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

R. Bolli, M. O. Jeroudi, B. S. Patel, C. M. DuBose, E. K. Lai, R. Roberts, P. B. McCay

Research output: Contribution to journalArticle

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 O2, (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, α-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 (Δ = -100%, P <0.01 vs. group I) and markedly inhibited after reperfusion (Δ = -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 repefusion [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 O2, and (iii) 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.

Original languageEnglish (US)
Pages (from-to)4695-4699
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume86
Issue number12
StatePublished - 1989
Externally publishedYes

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Myocardial Stunning
Catalase
Free Radicals
Dogs
Oxygen
Reperfusion
Ischemia
Electron Spin Resonance Spectroscopy
Coronary Occlusion
Superoxide Dismutase
Spectrum Analysis
Myocardium
Thorax
Control Groups

ASJC Scopus subject areas

  • General
  • Genetics

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Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog. / Bolli, R.; Jeroudi, M. O.; Patel, B. S.; DuBose, C. M.; Lai, E. K.; Roberts, R.; McCay, P. B.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 86, No. 12, 1989, p. 4695-4699.

Research output: Contribution to journalArticle

Bolli, R. ; Jeroudi, M. O. ; Patel, B. S. ; DuBose, C. M. ; Lai, E. K. ; Roberts, R. ; McCay, P. B. / Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog. In: Proceedings of the National Academy of Sciences of the United States of America. 1989 ; Vol. 86, No. 12. pp. 4695-4699.
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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 O2, (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, α-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 (Δ = -100{\%}, P <0.01 vs. group I) and markedly inhibited after reperfusion (Δ = -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 repefusion [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 O2, and (iii) 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.",
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T1 - Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog

AU - Bolli, R.

AU - Jeroudi, M. O.

AU - Patel, B. S.

AU - DuBose, C. M.

AU - Lai, E. K.

AU - Roberts, R.

AU - McCay, P. B.

PY - 1989

Y1 - 1989

N2 - 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 O2, (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, α-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 (Δ = -100%, P <0.01 vs. group I) and markedly inhibited after reperfusion (Δ = -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 repefusion [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 O2, and (iii) 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.

AB - 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 O2, (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, α-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 (Δ = -100%, P <0.01 vs. group I) and markedly inhibited after reperfusion (Δ = -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 repefusion [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 O2, and (iii) 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.

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