Targeted Antioxidant Properties ofN-[(Tetramethyl-3-pyrroline-3-carboxamido)propyl]phthalimide and Its Nitroxide Metabolite in Preventing Postischemic Myocardial Injury1
- Department of Medicine, Division of Cardiology and the EPR Center, Johns Hopkins University, School of Medicine, Baltimore, Maryland; and1Institute of Organic and Medicinal Chemistry, University of Pécs, Pécs, Hungary (K.H.)
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
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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
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↵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
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- Received June 30, 1999.
- Accepted November 19, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
