The Role of Reduced Oxygen Intermediates during Myocardial Ischemia

  • M. L. Hess
  • R. Franson
  • N. H. Manson
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 49)

Abstract

The following study has two principal aims: 1) the demonstration that oxygen free radicals possess negative inotropic properties and 2) the characterization of the role of the oxygen free radicals during myocardial ischemia in producing the disruption of the excitation-contraction coupling system. In the intact dog, the infusion of phorbol myristate acetate (known to activate neutrophils and generate hydrogen peroxide and hydroxyl radical) resulted in a decrease in mean arterial pressure and cardiac index over 45 min from 105 ± 7.4 to 28 ± 8 mm Hg and 0.20 ± 0.02 to 0.04 ± 0.01 1/min/kg (p<0.01), respectively. This depression of cardiovascular function was inhibited by either pretreatment with superoxide dismutase + catalase or neutrophil depletion. During 30 min of global myocardial ischemia, sarco-plasmic reticulum calcium uptake rates and Ca2+-ATPase activity decreased from 1.38 ± 0.1 to 0.25 ± 0.02 μmoles Ca2+/mg-min and 2.35 ± 0.05 to 0.6 ± 0.03 pmoles Pi/mg-min (p<0.01), respectively. Acidosis (pH = 6.4) significantly increased this rate of decay of sarcoplasmic reticulum function. In vitro, an exogenous free radical generating system (xanthine-xanthine oxidase) produced similar effects on cardiac sarcoplasmic reticulum. In addition, 30 min of normothermic, global ischemia resulted in activation of a phospholipase C-sphingomyelinase with a pH optimum of 5.0. Pretreatment of the heart with superoxide dismutase and catalase inhibited the activation of the sphingomyelinase and preserved sarcoplasmic reticulum calcium uptake rates and Ca2+-ATPase activity. It is concluded that oxygen free radicals, now demonstrated to be potent negative inotropic agents, contribute to the intracellular breakdown of the excitation-contraction coupling system during primary myocardial ischemia by activating a highly toxic sphingomyelinase which in turn disrupts the sarcoplasmic reticulum calcium transport system.

Keywords

Depression Ischemia Superoxide Oxalate NADH 

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Copyright information

© Martinus Nijhoff Publishing, Boston 1985

Authors and Affiliations

  • M. L. Hess
    • 1
  • R. Franson
    • 1
  • N. H. Manson
    • 1
  1. 1.The Departments of Medicine, Biochemistry and Physiology and BiophysicsThe Medical College of VirginiaRichmondUSA

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