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Tatezawa R, Abumiya T, Ito Y, Gekka M, Okamoto W, Ishii K, Kohyama N, Komatsu T, Fujimura M. Neuroprotective effects of a hemoglobin-based oxygen carrier (stroma-free hemoglobin nanoparticle) on ischemia reperfusion injury. Brain Res 2023; 1821:148592. [PMID: 37748569 DOI: 10.1016/j.brainres.2023.148592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/17/2023] [Accepted: 09/20/2023] [Indexed: 09/27/2023]
Abstract
The application of hemoglobin (Hb)-based oxygen carriers (HBOCs) to the treatment of cerebral ischemia has been investigated. A cluster of 1 Hb and 3 human serum albumins (Hb-HSA3) was found to exert neuroprotective effects on ischemia/reperfusion injury. Stroma-free hemoglobin nanoparticles (SFHbNP), a subsequently developed HBOC consisting of a spherical polymerized stroma-free Hb core with a HSA shell, contains the natural antioxidant enzyme catalase and, thus, is expected to exert additive effects. We herein investigated whether SFHbNP exerted enhanced neuroprotective effects in a rat transient middle cerebral artery occlusion (tMCAO) model. Rats were subjected to 2-hour tMCAO and divided into the following 3 groups with the intravenous administration of the respective reagents: (1) phosphate-buffered saline (PBS), as a vehicle (2) Hb-HSA3, and (3) SFHbNP. After 24-hour reperfusion, infarct and edema volumes decreased in the order of the PBS, Hb-HSA3, and SFHbNP groups, with a significant difference (p < 0.05) between the PBS and SFHbNP groups. Similar reductions were observed in oxidative stress, leukocyte recruitment, and blood-brain barrier disruption in the order of the PBS, Hb-HSA3, and SFHbNP groups. In the early phase of reperfusion within 6 h, microvascular HBOC perfusion and cerebral blood flow were maintained at high levels during the reperfusion period in the Hb-HSA3 and SFHbNP groups. However, a difference was observed in tissue oxygen partial pressure levels, which significantly decreased after 6-hour reperfusion in the Hb-HSA3 group, but remained high in the SFHbNP group. A superior oxygen transport ability appears to be related to the enhanced neuroprotective effects of SFHbNP.
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Affiliation(s)
- Ryota Tatezawa
- Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Takeo Abumiya
- Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
| | - Yasuhiro Ito
- Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Masayuki Gekka
- Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Wataru Okamoto
- Department of Applied Chemistry, Faculty of Science and Engineering, Chuo University, Tokyo, Japan
| | - Kohta Ishii
- Department of Applied Chemistry, Faculty of Science and Engineering, Chuo University, Tokyo, Japan
| | - Natsumi Kohyama
- Department of Applied Chemistry, Faculty of Science and Engineering, Chuo University, Tokyo, Japan
| | - Teruyuki Komatsu
- Department of Applied Chemistry, Faculty of Science and Engineering, Chuo University, Tokyo, Japan
| | - Miki Fujimura
- Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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Abutarboush R, Aligbe C, Pappas G, Saha B, Arnaud F, Haque A, Auker C, McCarron R, Scultetus A, Moon-Massat P. Effects of the Oxygen-Carrying Solution OxyVita C on the Cerebral Microcirculation and Systemic Blood Pressures in Healthy Rats. J Funct Biomater 2014; 5:246-58. [PMID: 25411852 PMCID: PMC4285405 DOI: 10.3390/jfb5040246] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 11/07/2014] [Accepted: 11/12/2014] [Indexed: 11/26/2022] Open
Abstract
The use of hemoglobin-based oxygen carriers (HBOC) as oxygen delivering therapies during hypoxic states has been hindered by vasoconstrictive side effects caused by depletion of nitric oxide (NO). OxyVita C is a promising oxygen-carrying solution that consists of a zero-linked hemoglobin polymer with a high molecular weight (~17 MDa). The large molecular weight is believed to prevent extravasation and limit NO scavenging and vasoconstriction. The aim of this study was to assess vasoactive effects of OxyVita C on systemic blood pressures and cerebral pial arteriole diameters. Anesthetized healthy rats received four intravenous (IV) infusions of an increasing dose of OxyVita C (2, 25, 50, 100 mg/kg) and hemodynamic parameters and pial arteriolar diameters were measured pre- and post-infusion. Normal saline was used as a volume-matched control. Systemic blood pressures increased (P ≤ 0.05) with increasing doses of OxyVita C, but not with saline. There was no vasoconstriction in small (<50 µm) and medium-sized (50–100 µm) pial arterioles in the OxyVita C group. In contrast, small and medium-sized pial arterioles vasoconstricted in the control group. Compared to saline, OxyVita C showed no cerebral vasoconstriction after any of the four doses evaluated in this rat model despite increases in blood pressure.
