2,2,5,5-Tetramethylpyrroline-based compounds in prevention of oxyradical-induced myocardial damage.
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.
Halmosi
Robert
R
University of Pecs, Medical School 1st Department of Medicine, Pecs, Hungary.
Deres
Peter
P
Toth
Ambrus
A
Berente
Zoltan
Z
Kalai
Tamas
T
Sumegi
Balazs
B
Hideg
Kalman
K
Toth
Kalman
K
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
D000975:Antioxidants; C441088:H 2545; D007211:Indoles; D011758:Pyrroles; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide