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The effects of dihydroxyfumarate on isolated rabbit papillary muscle function: evidence for an iron dependent
Abstract:
To delineate the active free radical species mediating the toxic effects of autoxidizing dihydroxyfumarate (DHF), isolated rabbit right ventricular papillary muscles were exposed to 4.5 mM DHF in the presence of FeCl3, ADP and bovine albumin. In the absence of free radical scavengers a 47.3 +/- 11.5% (mean +/- standard deviation) depression in contractile force was noted over 60 minutes. Neither the combination of superoxide dismutase (SOD) 3,200 u/cc and catalase (CAT) 2,950 u/cc nor mannitol 0.1 M provided statistically significant protection. Deferoxamine mesylate (DFX) 10 mg/cc (15 mM) did provide significant protection of muscle function both in the presence and absence of SOD and CAT (p less than 0.01). The degree of protection conferred by DFX alone was statistically similar to that of DFX with SOD and CAT. This data suggests the involvement of an iron-oxygen complex not dependent on superoxide or hydrogen peroxide for its formation and not readily scavenged by mannitol. The perferryl ion may be representative of such a species. Alternatively, a reactive complex similar to the 'Crypto-OH' radical proposed by Youngman may be formed by the reaction of DHF with iron and oxygen.
Insights
Free radical species from dihydroxyfumarate (DHF) autoxidation impair heart muscle function. Deferoxamine mesylate (DFX) protected muscle, suggesting iron-oxygen complexes, not superoxide or hydrogen peroxide, mediate toxicity.
Area of Science:
- Cardiovascular Physiology
- Free Radical Biology
- Biochemistry
Background:
- Autoxidation of dihydroxyfumarate (DHF) generates reactive species.
- These species can induce cellular damage, particularly in cardiac tissues.
Purpose of the Study:
- To identify the specific free radical species responsible for DHF-induced toxicity in cardiac muscle.
- To evaluate the protective effects of various scavengers against DHF-induced damage.
Main Methods:
- Isolated rabbit right ventricular papillary muscles were used.
- Muscles were exposed to DHF with FeCl3, ADP, and bovine albumin.
- Effects of superoxide dismutase (SOD), catalase (CAT), mannitol, and deferoxamine mesylate (DFX) were assessed on contractile force.
Main Results:
- DHF exposure caused a significant depression in muscle contractile force (47.3%).
- SOD/CAT and mannitol offered no significant protection.
- DFX provided significant protection, independent of SOD/CAT presence.
Conclusions:
- The toxic species are likely iron-oxygen complexes, possibly perferryl or a 'Crypto-OH' radical.
- These complexes are not dependent on superoxide or hydrogen peroxide.
- DFX is effective in mitigating DHF-induced cardiac muscle dysfunction.