Protective effects of ranolazine in guinea‐pig hearts during low‐flow ischaemia and their association with increases in active pyruvate dehydrogenase

Abstract

1In isolated Langendorff-perfused, electrically-paced, hearts of guinea-pigs, global low-flow-ischaemia (LFI; at 0.7 ml min-') 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) JAmol g-' dry weight.2 The presence of ranolazine [(±)-N-(2,6-dimethyl-phenyl)-4[2-hydroxy-3-(2-methoxy-phenoxyl)-propyl]-1-piperazine acetamide dihydro-chloride; at 10 JAM, 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) JAmol g-' 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.

Improved Left Ventricular Function and Reduced Necrosis after Myocardial Ischemia/Reperfusion in Rabbits Treated with Ranolazine, an Inhibitor of the Late Sodium Channel

“…This dose of ranolazine was based on therapeutic levels for angina treatment in humans and may not have provided maximal efficacy in our model. Based on results of other studies describing the cardioprotective effects of ranolazine in isolated perfused hearts (Clarke et al, 1993;Gralinski et al, 1994), concentrations of 15 and 20 M ranolazine were found to be more efficacious than 5 and 10 M, concentrations similar to that achieved in our study. In the present study, the dose used yielded plasma concentrations within the range of clinical therapeutic plasma levels, as was our intention.…”

“…Gralinski et al (1994) noted that the increase in tissue calcium seen in control hearts was completely prevented by 20 M ranolazine. In a guinea pig heart model of low-flow ischemia, Clarke et al (1993) found that hearts perfused with ranolazine had less LDH and CK release during the ischemic period and that tissue ATP was preserved.…”

“…For example, ranolazine reduced myocardial creatine kinase (CK) release in isolated guinea pig hearts (Clarke et al, 1993) and baboons (Allely and Alps, 1990), but in a study in dogs, no reduction in infarct size was found . Ranolazine also improved left ventricular developed pressure after global ischemia in an isolated perfused rabbit heart .…”

Analytical and semipreparative resolution of ranolazine enantiomers by liquid chromatography using polysaccharide chiral stationary phases

“…1) is a novel antiischemia and antianginal agent that has been found to be effective to treat chronic angina [1][2][3]. It works by inhibiting fatty acid betaoxidation and by increasing the active fraction of pyruvate dehydrogenase [4,5]. Ranolazine appears to switch adenosine triphosphate (ATP) production away from fatty acid oxidation to more oxygen-efficient carbohydrate oxidation as a substrate for ATP production, especially when free fatty acids are elevated during ischemia [6].…”

Synthesis of Ranolazine Metabolites and Their Anti-myocardial Ischemia Activities

“…1) is a piperazine derivative developed by Syntex Laboratories, which has been shown to have anti-ischemic action. [2][3][4][5] It's a partial fatty acid oxidation (pFOX) inhibitor. Its mechanism has not been fully understood.…”