Reactive oxygen species mediate endothelium-dependent relaxations in tetrahydrobiopterin-deficient mice.

(6R)-5,6,7,8-Tetrahydro-biopterin (H(4)B) 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 H(4)B synthesis. A relative shortage of H(4)B 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 H(4)B deficiency on endothelial function. Aortas from 8-week-old hph-1 and wild-type mice (C57BLxCBA) were compared. H(4)B levels were determined by high-performance liquid chromatography and NO synthase activity by [(3)H]citrulline assay in homogenized tissue. Superoxide production by the chemiluminescence method was measured. Isometric tension was continuously recorded. The intracellular levels of H(4)B 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 N(G)-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 H(4)B, the differences between the 2 groups disappeared. Our findings demonstrate that H(4)B deficiency leads to eNOS dysfunction with the formation of reactive oxygen species, which become mediators of endothelium-dependent relaxations. A decreased availability of H(4)B may favor an impaired activity of eNOS and thus contribute to the development of vascular diseases

An Integrated View of the Use of Quality Cost Information, the Improvement of the Quality Management System and Effects on Performance: a Study in Portuguese Companies

The literature focusing on quality costs has placed great importance on issues related to identifying, measuring and reporting quality cost information. Less attention has been paid to how this information is used in the management process and how it can enhance internal capabilities and thereby improve company performance. In addition to addressing this question, we analyse how the extensive use of quality costs can boost organisational learning and innovation in organisations' internal processes, thus leading to an overall improvement in the quality management system that is reflected in financial and non-financial performance. The conceptual model developed involves these relationships and has been tested using the structural equation modelling technique. To this end, a questionnaire survey was conducted in Portuguese companies with the ISO 9000 certification. The results shed light on the causal links between the variables, and thus validate the conceptual model indicating that the use of quality cost information has a positive effect on both the development of quality management systems and performanc