PROTECTIVE EFFECTS OF RANOLAZINE IN GUINEA-PIG HEARTS DURING LOW-FLOWISCHEMIA AND THEIR ASSOCIATION WITH INCREASES IN ACTIVE PYRUVATE-DEHYDROGENASE

1 In isolated Langendorff-perfused, electrically-paced, hearts of guin ea-pigs, global low-flow-ischaemia (LFI; at 0.7 ml min-1) resulted in marked increases in the rates of release of lactate, lactate dehydroge nase (LDH) and creatine kinase (CK) over a 30 min period. At the end o f 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 wei ght. 2 The presence of ranolazine ydroxy-3-(2-methoxy-phenoxyl)-propyl ]-1-piperazine acetamide dihydro-chloride; RS-43285-193] at 10 mum, fr om 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 dr y wt.). Ranolazine did not prevent the reductions in creatine phosphat e or glycogen observed in LFI, nor did it have any significant effects on any contractile parameters before or during the LFI period. 3 Neit her ranolazine nor LFI affected the total amounts of tissue pyruvate d ehydrogenase (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 significant ly prevented by ranolazine (67.2 +/- 6.8%). This effect of ranolazine on PDH may be part of the mechanism whereby the compound reduces lacta te release and preserves tissue ATP during ischaemia.