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Increased superoxide production causes coronary endothelial dysfunction and depressed oxygen consumption in the failing heart

¹Departments of Medicine and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota; ²Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia; and ³Metaphore Pharmaceuticals, St. Louis, Missouri

Submitted 5 September 2003 ; accepted in final form 6 August 2004

This study examined whether increased superoxide (O₂^–·) production contributes to coronary endothelial dysfunction and decreased coronary blood flow (CBF) in congestive heart failure (CHF). To test this hypothesis, the effects of the low-molecular-weight SOD mimetic M40401 on CBF and myocardial oxygen consumption (MO₂) were examined in dogs during normal conditions and after CHF was produced by 4 wk of rapid ventricular pacing. The development of CHF was associated with decreases of left ventricular (LV) systolic pressure, maximum first derivative of LV pressure, MO₂, and CBF at rest and during treadmill exercise as well as endothelial dysfunction with impaired vasodilation in response to intracoronary acetylcholine. M40401 increased CBF (18 ± 5%, P < 0.01) and MO₂ (14 ± 6%, P < 0.01) in CHF dogs and almost totally reversed the impaired CBF response to acetylcholine. M40401 had no effect on acetylcholine-induced coronary vasodilation, CBF, or MO₂ in normal dogs. Western blot analysis demonstrated that extracellular SOD (EC-SOD) was significantly decreased in CHF hearts, whereas mitochondrial Mn-containing SOD was increased. Cytosolic Cu/Zn-containing SOD was unchanged. Both increased O₂^–· production and decreased vascular O₂^–· scavenging ability by EC-SOD could have contributed to endothelial dysfunction in the failing hearts.

free radicals; myocardium; nitric oxide

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