Neuronal nitric oxide synthase-derived hydrogen peroxide effect in grafts used in human coronary bypass surgery

Recently, H₂O₂ has been identified as the endothelium-dependent hyperpolarizing factor (EDHF), which mediates flow-induced dilation in human coronary arteries. Neuronal nitric oxide synthase (nNOS) is expressed in the cardiovascular system and, besides NO, generates H₂O₂. The role of nNOS-derived H₂O₂ in human vessels is so far unknown. The present study was aimed at investigating the relevance of nNOS/H₂O₂ signaling in the human internal mammary artery (IMA) and saphenous vein (SV), the major conduits used in coronary artery bypass grafting. In the IMA, but not in the SV, ACh (acetylcholine)-induced vasodilatation was decreased by selective nNOS inhibition with TRIM or Inhibitor 1, and by catalase, which specifically decomposes H₂O₂. Superoxide dismutase (SOD), which generates H₂O₂ from superoxide, decreased the vasodilator effect of ACh on SV. In the IMA, SOD diminished phenylephrine-induced contraction in endothelium-containing, but not in endothelium-denuded vessels. Importantly, while exogenous H₂O₂ produced vasodilatation in IMA, it constricted SV. ACh increased H₂O₂ production in both sets of vessels. In the IMA, the increase in H₂O₂ was inhibited by catalase and nNOS blockade. In SV, H₂O₂ production was abolished by catalase and reduced by nNOS inhibition. Immunofluorescence experiments showed the presence of nNOS in the vascular endothelium and smooth muscle cells of both the IMA and SV. Together, our results clearly show that H₂O₂ induced endothelium-dependent vascular relaxation in the IMA, whereas, in the SV, H₂O₂ was a vasoconstrictor. Thus, H₂O₂ produced in the coronary circulation may contribute to the susceptibility to accelerated atherosclerosis and progressive failure of the SV used as autogenous graft in coronary bypass surgery.