title: 2,2,5,5-Tetramethylpyrroline-based compounds in prevention of oxyradical-induced myocardial damage.
abstract: Reactive oxygen species have been known to play a major role in a wide variety of pathophysiologic processes. A new compound, H-2545, based on a 2,2,5,5-tetramethyl-3-pyrroline-3-carboxamide structure, has been reported to exhibit antiarrhythmic function as well as favorable antioxidant properties. Studies were performed in an isolated rat heart model to measure the efficacy of H-2545 and its metabolite, H-2954, in preventing ischemia-reperfusion and hydrogen peroxide-induced oxidative myocardial damage: lipid peroxidation, protein oxidation, activity of respiratory complexes, NAD, and high-energy phosphate metabolism. The cardioprotective effects of examined compounds were compared with that of a well-known water-soluble vitamin E analog, Trolox. To determine whether the antioxidant property of H-2545 is due to the pyrroline ring, the scavenger effects of mexiletine and HO-2434 (mexiletine substituted with a pyrroline group) were compared. The results showed that H-2545 decreased significantly the ischemia-reperfusion-induced thiobarbituric acid reactive substance (TBARS) formation, the protein oxidation and ssDNA break formation in perfused rat hearts. H-2545 decreased the NAD loss in postischemic hearts. The activity of respiratory complexes, myocardial energy metabolism, and functional myocardial recovery were also improved during reperfusion by adding H-2545 to the perfusion medium. H-2954 exerted significantly lower protection against ischemia-reperfusion-induced myocardial injury than H-2545, and it was comparable to that of Trolox. Both H-2545 and H-2954 are highly effective against H O -induced oxidative myocardial cell damage. The findings show that substitution of mexiletine with a 2,2,5,5-tetramethyl-pyrroline group (HO-2434) increased its antioxidant and cardioprotective effects. In conclusion, these results suggest that sterically hindered pyrroline derivatives accumulating in membranes can be highly effective at preventing oxidative myocardial cell damage.
authors.affiliation: University of Pecs, Medical School 1st Department of Medicine, Pecs, Hungary.
authors.forename: Robert
authors.initials: R
authors.lastname: Halmosi
authors.forename: Peter
authors.initials: P
authors.lastname: Deres
authors.forename: Ambrus
authors.initials: A
authors.lastname: Toth
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Berente
authors.forename: Tamas
authors.initials: T
authors.lastname: Kalai
authors.forename: Balazs
authors.initials: B
authors.lastname: Sumegi
authors.forename: Kalman
authors.initials: K
authors.lastname: Hideg
authors.forename: Kalman
authors.initials: K
authors.lastname: Toth
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000517:prevention & control*; D006861:Hydrogen Peroxide / Q000037:antagonists & inhibitors / Q000633:toxicity; D007211:Indoles / Q000627:therapeutic use*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D011758:Pyrroles / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000517:prevention & control
chemical_list: D000975:Antioxidants; C441088:H 2545; D007211:Indoles; D011758:Pyrroles; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide