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

This study examined whether increased superoxide (O-2(-.)) 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 (M(V) over dot O-2) 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, M(V) over dot O-2, 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 M(V) over dot O-2 ( 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 M(V) over dot O-2 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 O-2(-.) production and decreased vascular O-2(-.) scavenging ability by EC-SOD could have contributed to endothelial dysfunction in the failing hearts.