Targeted antioxidant properties of N-[(tetramethyl-3-pyrroline-3-carboxamido)propyl]phthalimide and its nitroxide metabolite in preventing postischemic myocardial injury.
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 that TPC-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 microM 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.
Shankar
R A
RA
Department of Medicine, Division of Cardiology, Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA.
Hideg
K
K
Zweier
J L
JL
Kuppusamy
P
P
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D005260:Female; D005609:Free Radicals; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D018384:Oxidative Stress; D010797:Phthalimides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000975:Antioxidants; D005609:Free Radicals; C405208:N-((2,2,5,5-tetramethyl-3-pyrroline-3-carboxamido)propyl)phthalimide; D010797:Phthalimides