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Affiliation(s)
- Rania Abutarboush
- NeuroTrauma Department, Naval Medical Research Center (NMRC), Silver Spring, MD 20910, USA.
| | - Chioma Aligbe
- NeuroTrauma Department, Naval Medical Research Center (NMRC), Silver Spring, MD 20910, USA.
| | - Georgina Pappas
- NeuroTrauma Department, Naval Medical Research Center (NMRC), Silver Spring, MD 20910, USA.
| | - Biswajit Saha
- NeuroTrauma Department, Naval Medical Research Center (NMRC), Silver Spring, MD 20910, USA.
| | - Francoise Arnaud
- NeuroTrauma Department, Naval Medical Research Center (NMRC), Silver Spring, MD 20910, USA.
| | - Ashraful Haque
- NeuroTrauma Department, Naval Medical Research Center (NMRC), Silver Spring, MD 20910, USA.
| | - Charles Auker
- NeuroTrauma Department, Naval Medical Research Center (NMRC), Silver Spring, MD 20910, USA.
| | - Richard McCarron
- NeuroTrauma Department, Naval Medical Research Center (NMRC), Silver Spring, MD 20910, USA.
| | - Anke Scultetus
- NeuroTrauma Department, Naval Medical Research Center (NMRC), Silver Spring, MD 20910, USA.
| | - Paula Moon-Massat
- NeuroTrauma Department, Naval Medical Research Center (NMRC), Silver Spring, MD 20910, USA.
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Al Asmari AK, Al Omani S, Elfaki I, Tariq M, Al Malki A, Al Asmary S. Gastric antisecretory and antiulcer activity of bovine hemoglobin. World J Gastroenterol 2013; 19:3291-3299. [PMID: 23745031 PMCID: PMC3671081 DOI: 10.3748/wjg.v19.i21.3291] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2012] [Revised: 03/09/2013] [Accepted: 04/16/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate gastric antisecretory and gastroprotective activity of bovine hemoglobin (B-Hb) in rats.
METHODS: Adult Albino-Wistar rats were divided into groups of 6 animals each. B-Hb in doses of 100, 300 and 900 mg/kg body weight was tested for gastric acid secretion and antiulcer activity. Gastric secretions were measured 6 h after pylorus ligation in rats pretreated with B-Hb. The acidity was measured by titrating gastric contents against 0.01 mol/L NaOH to pH 7. Indomethacin ulcers were produced by oral administration of 30 mg/kg bw in the rats pretreated with B-Hb one hour before indomethacin. Six hours after indomethacin stomach removed and ulcer index was recorded. Ethanol ulcer were produced by 1 mL of ethanol in the rats pretreated with B-Hb 30 min before the ethanol. One hour after ethanol stomach were cut open to score ulcers. Histological examination and analysis of gastric wall mucus, non-protein sulfhydryl groups (NP-SH), and myeloperoxidase (MPO) were carried in gastric tissue following ethanol administration.
