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Research ArticleCARDIOVASCULAR

Targeted Antioxidant Properties ofN-[(Tetramethyl-3-pyrroline-3-carboxamido)propyl]phthalimide and Its Nitroxide Metabolite in Preventing Postischemic Myocardial Injury

Ravi A. Shankar, Kalman Hideg, Jay L. Zweier and Periannan Kuppusamy
Journal of Pharmacology and Experimental Therapeutics March 2000, 292 (3) 838-845;
Ravi A. Shankar
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Kalman Hideg
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Jay L. Zweier
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Periannan Kuppusamy
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Abstract

We investigated the cardioprotective efficacy of a new compound based on 2,2,5,5-tetramethyl-3-pyrroline-3-carboxamide (TPC-NH). Biochemical studies using electron paramagnetic resonance (EPR) spectroscopy suggest thatTPC-NH is a scavenger of reactive oxygen species. In vitro cellular studies show that TPC-NH protects isolated cardiomyocytes against oxidative damage caused by superoxide radicals. Ex vivo EPR studies on the isolated rat heart indicate that the TPC-NH is metabolically oxidized to the nitroxide form. Studies were also performed in the isolated rat heart model to measure the efficacy of TPC-NH and its metabolites in preventing postischemic reperfusion injury. Serial measurements of contractile function were performed on hearts subjected to ischemia-reperfusion. Hearts were either untreated or treated with 50 μM TPC-NH or with its metabolites for 1 min before ischemia and during the first 5 min of reflow. TPC-NH showed marked protection with a more than 3-fold increased recovery of contractile function compared with control hearts, whereas its oxidative metabolites exhibited significant but lower protection. Thus,TPC-NH and, to a lesser extent, its oxidation metabolites exhibit potent membrane-targeted antioxidant action and exert marked protection against myocardial injury in the postischemic heart.

Footnotes

  • Send reprint requests to: Periannan Kuppusamy, Ph.D., The EPR Center, 5501 Hopkins Bayview Circle, Room LB-68, Baltimore, MD 21224. E-mail: kuppu{at}welch.jhu.edu

  • ↵1 This work was supported in part by National Cancer Institute Grant CA78886, National Institutes of Health Grant HL38324, Hungarian Research Foundation OTKA Grant T 021277, and Hungarian Academy of Sciences Grant AKP 97-13 4,2 (K.H.). P.K. was supported by an Established Investigator Award from the American Heart Association during the tenure of this study.

  • Abbreviations:
    ROS
    reactive oxygen species
    TPC-NH
    N-[(2,2,5,5-tetramethyl-3-pyrroline-3-carboxamido)propyl]phthalimide
    TPC-NOH
    N-[(1-hydroxyl-2,2,5,5-tetramethyl-3-pyrrolin-3-carboxamido)propyl]phthalimide
    TPC-NO
    N-[(1-oxyl-2,2,5,5-tetramethyl-3-pyrroline-3-carboxamido)propyl]phthalimide
    AAPH
    2,2′-azobis-2-amidinopropane dihydrochloride
    DTPA
    diethylenetriaminepentaacetate
    X
    xanthine
    XO
    xanthine oxidase
    EPR
    electron paramagnetic resonance
    LVEDP
    left ventricular end-diastolic pressure
    LVSP
    left ventricular systolic pressure
    LVDP
    left ventricular developed pressure
    HR
    heart rate
    CF
    coronary flow
    RPP
    rate-pressure product
    LDH
    lactate dehydrogenase
    • Received June 30, 1999.
    • Accepted November 19, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 292 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 292, Issue 3
1 Mar 2000
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Research ArticleCARDIOVASCULAR

Targeted Antioxidant Properties ofN-[(Tetramethyl-3-pyrroline-3-carboxamido)propyl]phthalimide and Its Nitroxide Metabolite in Preventing Postischemic Myocardial Injury

Ravi A. Shankar, Kalman Hideg, Jay L. Zweier and Periannan Kuppusamy
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 838-845;

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Research ArticleCARDIOVASCULAR

Targeted Antioxidant Properties ofN-[(Tetramethyl-3-pyrroline-3-carboxamido)propyl]phthalimide and Its Nitroxide Metabolite in Preventing Postischemic Myocardial Injury

Ravi A. Shankar, Kalman Hideg, Jay L. Zweier and Periannan Kuppusamy
Journal of Pharmacology and Experimental Therapeutics March 1, 2000, 292 (3) 838-845;
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