Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog.

Abstract

Electron paramagnetic resonance (EPR) spectroscopy was used to investigate whether (i) the free radicals produced in the "stunned" myocardium (myocardium with postischemic contractile dysfunction) are derived from 02, (ii) inhibition of radical reactions improves function, and (iii) i.v. spin traps are effective. Open-chest dogs undergoing a 15-min coronary occlusion received an i.v. infusion of the spin trap, a-phenyl N-tert-butylnitrone (PBN) (50 mg/kg). In group I (n = 6), EPR signals characteristic of radical adducts of PBN appeared in the coronary venous blood during ischemia and increased dramatically after reperfusion. In group II (n = 6), which received PBN and i.v. superoxide dismutase (SOD; 16,000 units/kg) plus catalase (12,000 units/kg), myocardial production of PBN adducts was undetectable during ischemia (A = -100%, P < 0.01 vs. group I) and markedly inhibited after reperfusion (A = -86%, P < 0.001). This effect was seen at all levels of ischemic zone flow but was relatively greater in the low-flow range. In group III (n = 8), the same dosages of SOD and catalase without PBN markedly enhanced contractile recovery (measured as systolic wall thickening) after reperfusion [P < 0.01 at 3 hr vs. controls (group IV, n = 7)]. Systemic plasma activity of SOD and catalase averaged 127 ± 24 and 123 ± 82 units/ml, respectively, 2 min after reperfusion. PBN produced no apparent adverse effects and actually improved postischemic contractile recovery in group I (P < 0.05 at 3 hr vs. controls). This study shows that (i) SOD and catalase are highly effective in blocking free radical reactions in vivo, (ii) the radicals generated in the "stunned" myocardium are derived from univalent reduction of 02, and (iu) inhibition of radical reactions improves functional recovery. The results provide direct, in vivo evidence to support the hypothesis that reactive oxygen metabolites play a causal role in the myocardial "stunning" seen after brief ischemia.Periods of myocardial ischemia that are too brief to cause necrosis are nevertheless followed by prolonged depression of contractility (1-3) or "stunning" (4), which is associated with numerous functional abnormalities (1)(2)(3)(4). Recent studies have shown that myocardial stunning can be attenuated by antioxidants (5-11), suggesting that the accumulation of reactive oxygen metabolites, such as superoxide radical (02-), hydrogen peroxide (H202), and hydroxyl radical (HO-), may play an important role in the pathogenesis of postischemic dysfunction. However, demonstration of the free radical hypothesis of myocardial stunning remains inconclusive because the evidence is indirect. In particular, it has not been determined whether oxygen-derived radicals are actually generated after a brief coronary occlusion and, if so, whether their generation is actually necessary for dysfunction to occur. An unambiguous link in vivo between oxyradical formation and myocardial stunning could be established if one could directly quantitate free radical generation with and without antio...

Developmental and age-related processes that influence the longevity and senescence of photosynthetic tissues in arabidopsis.

“…Perhaps, the simplest explanation for the observed functional decline in photosynthesis may be that maintenance and repair of the photosynthetic apparatus does not keep pace with the damaging effects of the free-radical byproducts of photosynthesis in the leaf (Bowler et al, 1992). In this sense, functional senescence of leaves may conform to free-radical theories of aging applied to animal systems (Harman, 1981;Bolli et al, 1989).…”

Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning

“…33,38,39 At the time of this writing, at least 22 full-length articles have been published that have examined the effect of antioxidants on myocardial stunning after a 15-minute coronary occlusion; all of these articles (except those that used superoxide dismutase alone [40][41][42] or catalase alone 40 ) have reported a protective effect of antioxidants against stunning. 37 Furthermore, generation of ROS in stunned myocardium has been demonstrated directly by both spin trapping 9,39,[43][44][45][46][47] and aromatic hydroxylation 48 techniques, and attenuation of ROS generation has repeatedly been shown to result in attenuation of contractile dysfunction. 9,39,43,45,46 A role of ROS in the genesis of myocardial stunning can now be regarded as a proven hypothesis.…”

“…37 Furthermore, generation of ROS in stunned myocardium has been demonstrated directly by both spin trapping 9,39,[43][44][45][46][47] and aromatic hydroxylation 48 techniques, and attenuation of ROS generation has repeatedly been shown to result in attenuation of contractile dysfunction. 9,39,43,45,46 A role of ROS in the genesis of myocardial stunning can now be regarded as a proven hypothesis. Nevertheless, it remains unclear whether ROS play a role in all settings of stunning.…”

Myocardial ischemia results in tetrahydrobiopterin (BH 4 ) oxidation with impaired endothelial function ameliorated by BH 4

“…With oxidative stress, intracellular BH 4 content might transiently fall below a critical threshold (15), leading to NOS uncoupling (13) and preferential production of • O 2 Ϫ rather than NO. In the ischemic and reperfused heart, there is a marked increase in oxygen radical generation (16,17). Radical generation occurs within both the endothelium and myocytes (18)(19)(20).…”