Targeted antioxidant properties of N-[(tetramethyl-3-pyrroline3-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 u sing 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 cause d by superoxide radicals. Ex vivo EPR studies on the isolated rat heart ind icate that the TPC-NH is metabolically oxidized to the nitroxide form. Stud ies were also performed in the isolated rat heart model to measure the effi cacy of TPC-NH and its metabolites in preventing postischemic reperfusion i njury. Serial measurements of contractile function were performed on hearts subjected to ischemia-reperfusion. Hearts were either untreated or treated with 50 mM TPC-NH or with its metabolites for 1 min before ischemia and du ring the first 5 min of reflow. TPC-NH showed marked protection with a more than 3-fold increased recovery of contractile function compared with contr ol hearts, whereas its oxidative metabolites exhibited significant but lowe r protection. Thus, TPC-NH and, to a lesser extent, its oxidation metabolit es exhibit potent membrane-targeted antioxidant action and exert marked pro tection against myocardial injury in the postischemic heart.