Vol. 292, Issue 3, 838-845, March 2000

Targeted Antioxidant Properties of N-[(Tetramethyl-3-pyrroline-3-carboxamido)propyl]phthalimide and Its Nitroxide Metabolite in Preventing Postischemic Myocardial Injury¹

Ravi A. Shankar, Kalman Hideg, Jay L. Zweier and Periannan Kuppusamy

Department of Medicine, Division of Cardiology and the EPR Center, Johns Hopkins University, School of Medicine, Baltimore, Maryland; and Institute of Organic and Medicinal Chemistry, University of Pécs, Pécs, Hungary (K.H.)

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 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.