Hemodialysis-induced release of hemoglobin limits nitric oxide bioavailability and impairs vascular function.

OBJECTIVES: This study sought to characterize the impact of hemodialysis (HD)-induced release of hemoglobin on the bioavailability of nitric oxide (NO) and endothelial function. BACKGROUND: Patients on chronic HD suffer from endothelial dysfunction and a massively increased risk for cardiovascular events. Although dialysis-dependent and -independent factors are discussed, the exact mechanisms are not fully understood. METHODS: In 14 HD patients (56+/-15 years of age), endothelial function was determined by measuring flow-mediated dilation (FMD) of the brachial artery using high-resolution ultrasound before and after treatment. The NO consumption activity of plasma isolated from patients before and after hemodialysis was studied with an NO-sensitive electrode. RESULTS: HD impaired FMD (3.5+/-2.6% to 1.7+/-1.4%, p=0.04) without affecting brachial artery diameter (4.7+/-0.6 mm vs. 4.4+/-0.9 mm, p=0.27). This was accompanied by an increase in cell-free plasma hemoglobin (196+/-43 mg/l to 285+/-109 mg/l, p=0.01), which led to a decrease in the bioavailability of free NO by more than 70%. Oxidation of the released plasma ferrous hemoglobin prevented the consumption of NO. The amount of decompartmentalized hemoglobin after HD correlated inversely with the change in FMD (r=-0.65, p=0.041). CONCLUSIONS: Our data support a role of HD-induced release of hemoglobin in the pathogenesis of endothelial dysfunction in patients with end-stage renal disease. Approaches that oxidize free plasma hemoglobin may restore NO bioavailability and may have potential beneficial effects on vascular function. (Influence of Hemodialysis on Endothel-Depending Dilatation of Peripheral Arteries; NCT00764192).

Clinical research for patient empowerment--a qualitative approach on the improvement of heart health promotion in chronic illness.

BACKGROUND: Concepts of health management and improved quality of health care are of growing importance. In this context, the concept of empowerment is widely accepted in health-related disciplines. The aim of the present study was to investigate whether theory-based empowerment, using motivational interviewing, can be facilitated within clinical research in patients with severe chronic diseases. MATERIAL/METHODS: We here present a qualitative in-depth interview study using grounded theory methodology. Participants were twenty-seven patients undergoing chronic haemodialysis who were taking part in a research programme investigating cardiovascular function in chronic renal failure (CRF) by ultrasound measurements and blood samples. RESULTS: With the exception of one patient, all interviewed patients emphasized the benefit of the detailed and structured information given. All patients pointed out a deepened understanding of cardiovascular health and its relation to CRF. Improved health knowledge was associated with a strengthened sense of control in our participants. This process resulted in high levels of patient satisfaction. Fifty percent of the interviewed patients were more likely to attend further education sessions with cardiologists and primary care practitioners to improve health management. CONCLUSIONS: Facilitating empowerment in a clinical research project is ethically essential and can positively enhance self-care-oriented, disease-specific skills in patients with severe chronic diseases. Clinical research may open up new avenues to additionally strengthen patient sovereignty in interdisciplinary health sciences.

Nitric oxide synthase-derived plasma nitrite predicts exercise capacity.

BACKGROUND: Nitrite is the main oxidation product of nitric oxide (NO) in plasma. It sensitively reflects changes in endothelial NO synthase (eNOS) activity under fasting conditions and serves as an endocrine NO donor, contributing to the regulation of blood flow through reaction with haemoglobin. As NO is necessary to maintain an adequate vascular response to the increased demands of blood flow, it is believed to be important for vasodilation induced by exercise. OBJECTIVE: To investigate whether the capacity of the vasculature to produce nitrite is associated with exercise performance. DESIGN: With the use of chemiluminescence detection, nitrite concentrations in 55 healthy subjects (mean (SEM) age 40 (2) years; 22 men) were studied before and after an exercise test, and endothelial function was determined by measuring flow-mediated dilation of the brachial artery using high-resolution ultrasound. In a subset of subjects, the NOS inhibitor, N(G)-monomethyl-L-arginine, was applied to elucidate the effect of eNOS on changes in nitrite. RESULTS: Exercise significantly (p<0.001) increased plasma nitrite from 97 (6) to 125 (8) nM. The relative increase in plasma nitrite was related to flow-mediated dilation (6.1 (0.3)%; r = 0.36; p = 0.01). N(G)-Monomethyl-L-arginine blocked increases in nitrite. Post-exercise nitrite concentration correlated with exercise performance, as determined by maximally reached stress power (r = 0.37; p<0.007), and inversely with age. Multivariate analysis showed that both age and post-exercise nitrite concentration were independent predictors of stress endurance and power. CONCLUSION: The results suggest a role for plasma nitrite in the adaptation of haemodynamics during exercise. An impaired increase in plasma nitrite may limit exercise capacity.

Nitrite reductase function of deoxymyoglobin: oxygen sensor and regulator of cardiac energetics and function.

Although the primary function of myoglobin (Mb) has been considered to be cellular oxygen storage and supply, recent studies have suggested to classify Mb as a multifunctional allosteric enzyme. In the heart, Mb acts as a potent scavenger of nitric oxide (NO) and contributes to the attenuation of oxidative damage. Here we report that a dynamic cycle exists in which a decrease in tissue oxygen tension drives the conversion of Mb from being an NO scavenger in normoxia to an NO producer in hypoxia. The NO generated by reaction of deoxygenated Mb with nitrite is functionally relevant and leads to a downregulation of cardiac energy status, which was not observed in mice lacking Mb. As a consequence, myocardial oxygen consumption is reduced and cardiac contractility is dampened in wild-type mice. We propose that this pathway represents a novel homeostatic mechanism by which a mismatch between oxygen supply and demand in muscle is translated into the fractional increase of deoxygenated Mb exhibiting enhanced nitrite reductase activity. Thus, Mb may act as an oxygen sensor which through NO can adjust muscle energetics to limited oxygen supply.

Recent methodological advances in the analysis of nitrite in the human circulation: nitrite as a biochemical parameter of the L-arginine/NO pathway.

Nitric oxide (NO) plays a pivotal role in the modulation of multiple physiological processes. It acts as a messenger molecule within the cardiovascular system. NO is a highly unstable free radical in circulating blood and is oxidized rapidly to nitrite and nitrate. Recent studies suggest that nitrite has the potential to function as a surrogate of NO production under physiological and pathophysiological conditions and could therefore be of high relevance as a biochemical parameter in experimental and clinical studies. Under hypoxic conditions nitrite is reduced to bioactive NO by deoxyhemoglobin. This mechanism may represent a dynamic cycle of NO generation to adapt the demand and supply for the vascular system. Because of these potential biological functions the concentration of nitrite in blood is thought to be of particular importance. The determination of nitrite in biological matrices represents a considerable analytical challenge. Methodological problems often arise from pre-analytical sample preparation, sample contamination due to the ubiquity of nitrite, and from lack of selectivity and sensitivity. These analytical difficulties may be a plausible explanation for reported highly diverging concentrations of nitrite in the human circulation. The aim of this article is to review the methods of quantitative analysis of nitrite in the human circulation, notably in plasma and blood, and to discuss pre-analytical and analytical factors potentially affecting accurate quantification of nitrite in these human fluids.