Circulating blood endothelial nitric oxide synthase contributes to the regulation of systemic blood pressure and nitrite homeostasis.

OBJECTIVE: Mice genetically deficient in endothelial nitric oxide synthase (eNOS(-/-)) are hypertensive with lower circulating nitrite levels, indicating the importance of constitutively produced nitric oxide (NO•) to blood pressure regulation and vascular homeostasis. Although the current paradigm holds that this bioactivity derives specifically from the expression of eNOS in endothelium, circulating blood cells also express eNOS protein. A functional red cell eNOS that modulates vascular NO• signaling has been proposed. APPROACH AND RESULTS: To test the hypothesis that blood cells contribute to mammalian blood pressure regulation via eNOS-dependent NO• generation, we cross-transplanted wild-type and eNOS(-/-) mice, producing chimeras competent or deficient for eNOS expression in circulating blood cells. Surprisingly, we observed a significant contribution of both endothelial and circulating blood cell eNOS to blood pressure and systemic nitrite levels, the latter being a major component of the circulating NO• reservoir. These effects were abolished by the NOS inhibitor L-NG-nitroarginine methyl ester and repristinated by the NOS substrate L-arginine and were independent of platelet or leukocyte depletion. Mouse erythrocytes were also found to carry an eNOS protein and convert (14)C-arginine into (14)C-citrulline in NOS-dependent fashion. CONCLUSIONS: These are the first studies to definitively establish a role for a blood-borne eNOS, using cross-transplant chimera models, that contributes to the regulation of blood pressure and nitrite homeostasis. This work provides evidence suggesting that erythrocyte eNOS may mediate this effect.

Emerging roles of network analysis for epilepsy.

In recent years there has been increasing interest in applying network science tools to EEG data. At the 2018 American Epilepsy Society conference in New Orleans, LA, the yearly session of the Engineering and Neurostimulation Special Interest Group focused on emerging, translational technologies to analyze seizure networks. Each speaker demonstrated practical examples of how network tools can be utilized in clinical care and provide additional data to help care for patients with intractable epilepsy. The groups presented advances using tools from functional connectivity, control theory, and graph theory to analyze human EEG data. These tools have great potential to augment clinical interpretation of EEG signals.

Dietary nitrate and nitrite modulate blood and organ nitrite and the cellular ischemic stress response.

Dietary nitrate, found in abundance in green vegetables, can be converted to the cytoprotective molecule nitrite by oral bacteria, suggesting that nitrate and nitrite may represent active cardioprotective constituents of the Mediterranean diet. We therefore tested the hypothesis that dietary nitrate and nitrite levels modulate tissue damage and ischemic gene expression in a mouse liver ischemia-reperfusion model. We found that stomach content, plasma, heart, and liver nitrite levels were significantly reduced after dietary nitrate and nitrite depletion and could be restored to normal levels with nitrite supplementation in water. Remarkably, we confirmed that basal nitrite levels significantly reduced liver injury after ischemia-reperfusion. Consistent with an effect of nitrite on the posttranslational modification of complex I of the mitochondrial electron transport chain, the severity of liver infarction was inversely proportional to complex I activity after nitrite repletion in the diet. The transcriptional response of dietary nitrite after ischemia was more robust than after normoxia, suggesting a hypoxic potentiation of nitrite-dependent transcriptional signaling. Our studies indicate that normal dietary nitrate and nitrite levels modulate ischemic stress responses and hypoxic gene expression programs, supporting the hypothesis that dietary nitrate and nitrite are cytoprotective components of the diet.