Artery-to-vein differences in nitric oxide metabolites are diminished in sepsis*

Abstract

Objective Nitric oxide (NO) deficiency may contribute to microvascular dysfunction in sepsis. Current physiologic paradigms contend that nitrite and/ or S-nitrosohemoglobin (SNOHb) mediate intravascular delivery of NO. These NO metabolites are purportedly consumed during hemoglobin deoxygenation producing NO and coupling intravascular NO delivery with metabolic demand. Systemic nitrite and SNOHb consumption can be assessed by comparing their concentrations in arterial vs. venous blood. We hypothesized that arterial vs. venous (A-V) differences in nitrite and SNOHb are diminished in sepsis and associated with mortality. Design Case-control and prospective cohort study Setting Adult intensive care units of an academic medical center Patients and subjects 87 critically ill septic patients and 52 control subjects Interventions None Measurements and Main Results Nitrite and SNOHb were measured using tri-iodide-based reductive chemiluminescence. In control subjects, arterial plasma, whole blood and red blood cell nitrite levels were higher than the corresponding venous levels. In contrast, SNOHb was higher in venous compared to arterial blood. In septic patients, A-V RBC nitrite and SNOHb differences were absent. Moreover, the plasma nitrite A-V difference was absent in non-survivors. Conclusions In health, nitrite levels are higher in arterial vs. venous blood (suggesting systemic nitrite consumption) whereas SNOHb levels are higher in venous vs. arterial blood (suggesting systemic SNOHb production). These A-V differences are diminished in sepsis, and diminished A-V plasma nitrite differences are associated with mortality. These data suggest pathologic disruption of systemic nitrite utilization in sepsis.

Erythrocyte-dependent regulation of human skeletal muscle blood flow: role of varied oxyhemoglobin and exercise on nitrite, S-nitrosohemoglobin, and ATP

“…Significant arteriovenous nitrite gradients in plasma were observed across the exercising limb, in line with previous data across the human forearm (8,20,38) or across the systemic circulation (41). Lower venous vs. arterial plasma nitrite concentrations is in agreement with the maximal nitrite reductase activity of deoxyhemoglobin, estimated at 50% O 2 Hb saturation (17), a level never encountered in our arterial blood samples but of increasing prevalence in venous blood with exercise and graded hypoxia (range in venous O 2 Hb saturation during exercise ϭ 21-45%).…”

ANESTEZJOLOGIA I INTENSYWNA TERAPIA Inhaled nitric oxide effects outside the lungs – experimental and clinical evidence

“…Higher arterial vs. venous (A-V) concentrations of nitrite and SNOHb suggest consumption of the metabolite and NO release in the systemic vasculature. Nitrite and SNOHb A-V differences are diminished in patients with severe sepsis and septic shock, and are associated with higher mortality [36]. In animal experiments nitrite therapy might protect against both TNF-α (tumor necrosis factor α) and LPS-induced toxicity in mice.…”

“…It is possible that prolonged and more massive LPS exposure in our study underlay much greater organ damage and partly undermined the beneficial effects of this combined therapy [39]. Since sepsis is increasingly recognized as a disease of the microcirculation, in which enhanced vasoconstriction and mitochondrial dysfunction cause irreversible damage and organ failure, novel therapies based on iNO and NO donors alone or combined with other therapies to rescue the microcirculation and reverse hypoxia and ischemia might be very promising [33,36].…”

“…In addition, sepsis non-survivors are distinguished from survivors by an isolated rise in venous plasma nitrite. The authors hypothesized that these results reflect dysregulated intra-erythrocytic deoxyhemoglobin-mediated nitrite reduction, the interdependent system comprising the RBC membrane, membrane-associated proteins, deoxyhemoglobin, and nitrite [36]. Septic shock is characterized by abnormally high mixed venous hemoglobin (Hb) oxygen saturation, which could impair hemoglobin nitrite reductase activity.…”

Asphyxia and Therapeutic Hypothermia Modulate Plasma Nitrite Concentrations and Carotid Vascular Resistance in Preterm Fetal Sheep

“…[39][40][41] A limitation of the current study is that nitrite was used as an indirect measure of NOS activity and we were not able to obtain preductal venous measurements, which can help estimate nitrite metabolism. 42 Endothelium-derived NO is oxidized to nitrite in the plasma by enzyme-mediated reactions, 43 which have been recently confirmed to be present in adult and fetal sheep plasma. 44 Under steady state conditions, up to 75% of plasma nitrite is derived from endothelial NO, making it a useful index of eNOS activity.…”