RESULTS: In control rats pylorus ligation for 6 h resulted in the accumulation of 8.1 ± 0.61 mL of gastric secretion. The treatment of the rats with 100, 300 and 900 mg/kg of B-Hb produced a significant decrease in the volume of gastric secretion 5.6 ± 0.63, 5.5 ± 0.75 and 4.7 ± 0.58 mL respectively as compared to the control group [analysis of variance (ANOVA) F = 4.77, P < 0.05]. The lesion area in the control group was found to be 22.4 ± 3.2 mm2 six hours after the administration of indomethacin. Treatment of rats with B-Hb at doses of 100 mg/kg (24.3 ± 3.29 mm2), 300 mg/kg (16.2 ± 1.45 mm2) and 900 mg/kg (12.6 ± 1.85 mm2) produced a dose dependent decreased the lesion scores (ANOVA F = 4.50, P < 0.05). The ulcer index following one hour after 1 mL ethanol was 7.1 ± 0.31. Pretreatment of rats with B-Hb at the doses of 100 mg/kg (2.5 ± 0.42), 300 mg/kg (2.1 ± 0.4) and 900 mg/kg (0.7 ± 0.21) significantly inhibited the formation of gastric lesions (ANOVA F = 63.26, P < 0.0001). Histological examination of gastric mucosa following ethanol showed significant lesions in the form of gastric pits with detachment of the surface epithelium; vacuolation of epithelial cells and elongation of microvessels. The changes were dose-dependently attenuated by B-Hb. The treatment of rats with ethanol significantly decreased the Alcian blue binding capacity of gastric wall mucus (480 ± 25.6 μg Alcian blue/g of tissue) as compared to control rats (667 ± 25.8 μg). Pretreatment of rats with B-Hb at the doses of 100 mg/kg (516 ± 31.6 μg/g), 300 mg/kg (558 ± 28.8 μg/g) and 900 mg/kg (654 ± 33.8 μg/g) significantly attenuated ethanol induced depletion of gastric wall mucus (ANOVA F = 8.05, P < 0.005). A significant and dose dependent increase of gastric mucosal NP-SH (ANOVA F = 19.62, P < 0.001) and decrease in MPO activity (ANOVA F = 3.1, P < 0.05) was observed in B-Hb treated rats.
CONCLUSION: B-Hb possesses significant gastric antisecretory and gastroprotective activity against experimentally induced gastric lesion. The gastroprotective effects of B-Hb are accompanied by inhibition of neutrophils activity, reduction of oxidative stress and maintenance of mucosal integrity.
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Ananthakrishnan R, Li Q, O’Shea KM, Quadri N, Wang L, Abuchowski A, Schmidt AM, Ramasamy R. Carbon monoxide form of PEGylated hemoglobin protects myocardium against ischemia/reperfusion injury in diabetic and normal mice. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2013; 41:428-36. [DOI: 10.3109/21691401.2012.762370] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Zhang J, Cao S, Kwansa H, Crafa D, Kibler KK, Koehler RC. Transfusion of hemoglobin-based oxygen carriers in the carboxy state is beneficial during transient focal cerebral ischemia. J Appl Physiol (1985) 2012; 113:1709-17. [PMID: 23042910 DOI: 10.1152/japplphysiol.01079.2012] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Exchange transfusion of large volumes of hemoglobin (Hb)-based oxygen carriers can protect the brain from middle cerebral artery occlusion (MCAO). Hb in the carboxy state (COHb) may provide protection at relatively low volumes by enhancing vasodilation. We determined whether transfusion of rats with 10 ml/kg PEGylated COHb [polyethylene glycol (PEG)-COHb] at 20 min of 2-h MCAO was more effective in reducing infarct volume compared with non-carbon monoxide (CO) PEG-Hb. After PEG-COHb transfusion, whole blood and plasma COHb was <3%, indicating rapid release of CO. PEG-COHb transfusion significantly reduced infarct volume (15 ± 5% of hemisphere; mean ± SE) compared with that in the control group (35 ± 6%), but non-CO PEG-Hb did not (24 ± 5%). Chemically dissimilar COHb polymers were also effective. Induction of MCAO initially produced 34 ± 2% dilation of pial arterioles in the border region that subsided to 10 ± 1% at 2 h. Transfusion of PEG-COHb at 20 min of MCAO maintained pial arterioles in a dilated state (40 ± 5%) at 2 h, whereas transfusion of non-CO PEG-Hb had an intermediate effect (22 ± 3%). When transfusion of PEG-COHb was delayed by 90 min, laser-Doppler flow in the border region increased from 57 ± 9 to 82 ± 13% of preischemic baseline. These data demonstrate that PEG-COHb is more effective than non-CO PEG-Hb at reducing infarct volume, sustaining cerebral vasodilation, and improving collateral perfusion in a model of transient focal cerebral ischemia when given at a relatively low dose (plasma Hb concentration < 1 g/dl). Use of acellular Hb as a CO donor that is rapidly converted to an oxygen carrier in vivo may permit potent protection at low transfusion volumes.
