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A comparison between ranolazine and CVT-4325, a novel inhibitor of fatty acid oxidation, on cardiac metabolism and left ventricular function in rat isolated perfused heart during ischemia and reperfusion.
J Pharmacol Exp Ther. 2007 Apr; 321(1):213-20.JP

Abstract

Inhibition of fatty acid oxidation has been reported to be cardioprotective against myocardial ischemic injury; however, recent studies have questioned whether the cardioprotection associated with putative fatty acid oxidation inhibitors, such as ranolazine and trimetazidine, are due to changes in substrate oxidation. Therefore, the goals of this study were to compare the effects of ranolazine with a new fatty acid oxidation inhibitor, CVT-4325 [(R)-1-(2-methylbenzo[d]thiazol-5-yloxy)-3-(4-((5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-piperazin-1-yl)propan-2-ol], on carbohydrate and fatty acid oxidation and on left ventricular (LV) function in the response to ischemia/reperfusion in rat isolated perfused hearts. Metabolic fluxes were determined in hearts perfused in an isovolumic Langendorff mode using 13C nuclear magnetic resonance isotopomer analysis or in isolated working hearts using [14C]glucose and [3H]palmitate, with and without 10 microM ranolazine or 3 microM CVT-4325. Isovolumic perfused hearts were also subjected to 30 min of low-flow ischemia (0.3 ml/min) and 60 min of reperfusion, and working hearts were subjected to 15 min of zero-flow ischemia and 60 min of reperfusion. Regardless of the experimental protocol, ranolazine had no effect on carbohydrate or fatty acid oxidation, whereas CVT-4325 significantly reduced fatty acid oxidation up to approximately 7-fold with a concomitant increase in carbohydrate oxidation. At these same concentrations, although ranolazine significantly improved LV functional recovery following ischemia/reperfusion, CVT-4325 had no significant protective effect. These results demonstrate that at pharmacologically relevant concentrations, ischemic protection by ranolazine was not mediated by inhibition of fatty acid oxidation and conversely that inhibition of fatty acid oxidation with CVT-4325 was not associated with improved LV functional recovery.

Authors+Show Affiliations

Division of Cardiovascular Disease, Department of Medicine, University of Alabama, Birmingham, AL 35294-0005, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17202401

Citation

Wang, Peipei, et al. "A Comparison Between Ranolazine and CVT-4325, a Novel Inhibitor of Fatty Acid Oxidation, On Cardiac Metabolism and Left Ventricular Function in Rat Isolated Perfused Heart During Ischemia and Reperfusion." The Journal of Pharmacology and Experimental Therapeutics, vol. 321, no. 1, 2007, pp. 213-20.
Wang P, Fraser H, Lloyd SG, et al. A comparison between ranolazine and CVT-4325, a novel inhibitor of fatty acid oxidation, on cardiac metabolism and left ventricular function in rat isolated perfused heart during ischemia and reperfusion. J Pharmacol Exp Ther. 2007;321(1):213-20.
Wang, P., Fraser, H., Lloyd, S. G., McVeigh, J. J., Belardinelli, L., & Chatham, J. C. (2007). A comparison between ranolazine and CVT-4325, a novel inhibitor of fatty acid oxidation, on cardiac metabolism and left ventricular function in rat isolated perfused heart during ischemia and reperfusion. The Journal of Pharmacology and Experimental Therapeutics, 321(1), 213-20.
Wang P, et al. A Comparison Between Ranolazine and CVT-4325, a Novel Inhibitor of Fatty Acid Oxidation, On Cardiac Metabolism and Left Ventricular Function in Rat Isolated Perfused Heart During Ischemia and Reperfusion. J Pharmacol Exp Ther. 2007;321(1):213-20. PubMed PMID: 17202401.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A comparison between ranolazine and CVT-4325, a novel inhibitor of fatty acid oxidation, on cardiac metabolism and left ventricular function in rat isolated perfused heart during ischemia and reperfusion. AU - Wang,Peipei, AU - Fraser,Heather, AU - Lloyd,Steven G, AU - McVeigh,Jeffrey J, AU - Belardinelli,Luiz, AU - Chatham,John C, Y1 - 2007/01/03/ PY - 2007/1/5/pubmed PY - 2007/5/15/medline PY - 2007/1/5/entrez SP - 213 EP - 20 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 321 IS - 1 N2 - Inhibition of fatty acid oxidation has been reported to be cardioprotective against myocardial ischemic injury; however, recent studies have questioned whether the cardioprotection associated with putative fatty acid oxidation inhibitors, such as ranolazine and trimetazidine, are due to changes in substrate oxidation. Therefore, the goals of this study were to compare the effects of ranolazine with a new fatty acid oxidation inhibitor, CVT-4325 [(R)-1-(2-methylbenzo[d]thiazol-5-yloxy)-3-(4-((5-(4-(trifluoromethyl)phenyl)-1,2,4-oxadiazol-3-yl)methyl)-piperazin-1-yl)propan-2-ol], on carbohydrate and fatty acid oxidation and on left ventricular (LV) function in the response to ischemia/reperfusion in rat isolated perfused hearts. Metabolic fluxes were determined in hearts perfused in an isovolumic Langendorff mode using 13C nuclear magnetic resonance isotopomer analysis or in isolated working hearts using [14C]glucose and [3H]palmitate, with and without 10 microM ranolazine or 3 microM CVT-4325. Isovolumic perfused hearts were also subjected to 30 min of low-flow ischemia (0.3 ml/min) and 60 min of reperfusion, and working hearts were subjected to 15 min of zero-flow ischemia and 60 min of reperfusion. Regardless of the experimental protocol, ranolazine had no effect on carbohydrate or fatty acid oxidation, whereas CVT-4325 significantly reduced fatty acid oxidation up to approximately 7-fold with a concomitant increase in carbohydrate oxidation. At these same concentrations, although ranolazine significantly improved LV functional recovery following ischemia/reperfusion, CVT-4325 had no significant protective effect. These results demonstrate that at pharmacologically relevant concentrations, ischemic protection by ranolazine was not mediated by inhibition of fatty acid oxidation and conversely that inhibition of fatty acid oxidation with CVT-4325 was not associated with improved LV functional recovery. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/17202401/A_comparison_between_ranolazine_and_CVT_4325_a_novel_inhibitor_of_fatty_acid_oxidation_on_cardiac_metabolism_and_left_ventricular_function_in_rat_isolated_perfused_heart_during_ischemia_and_reperfusion_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=17202401 DB - PRIME DP - Unbound Medicine ER -