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Cited by 291Cardiac Ischemia and ReperfusionCardiovascular Function and Risk FactorsNeurological Disorders and Treatments

Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts

McCormack, James G., Barr, Rick L., Wolff, Andrew A., Lopaschuk, Gary D.·1996·Circulation
DOI 10.1161/01.cir.93.1.135
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Abstract

BACKGROUND: Ranolazine is a novel antianginal agent that may reduce symptoms without affecting hemodynamics and has shown cardiac antiischemic effects in in vivo and in vitro models. In one study it increased active pyruvate dehydrogenase (PDHa). Other agents that increase PDHa and so increase glucose and decrease fatty acid (FA) oxidation are beneficial in ischemic-reperfused hearts. Effects of ranolazine on glucose and palmitate oxidation and glycolysis were assessed in isolated rat hearts. METHODS AND RESULTS: Working hearts were perfused with Krebs-Henseleit buffer plus 3% albumin under normoxic conditions and on reperfusion after 30-minute no-flow ischemia and under conditions designed to give either low [low (Ca) (1.25 mmol/L), high [FA] (1.2 mmol/L palmitate; with/without insulin] or high (2.5 mmol/L Ca, 0.4 mmol/L palmitate; with/without pacing) glucose oxidation rates; Langendorff-perfused hearts (high Ca, low FA) were subjected to varying degrees of low-flow ischemia. Glycolysis and glucose oxidation were measured with the use of [5-3H/U-14C]-glucose and FA oxidation with the use of [1-14C]- or [9,10-3H]-palmitate. In working hearts, 10 micromol/L ranolazine significantly increased glucose oxidation 1.5-fold to 3-fold under conditions in which the contribution of glucose to overall ATP production was low (low Ca, high FA, with insulin), high (high Ca, low Fa, with pacing), or intermediate. In some cases, reductions in FA oxidation were seen. No substantial changes in glycolysis were noted with/without ranolazine; rates were approximately 10-fold glucose oxidation rates, suggesting that pyruvate supply was not limiting. Insulin increased basal glucose oxidation and glycolysis but did not alter ranolazine responses. In normoxic Langendorff hearts (high Ca, low FA; 15 mL/min), all basal rates were lower compared with working hearts, but 10 micromol/L ranolazine similarly increased glucose oxidation; ranolazine also significantly increased it during flow reduction to 7, 3, and 0.5 mL/min. Ranolazine did not affect baseline contractile or hemodynamic parameters or O2 use. In reperfused ischemic working hearts, ranolazine significantly improved functional outcome, which was associated with significant increases in glucose oxidation, a reversal of the increased FA oxidation seen in control reperfusions (versus preischemic), and a smaller but significant increase in glycolysis. CONCLUSIONS: Beneficial effects of ranolazine in cardiac ischemia/reperfusion may be due, at least in part, to a stimulation of glucose oxidation and a reduction in FA oxidation, allowing improved ATP/O2 and reduction in the buildup of H+, lactate, and harmful fatty acyl intermediates.

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  • Ranolazine inhibits potassium and sodium currents and increases glucose metabolism at the expense of free fatty acid metabolism, thereby enhancing efficient use of oxygen.

    “The antianginal compound ranolazine inhibits potassium and sodium currents and increases glucose metabolism at the expense of free fatty acid metabolism, thereby enhancing efficient use of oxygen.676, 677”

    From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [677]

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Authors
McCormack, J. G., Barr, R. L., Wolff, A. A., & Lopaschuk, G. D.
Affiliations
University of Alberta (CA)
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
1996-01
Volume
93
Issue
1
Pages
135-142
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/01.cir.93.1.135
OpenAlex
W1963627099
Cited by
291
References
30
Citations by year
2026: 2 · 2025: 6 · 2024: 5 · 2023: 9 · 2022: 4 · 2021: 10 · 2020: 4 · 2019: 4 · 2018: 6 · 2017: 7 · 2016: 13 · 2015: 7 · 2014: 13 · 2013: 15 · 2012: 10
FWCI
6.06
Type
journal article
Language
en
Open access
closed
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Function and Risk Factors
  • Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
Keywords
ranolazine, glucose oxidation, myocardial ischemia, ischemia-reperfusion injury, pyruvate dehydrogenase, fatty acid oxidation, glycolysis, palmitate, insulin, calcium, antianginal drugs, myocardial energy metabolism, Langendorff heart, low-flow ischemia, pacing, oxygen consumption, ATP production, anti-ischemic effect
MeSH terms
Ranolazine, Acetanilides, Animals, Fatty Acids, Glucose, Hemodynamics, Male, Myocardial Contraction, Oxidation-Reduction, Piperazines, Myocardial Reperfusion Injury, Myocardial Ischemia, Rats, Sprague-Dawley, Rats

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