Pharmacologic Targeting of Red Blood Cells to Improve Tissue Oxygenation

Reynolds, James D.; Jenkins, Trevor; Matto, Faisal; Nazemian, Ryan; Farhan, Obada; Morris, Nathan; Longphre, John M.; Hess, Douglas T.; Moon, Richard E.; Piantadosi, Claude A.; Stamler, Jonathan S.

doi:10.1002/cpt.979

Cited by 13 publications

(12 citation statements)

References 47 publications

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“…Indeed, several clinical 24,25 and preclinical trials 26,27 have demonstrated the therapeutic benefits of renitrosylation, which acts to restore or enhance RBC-derived NO bioactivity. Of specific relevance to the current findings, we recently demonstrated in a clinical trial that pharmacological elevation of SNO-Hb increased StO 2 in healthy subjects under hypoxia (FiO 2 =0.12) 28 . And in a large animal preclinical model of donor support, increasing SNO-Hb after BD improved tissue blood flow and oxygenation, reduced markers of immune activation and cellular injury, and preserved organ function 29 .…”

Section: Discussionsupporting

confidence: 58%

Peripheral Tissue Oxygenation and the Number of Organs Transplanted per Donor

Perez-Protto

Reynolds

Nazemian

et al. 2018

Anaesth Intensive Care

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Current donor management practices target macrohaemodynamic parameters, but it is unclear if this leads to improvements in microvascular perfusion and tissue oxygenation; the latter may have more impact on organ status. In a recent preclinical study we determined that brain death impaired tissue perfusion and oxygen utilisation in swine while pharmacologic correction of these deficits improved organ function and reduced markers of tissue injury. As a first step in translating the preclinical findings, we conducted a prospective observational study to determine if there was an association between peripheral tissue oxygenation (measured by near-infrared spectroscopy) in deceased by neurological criteria human donors and the number of organs transplanted. In 60 donors, the mean time-weighted average of tissue oxygenation was 87.5% (standard deviation, SD, 5.2%) and the average number of organs transplanted was 3.5 (SD 2); there was a positive linear relationship between these two parameters. A 5% rise in tissue oxygenation was associated with an increase of 0.47 organs transplanted (95% confidence intervals 0.16 to 0.78) after adjusting for age (P=0.004). No such correlations were observed for the macrohaemodynamic or macro-oxygenation parameters (including arterial blood oxygenation). The results of this clinical trial are consistent with our preclinical work and support the postulate that targeting the microvasculature to improve tissue perfusion and tissue oxygen delivery in human donors has the potential to increase the quantity of organs suitable for transplant.

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Section: Discussionsupporting

confidence: 58%

Peripheral Tissue Oxygenation and the Number of Organs Transplanted per Donor

Perez-Protto

Reynolds

Nazemian

et al. 2018

Anaesth Intensive Care

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“…Yet another potentially interesting nitrosation reaction occurs between ethanol and nitrite in the acidic stomach to form the highly potent vasodilator ethyl nitrite (Gago et al, 2008), an organic nitrite that has been used as a pulmonary vasodilator in clinical studies (Moya et al, 2002;Reynolds et al, 2017). Besides being a vasodilator, ethyl nitrite is also a potent nitrosating agent with possible physiological or pathophysiological consequences locally in the stomach as well as systemically after absorption.…”

Section: Nutritional Aspects Interaction Of Nitrate With Other Dietary Compoundsmentioning

confidence: 99%

Metabolic Effects of Dietary Nitrate in Health and Disease

2018

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Nitric oxide (NO), generated from L-arginine and oxygen by NO synthases, is a pleiotropic signaling molecule involved in cardiovascular and metabolic regulation. More recently, an alternative pathway for the formation of this free radical has been explored. The inorganic anions nitrate (NO) and nitrite (NO), originating from dietary and endogenous sources, generate NO bioactivity in a process involving seemingly symbiotic oral bacteria and host enzymes in blood and tissues. The described cardio-metabolic effects of dietary nitrate from experimental and clinical studies include lowering of blood pressure, improved endothelial function, increased exercise performance, and reversal of metabolic syndrome, as well as antidiabetic effects. The mechanisms underlying the salutary metabolic effects of nitrate are being revealed and include interaction with mitochondrial respiration, activation of key metabolic regulatory pathways, and reduction of oxidative stress. Here we review the recent advances in the nitrate-nitrite-NO pathway, focusing on metabolic effects in health and disease.

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“…Notably, a cross-species dimorphism in arginine metabolism was identified in a non-targeted analysis and further validated using stable isotope-labeled arginine tracing. We highlight this pathway, given the importance of nitric oxide (NO) as an RBC-transported signaling molecule that modulates vascular responsiveness to hypoxia (Doctor and Stamler, 2011); in addition, NO depletion may be a relevant component of the storage lesion that affects transfusion efficacy (Bennett-Guerrero et al, 2007;Kanias et al, 2013;Reynolds et al, 2018). Further, in the context of cardiovascular disease (CVD), RBC imbalances in arginase and NO synthase suggest that increased RBC arginase-1 activity decreases NO bioavailability, superoxide production, endothelial dysfunction, and enhances post-ischemic cardiac failure (Yang et al, 2018;Mahdi et al, 2019;Pernow et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

ZOOMICS: Comparative Metabolomics of Red Blood Cells From Old World Monkeys and Humans

et al. 2020

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As part of the ZOOMICS project, we set out to investigate common and diverging metabolic traits in the blood metabolome across various species by taking advantage of recent developments in high-throughput metabolomics. Here we provide the first comparative metabolomics analysis of fresh and stored human (n = 21, 10 males, 11 females), olive baboon (n = 20), and rhesus macaque (n = 20) red blood cells at baseline and upon 42 days of storage under blood bank conditions. The results indicated similarities and differences across species, which ultimately resulted in a differential propensity to undergo morphological alterations and lyse as a function of the duration of refrigerated storage. Focusing on purine oxidation, carboxylic acid, fatty acid, and arginine metabolism further highlighted species-specific metabolic wiring. For example, through a combination of steady state measurements and 13 C 6 15 N 4-arginine tracing experiments, we report an increase in arginine catabolism into ornithine in humans, suggestive of species-specific arginase 1 activity and nitric oxide synthesis-an observation that may impact the translatability of cardiovascular disease studies carried out in non-human primates (NHPs). Finally, we correlated metabolic measurements to storage-induced morphological alterations via scanning electron microscopy and hemolysis, which were significantly lower in human red cells compared to both NHPs.

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Pharmacologic Targeting of Red Blood Cells to Improve Tissue Oxygenation

Cited by 13 publications

References 47 publications

Peripheral Tissue Oxygenation and the Number of Organs Transplanted per Donor

Peripheral Tissue Oxygenation and the Number of Organs Transplanted per Donor

Metabolic Effects of Dietary Nitrate in Health and Disease

ZOOMICS: Comparative Metabolomics of Red Blood Cells From Old World Monkeys and Humans

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