Pharmacologic Targeting of Red Blood Cells to Improve Tissue Oxygenation - PubMed (original) (raw)

Clinical Trial

. 2018 Sep;104(3):553-563.

doi: 10.1002/cpt.979. Epub 2018 Jan 17.

Affiliations

Clinical Trial

Pharmacologic Targeting of Red Blood Cells to Improve Tissue Oxygenation

James D Reynolds et al. Clin Pharmacol Ther. 2018 Sep.

Abstract

Disruption of microvascular blood flow is a common cause of tissue hypoxia in disease, yet no therapies are available that directly target the microvasculature to improve tissue oxygenation. Red blood cells (RBCs) autoregulate blood flow through S-nitroso-hemoglobin (SNO-Hb)-mediated export of nitric oxide (NO) bioactivity. We therefore tested the idea that pharmacological enhancement of RBCs using the S-nitrosylating agent ethyl nitrite (ENO) may provide a novel approach to improve tissue oxygenation. Serial ENO dosing was carried out in sheep (1-400 ppm) and humans (1-100 ppm) at normoxia and at reduced fraction of inspired oxygen (FiO2 ). ENO increased RBC SNO-Hb levels, corrected hypoxia-induced deficits in tissue oxygenation, and improved measures of oxygen utilization in both species. No adverse effects or safety concerns were identified. Inasmuch as impaired oxygenation is a major cause of morbidity and mortality, ENO may have widespread therapeutic utility, providing a first-in-class agent targeting the microvasculature.

© 2017 American Society for Clinical Pharmacology and Therapeutics.

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Conflict of interest statement

CONFLICT OF INTEREST

Dr. Reynolds has a financial interest in Miach Medical Innovations. Dr. Stamler has financial interests in Nivalis Therapeutics (formerly Nitrox), Adamas Pharma, LifeHealth, and Vindica Pharm. Drs. Moon, Piantadosi, Reynolds, and Stamler hold patents related to renitrosylation of blood, some of which have been licensed for commercial development. Both institutions are aware of these conflicts and appropriate management plans are in place. None of the other authors have relevant conflicts to disclose.

Figures

Figure 1

Figure 1

Responses to ethyl nitrite (ENO) dosing during hypoxia in sheep (n = 9). Time courses are presented as mean ± standard deviation of (a) percent arterial blood oxygen saturation, SaO2%; (b) percent methemoglobin, Met-Hb%; (c) heart rate, HR, in beats per min; (d) cardiac output, CO, in liters per min; (e) mean pulmonary arterial pressure, mPAP, in mm Hg; and (f) percent systemic venous oxygen saturation, SvO2%. The standard deviations (error bars) are marked every 15 min for clarity. Hypoxia was initiated for 60 min starting at time 0 (normoxic baseline) followed by ENO dosing from 1–400 ppm with each dose administered for 45 min followed by a 15-min washout period (solid rectangles). Met-Hb levels rose with dose escalation, providing a biomarker of ENO exposure. MB demarcates the i.v. administration of 1 mg/kg methylene blue to rapidly reduce metHb levels.

Figure 2

Figure 2

Responses during and after ethyl nitrite (ENO) dosing in hypoxic sheep. Time courses are presented as mean ± standard deviation of (a) percent arterial blood oxygen saturation, SaO2%; (b) percent methemoglobin, Met-Hb%; (c) mean arterial pressure, MAP, in mm Hg; (d) heart rate, HR, in beats per min; (e) cardiac output, CO, in liters per min; (f) mean pulmonary arterial pressure, mPAP, in mm Hg; (g) percent systemic venous oxygen saturation, SvO2%; and (h) systemic vascular resistance, SVR, in dynes*sec*cm−5. The standard deviations (error bars) are marked every 30 min for clarity. Hypoxia was initiated for 1 h starting at time 0 (normoxic baseline) then sheep received either 0 (n = 8; blue line), 1 (n = 8; red line), or 50 (n = 7; black line) ppm ENO for 4 h followed by an additional 4 h under hypoxia alone. ENO produced significant dose-dependent increases in CO and declines in SvO2 and SVR that carried into the postexposure period. See text for additional details.

Figure 3

Figure 3

Human trial flow chart. Clinical trial process for subjects who volunteered to participate in the ethyl nitrite (ENO) dosing study.

Figure 4

Figure 4

Responses to ethyl nitrite (ENO) during hypoxia in humans (n = 10). Time courses are presented as mean ± standard deviation of (a) percent arterial blood oxygen saturation, SaO2%; (b) percent change in S-nitrosylated hemoglobin, SNO-Hb (bars) and percent methemoglobin, Met-Hb% (line); (c) mean pulmonary arterial pressure, mPAP, in mm Hg; (d) cardiac output, CO, in liters per min; (e) systemic vascular resistance, SVR, in dynes*sec*cm−5; and (f) oxygen consumption, VO2, expressed as milliliters per min. Hypoxia was initiated at time 0 (normoxic baseline) followed by ENO dosing from 1–100 ppm with each dose administered for 20 min (no washout). Levels of SNO-Hb and Met-Hb escalated with ENO dose. Absolute values for the change in SNO-Hb, FeNOHb, and total NOHb are presented in (g) and demonstrate the selective S-nitrosylating activity of ENO. Total NOHb increased significantly from 1.27 ± 0.48 per Hb×10−3 to 1.87 ± 0.66 (_P_=0.005) after the 100 ppm dose, reflecting an increase in SNO-Hb (white bar; _P_=0.007), without change in FeNOHb (black bar; _P_=0.737). Also along the bottom row, group means are presented for (h) maximum CO and (i) minimum SVR (independent of ENO dose; ± ENO). CO increased significantly while SVR declined vs. their respective hypoxic baseline (all P < 0.05).

Figure 5

Figure 5

Effect of ethyl nitrite (ENO) on tissue oxygenation (StO2) and oxygen utilization in humans. (a) Calf muscle oxygenation measured with near infrared spectroscopy during hypoxia and dosing with 1–100 ppm ENO; each dose was administered for 20 min (no washout). Initiation of hypoxia (time 0; normoxic baseline) produced a significant decline in StO2 (*P < 0.05). For doses >10 ppm ENO, calf oxygenation increased, reaching normoxic levels at 40 ppm. At study completion, muscle StO2 was at normoxic (prehypoxic) levels (_P_=1.00). (b) Consistent with an ENO-induced increase in peripheral oxygen utilization there was a direct linear relationship between muscle StO2 and arterial-venous oxygen content difference (A-V Δ O2, mL/dL; _r_=0.44). (c) Brain StO2 declined with hypoxia, then remained significantly lower than the prehypoxic starting point throughout ENO dosing (*P < 10−7). (d) Consistent with the persistent decrease in cerebral oxygenation, there was no relationship between brain StO2 and A-V Δ O2 difference (_r_=0.09).

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