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Research ArticleCARDIOVASCULAR

Close Association Between the Reduction in Myocardial Energy Metabolism and Infarct Size: Dose-Response Assessment of Cyclosporine

Claus U. Niemann, Maythem Saeed, Haydar Akbari, Wolfgang Jacobsen, Leslie Z. Benet, Uwe Christians and Natalie Serkova
Journal of Pharmacology and Experimental Therapeutics September 2002, 302 (3) 1123-1128; DOI: https://doi.org/10.1124/jpet.102.036848
Claus U. Niemann
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Maythem Saeed
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Haydar Akbari
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Wolfgang Jacobsen
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Leslie Z. Benet
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Uwe Christians
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Natalie Serkova
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Abstract

Cyclosporine protects the heart against ischemia/reperfusion injury, but its effect on cardiac metabolism is largely unknown. We assessed cyclosporine-induced metabolic changes in the rat heart prior to occlusion using magnetic resonance spectroscopy (MRS) and correlated effects with infarct size in a coronary occlusion/reperfusion model. The two study groups were cyclosporine and cyclosporine + coronary occlusion (n = 20/group). Rats were pretreated with cyclosporine (5, 10, 15, and 25 mg/kg/day) or the vehicle by oral gavage for 3 days (n = 4/dose). On day 4, hearts of rats in the cyclosporine group were excised, and extracted cell metabolites were measured using 1H and 31P MRS. The second group was subjected to 30 min of coronary artery occlusion followed by 24 h of reperfusion. Infarct size and area at risk were measured using a double staining method. In the cyclosporine group, cyclosporine reduced cardiac energy metabolism (ATP:r = −0.89, P < 0.001) via depression of oxidative phosphorylation and the Krebs' cycle in a dose-dependent manner. The decrease of ATP levels was positively correlated with changes of NAD+ (r = 0.89), glutamate (r = 0.95), glutamine (r = 0.84), and glucose concentrations (r = 0.92, all P < 0.002). It was inversely correlated with lactate (r = −0.93,P < 0.001). In the coronary occlusion group, cyclosporine dose dependently reduced the ratio [area of infarct/area of the left ventricle] (r = −0.86,P < 0.01), with 15 mg/kg/day being the most effective cyclosporine dose. The reduction in infarct size correlated with the reduction in oxidative phosphorylation (ATP:r = 0.97; NAD+: r = 0.82, P < 0.01). The reduction in cardiac energy metabolism before occlusion may be the cause of myocardial preservation during ischemia/reperfusion.

Footnotes

  • This study was supported in part by Grants Se 985/1-1 (to N.S.) and Ch 95/6-2 (to U.C.) from the Deutsche Forschungsgemeinschaft (Germany).

  • DOI: 10.1124/jpet.102.036848

  • Abbreviations:
    MRS
    magnetic resonance spectroscopy
    PCA
    perchloric acid
    NMR
    nuclear magnetic resonance
    LPO
    lipid peroxidation
    TBA
    thiobarbituric acid
    LC
    liquid chromatography
    HPLC
    high-pressure LC
    MS
    mass spectroscopy
    PUFA
    polyunsaturated fatty acids
    TAG
    triacylglycerides
    • Received April 1, 2002.
    • Accepted May 9, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 302 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 302, Issue 3
1 Sep 2002
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Research ArticleCARDIOVASCULAR

Close Association Between the Reduction in Myocardial Energy Metabolism and Infarct Size: Dose-Response Assessment of Cyclosporine

Claus U. Niemann, Maythem Saeed, Haydar Akbari, Wolfgang Jacobsen, Leslie Z. Benet, Uwe Christians and Natalie Serkova
Journal of Pharmacology and Experimental Therapeutics September 1, 2002, 302 (3) 1123-1128; DOI: https://doi.org/10.1124/jpet.102.036848

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Research ArticleCARDIOVASCULAR

Close Association Between the Reduction in Myocardial Energy Metabolism and Infarct Size: Dose-Response Assessment of Cyclosporine

Claus U. Niemann, Maythem Saeed, Haydar Akbari, Wolfgang Jacobsen, Leslie Z. Benet, Uwe Christians and Natalie Serkova
Journal of Pharmacology and Experimental Therapeutics September 1, 2002, 302 (3) 1123-1128; DOI: https://doi.org/10.1124/jpet.102.036848
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