title: Increased superoxide production causes coronary endothelial dysfunction and depressed oxygen consumption in the failing heart.
abstract: 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 (MVo(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, MVo(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 MVo(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 MVo(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.
authors.affiliation: Department of Medicine, University of Minnesota Medical School, Minneapolis, MN, USA. chenx106@tc.umn.edu
authors.forename: YingJie
authors.initials: Y
authors.lastname: Chen
authors.forename: Mingxiao
authors.initials: M
authors.lastname: Hou
authors.forename: Yunfang
authors.initials: Y
authors.lastname: Li
authors.forename: Jay H
authors.initials: JH
authors.lastname: Traverse
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
authors.forename: Tohru
authors.initials: T
authors.lastname: Fukai
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bache
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure; D003199:Computer Systems; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D004285:Dogs; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000378:metabolism / Q000503:physiopathology*; D007527:Isoenzymes / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D019335:Nitroarginine / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology; D016277:Ventricular Function, Left
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; C426066:M40401; D009942:Organometallic Compounds; D014665:Vasodilator Agents; D013481:Superoxides; D019335:Nitroarginine; D008315:Malondialdehyde; D013482:Superoxide Dismutase; D000109:Acetylcholine