue ATP content was significantly reduced from a control value of 11.8 +/- 0.8 (5) to 5.6 +/- 0.8 (5) mumol g-1 dry weight. 2. The presence of ranolazine [(+/-)-N-(2,6-dimethyl-phenyl)-4[2-hydroxy-3-(2-methoxy-phenoxyl)- propyl] - l-piperazine acetamide dihydro-chloride; RS-43285-193] at 10 microM, from 20 min prior to and during LFI, resulted in significant reductions in the release of lactate, LDH and CK during the ischaemic period and a significant preservation of tissue ATP (9.0 +/- 1.1 (6) mumol g-1 dry wt.). Ranolazine did not prevent the reductions in creatine phosphate or glycogen observed in LFI, nor did it have any significant effects on any contractile parameters before or during the LFI period. 3. Neither ranolazine nor LFI affected the total amounts of tissue pyruvate dehydrogenase (PDH) activity; however, the significant reduction in the amount of active, non-phosphorylated PDH caused by LFI (from 88.2 +/- 5.5 to 44.2 +/- 3.2% of total activity) was partially but significantly prevented by ranolazine (67.2 +/- 6.8%). This effect of ranolazine on PDH may be part of the mechanism whereby the compound reduces lactate release and preserves tissue ATP during ischaemia.
Clarke
B
B
Department of Pharmacology, Syntex Research Centre, Riccarton, Edinburgh.
Spedding
M
M
Patmore
L
L
McCormack
J G
JG
D000083:Acetanilides; D000255:Adenosine Triphosphate / Q000378:metabolism; D000787:Angina Pectoris / Q000188:drug therapy*; D000818:Animals; D003402:Creatine Kinase / Q000378:metabolism; D005260:Female; D006003:Glycogen / Q000378:metabolism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D017202:Myocardial Ischemia / Q000201:enzymology / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology*; D010477:Perfusion; D010725:Phosphocreatine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism*; D000069458:Ranolazine
D000083:Acetanilides; D007773:Lactates; D010879:Piperazines; D011768:Pyruvate Dehydrogenase Complex; D010725:Phosphocreatine; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D006003:Glycogen; D000069458:Ranolazine; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase