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.