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Affiliation(s)
- Jian Zhang
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, Maryland 21287, USA
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Klaus JA, Kibler KK, Abuchowski A, Koehler RC. Early treatment of transient focal cerebral ischemia with bovine PEGylated carboxy hemoglobin transfusion. ACTA ACUST UNITED AC 2011; 38:223-9. [PMID: 20486873 DOI: 10.3109/10731199.2010.488635] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The effect of transfusion of PEGylated hemoglobin (PEG-Hb) was evaluated in anesthetized rats subjected to 2 hours of focal cerebral ischemia and 1 day of reperfusion. PEG-Hb was stored in the carboxy state (PEG-COHb) to reduce autooxidation and increase the shelf life. Transfusion of 10 ml/kg of PEG-COHb at 20 minutes of ischemia did not alter arterial blood pressure or increase red cell flux in the ischemic core. Plasma hemoglobin increased to only 0.6 g/dL, yet infarct volume was markedly decreased and neurological deficits were improved. We conclude that early topload transfusion of PEG-COHb protects the brain from ischemic stroke.
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Affiliation(s)
- Judith A Klaus
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University/JHMI, 600 North Wolfe Street, Baltimore, MD 21287, USA
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Faggiano S, Bruno S, Ronda L, Pizzonia P, Pioselli B, Mozzarelli A. Modulation of expression and polymerization of hemoglobin Polytaur, a potential blood substitute. Arch Biochem Biophys 2011; 505:42-7. [DOI: 10.1016/j.abb.2010.09.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2010] [Revised: 09/27/2010] [Accepted: 09/27/2010] [Indexed: 11/25/2022]
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Chiesa A, Brambilla P, Serretti A. Functional neural correlates of mindfulness meditations in comparison with psychotherapy, pharmacotherapy and placebo effect. Is there a link? Acta Neuropsychiatr 2010; 22:104-17. [PMID: 26952802 DOI: 10.1111/j.1601-5215.2010.00460.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
UNLABELLED Chiesa A, Brambilla P, Serretti A. Functional neural correlates of mindfulness meditations in comparison with psychotherapy, pharmacotherapy and placebo effect. Is there a link? OBJECTIVE Mindfulness meditations (MM) are a group of meditation practices which are increasingly receiving attention. The aim of the present work is to review current findings about the neural correlates of MM and compare such findings with other specific and non-specific treatments. METHODS A literature search was undertaken using MEDLINE, ISI web of knowledge, the Cochrane database and references of retrieved articles. Studies which focused on the functional neural correlates of MM, psychotherapy, pharmacotherapy and placebo published up to August 2009 were screened in order to be considered for the inclusion. RESULTS Main findings suggest that long-term MM practice allows a more flexible emotional regulation by engaging frontal cortical structures to dampen automatic amygdala activation. A large overlap exists between cerebral areas activated during MM, psychotherapy, pharmacotherapy and those activated by placebo. However, while MM, psychotherapy and placebo seem to act through a top-down regulation, antidepressants seem to act through a bottom-up process. CONCLUSION MM seem to target specific brain areas related to emotions and emotional regulation. Similar mechanisms have been observed also in other interventions, particularly psychotherapy.
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Affiliation(s)
- Alberto Chiesa
- 1Institute of Psychiatry, University of Bologna, Bologna, Italy
| | - Paolo Brambilla
- 2DPMSC, Section of Psychiatry, University of Udine, Udine, Italy
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Fronticelli C, Koehler RC. Design of recombinant hemoglobins for use in transfusion fluids. Crit Care Clin 2009; 25:357-71, Table of Contents. [PMID: 19341913 DOI: 10.1016/j.ccc.2008.12.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Molecular biology has been applied to the development of hemoglobin-based oxygen carrier (HBOC) proteins that can be expressed in bacteria or yeast. The transformation of the hemoglobin molecule into an HBOC requires a variety of modifications for rendering the acellular molecule of hemoglobin physiologically acceptable when transfused in circulation. Hemoglobins with different oxygen affinities can be obtained by introducing mutations at the heme pocket, the site of oxygen binding, or by introducing surface mutations that stabilize the hemoglobin molecule in the low-oxygen-affinity state. Modification of the size of the heme pocket is also used to hinder nitric oxide depletion and associated vasoconstriction. Introduction of cysteine residues on the hemoglobin surface allows formation of intermolecular bonds and formation of polymeric HBOCs. These polymers of recombinant hemoglobin have the characteristics of molecular size, molecular stability, and oxygen delivery to hypoxic tissue suitable for an HBOC.
