Increased inactivation of nitric oxide is involved in coronary endothelialdysfunction in heart failure

Recent evidence suggests the possibility that enhanced inactivation of endo thelium-derived nitric oxide (NO) by oxygen free radical (OFR) may cause en dothelial dysfunction in heart failure (HF). To test this hypothesis, we ex amined the effect of antioxidant therapy on endothelium-dependent vasodilat ion of the coronary circulation in a canine model of tachycardia-induced HF . Endothelium-dependent vasodilation was less than that in controls, and OF R formation in coronary arterial and myocardial tissues was greater in HF d ogs than those in controls. The immunohistochemical staining of 4-hydroxy-2 -nonenal, OFR-induced lipid peroxides was detected in coronary microvessels of HF dogs. Intracoronary infusion of the cell-permeable OFR scavenger Tir on inhibited OFR formation and improved endothelium-dependent vasodilation in HF dogs but not in controls. The NO synthesis inhibitor N-G-monomethyl-L -arginine (L-NMMA) diminished the beneficial effect of Tiron in HF dogs. En dothelium-independent vasodilation was similar between control and HF dogs, and no change in its response was noted by Tiron or Tiron plus L-NMMA in e ither group. In summary, antioxidant treatment with Tiron improved coronary vascular endothelium-dependent vasodilation by increasing NO activity in t achycardia-induced HF. Thus coronary endothelial dysfunction in HF may be, at least in part, due to increased inactivation of NO by OFR.