© 2001 American Heart Association, Inc.
Vascular Biology |
Reactive Oxygen Species Mediate Endothelium-Dependent Relaxations in Tetrahydrobiopterin-Deficient Mice
From Cardiology, Cardiovascular Research (F.C., T.F.L.), University Hospital, Zürich, Switzerland; IRCCS Neuromed (F.C., M.V.), Pozzilli, Italy; Medical Chemistry and Biochemistry (E.R.W.), University of Innsbruck, Innsbruck, Austria; Neurochemistry (J.E.B., M.P.B., S.J.H.), Institute of Neurology, Queen Square, London, UK; Biochemistry (J.R.T.), Imperial College, London, UK; and Cardiovascular Medicine (N.W., K.M.C.), University of Oxford, Oxford, UK.
Correspondence to Thomas F. Lüscher, MD, FHRCP, Professor and Head of Cardiology, University Hospital, CH-8091 Zürich, Switzerland. E-mail cardiotfl{at}gmx.ch
Abstract—(6R)-5,6,7,8-Tetrahydro-biopterin (H4B) is essential for the catalytic activity of all NO synthases. The hyperphenylalaninemic mouse mutant (hph-1) displays 90% deficiency of the GTP cyclohydrolase I, the rate-limiting enzyme in H4B synthesis. A relative shortage of H4B may shift the balance between endothelial NO synthase (eNOS)-catalyzed generation of NO and reactive oxygen species. Therefore, the hph-1 mouse represents a unique model to assess the effect of chronic H4B deficiency on endothelial function. Aortas from 8-week-old hph-1 and wild-type mice (C57BLxCBA) were compared. H4B levels were determined by high-performance liquid chromatography and NO synthase activity by [3H]citrulline assay in homogenized tissue. Superoxide production by the chemiluminescence method was measured. Isometric tension was continuously recorded. The intracellular levels of H4B as well as constitutive NO synthase activity were significantly lower in hph-1 compared with wild-type mice. Systolic blood pressure was increased in hph-1 mice. However, endothelium-dependent relaxations to acetylcholine were present in both groups and abolished by inhibition of NO synthase with NG-nitro-L-arginine methyl ester as well. Only in hph-1 mice were the relaxations inhibited by catalase and enhanced by superoxide dismutase. After incubation with exogenous H4B, the differences between the 2 groups disappeared. Our findings demonstrate that H4B deficiency leads to eNOS dysfunction with the formation of reactive oxygen species, which become mediators of endothelium-dependent relaxations. A decreased availability of H4B may favor an impaired activity of eNOS and thus contribute to the development of vascular diseases.
Key Words: NO synthase • superoxide anion • hydrogen peroxide • catalase GTP cyclohydrolase I
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