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Affiliation(s)
- Clara Fronticelli
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Blalock, Baltimore, MD 21287, USA.
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Kramer AH, Zygun DA. Anemia and red blood cell transfusion in neurocritical care. Crit Care 2009; 13:R89. [PMID: 19519893 PMCID: PMC2717460 DOI: 10.1186/cc7916] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2009] [Revised: 04/09/2009] [Accepted: 06/11/2009] [Indexed: 12/26/2022] Open
Abstract
INTRODUCTION Anemia is one of the most common medical complications to be encountered in critically ill patients. Based on the results of clinical trials, transfusion practices across the world have generally become more restrictive. However, because reduced oxygen delivery contributes to 'secondary' cerebral injury, anemia may not be as well tolerated among neurocritical care patients. METHODS The first portion of this paper is a narrative review of the physiologic implications of anemia, hemodilution, and transfusion in the setting of brain-injury and stroke. The second portion is a systematic review to identify studies assessing the association between anemia or the use of red blood cell transfusions and relevant clinical outcomes in various neurocritical care populations. RESULTS There have been no randomized controlled trials that have adequately assessed optimal transfusion thresholds specifically among brain-injured patients. The importance of ischemia and the implications of anemia are not necessarily the same for all neurocritical care conditions. Nevertheless, there exists an extensive body of experimental work, as well as human observational and physiologic studies, which have advanced knowledge in this area and provide some guidance to clinicians. Lower hemoglobin concentrations are consistently associated with worse physiologic parameters and clinical outcomes; however, this relationship may not be altered by more aggressive use of red blood cell transfusions. CONCLUSIONS Although hemoglobin concentrations as low as 7 g/dl are well tolerated in most critical care patients, such a severe degree of anemia could be harmful in brain-injured patients. Randomized controlled trials of different transfusion thresholds, specifically in neurocritical care settings, are required. The impact of the duration of blood storage on the neurologic implications of transfusion also requires further investigation.
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Affiliation(s)
- Andreas H Kramer
- Departments of Critical Care Medicine & Clinical Neurosciences, University of Calgary, Foothills Medical Center, 1403 29thSt. N.W., Calgary, AB, Canada, T2N 2T9
| | - David A Zygun
- Departments of Critical Care Medicine, Clinical Neurosciences, & Community Health Sciences, University of Calgary, Foothills Medical Center, 1403 29thSt. N.W., Calgary, AB, Canada, T2N 2T9
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Abstract
OBJECTIVE Hemoglobin-based oxygen carriers (HBOC) of several types scavenge nitric oxide from the vasculature resulting in vasoconstriction and hypertension, both systemic and pulmonary. Phosphodiesterase-5 (PDE5) inhibitors promote nitric oxide activity and enhance vasodilation. The purpose of this study was to determine whether combined therapy of glutaraldehyde-polymerized bovine hemoglobin (HBOC) with a PDE5 inhibitor would counter the negative hemodynamic consequences of HBOC therapy alone, resulting in improved hemodynamics and oxygen delivery. DESIGN A controlled, experimental study. SETTING A research laboratory at a university. SUBJECTS Conscious male Sprague-Dawley rats. INTERVENTIONS Glutaraldehyde-polymerized bovine hemoglobin (HBOC), sildenafil (PDE5 inhibitor), and lactated Ringer's solution (control). MEASUREMENTS AND MAIN RESULTS Infusion of the HBOC resulted in significant (p < 0.05) systemic and pulmonary vasoconstriction, with reduced cardiac output and reduced oxygen delivery to the periphery. Infusion of lactated Ringer's demonstrated no changes in the measured variables. Infusion of sildenafil alone reduced systemic and pulmonary artery blood pressure, while maintaining cardiac output and oxygen delivery. Combined HBOC and sildenafil infusion resulted in stable systemic blood pressure, cardiac output, and oxygen delivery. However, the addition of sildenafil to HBOC did not fully ameliorate the pulmonary vasoconstriction caused by HBOC. CONCLUSION The HBOC used in this study resulted in pulmonary and systemic hypertension, reduced cardiac output, and oxygen delivery. These negative consequences of HBOC treatment can be largely overcome by combing HBOC treatment with a PDE5 inhibitor (sildenafil). Thus, these data support the continued investigation of combined HBOC and PDE5 inhibitor treatment in circumstances in which HBOC therapy is being considered.
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Irwin D, Buehler PW, Alayash AI, Jia Y, Bonventura J, Foreman B, White M, Jacobs R, Piteo B, TissotvanPatot MC, Hamilton KL, Gotshall RW. Mixed S-nitrosylated polymerized bovine hemoglobin species moderate hemodynamic effects in acutely hypoxic rats. Am J Respir Cell Mol Biol 2009; 42:200-9. [PMID: 19395680 DOI: 10.1165/rcmb.2008-0364oc] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Hemoglobin (Hb)-based oxygen carriers (HBOCs) are being developed as a potential therapy for increasing tissue oxygenation, yet they have not reached their full potential because of unwanted hemodynamic side effects (vasoconstriction, low cardiac output, and oxygen delivery) due in part to nitric oxide (NO) scavenging by cell-free Hb. It may be possible to overcome the NO scavenging effect by coinfusing S-nitrosylated (SNO) HBOC along with unmodified HBOC. SNO-HBOC, like free Hb, may act as an NO donor in low-oxygen conditions. We hypothesized that an unaltered HBOC, polymerized bovine Hb (PBvHb), coinfused with an SNO-PBvHb, would improve hemodynamics and oxygen delivery during hypoxia. Vascular oxygen content and hemodynamics were determined after euvolemic rats were infused (3 ml) with lactated Ringer's solution, PBvHb, SNO-PBvHb, or PBvHb plus SNO-PBvHb (1:10) during normoxia or acute hypoxia (fraction of inspired oxygen = 10%, 120 min). Hemodynamic side effects resulting from PBvHb infusion (vasoconstriction, elevated pulmonary blood pressure, and reduced cardiac output) were offset by SNO-PBvHb in acute hypoxic, but not normoxic, conditions. These data support the potential use of HBOC mixed with SNO-HBOC for the treatment of conditions in which acute hypoxia is present, such as tumor oxygenation, wound healing, hemorrhagic trauma, and sickle cell and hemolytic anemia.
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Affiliation(s)
- David Irwin
- University of Colorado Health Science Center, Cardiovascular Pulmonary Research Laboratory, School of Medicine, 4200 East 9th Avenue, Denver, CO 80262, USA.
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Mito T, Nemoto M, Kwansa H, Sampei K, Habeeb M, Murphy SJ, Bucci E, Koehler RC. Decreased damage from transient focal cerebral ischemia by transfusion of zero-link hemoglobin polymers in mouse. Stroke 2009; 40:278-84. [PMID: 18988905 PMCID: PMC2612731 DOI: 10.1161/strokeaha.108.526731] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2008] [Accepted: 06/06/2008] [Indexed: 01/29/2023]
Abstract
BACKGROUND AND PURPOSE Transfusion of large polymers of hemoglobin avoids the peripheral extravasation and hypertension associated with crosslinked tetrameric hemoglobin transfusion and may be more effective in rescuing brain from focal ischemia. Effects of transfusion of high-oxygen-affinity hemoglobin polymers of different weight ranges were determined. METHODS Hypervolemic exchange transfusion was performed during 2 hours of middle cerebral artery occlusion in mice. RESULTS Compared to transfusion with a 5% albumin solution or no transfusion, infarct volume was reduced 40% by transfusion of a 6% solution containing hemoglobin polymers in the nominal range 500 to 14 000 kDa. Infarct volume was not significantly reduced by transfusion of a lower concentration of 2% to 3% of this size range of polymers, 6% hemoglobin solutions without removal of polymers <500 kDa or >14000 kDa, or crosslinked hemoglobin tetramers with normal oxygen affinity. Exchange transfusion with the 6% solution of the 500 to 14 000 kDa hemoglobin polymers did not improve the distribution of cerebral blood flow during focal ischemia and, in mice without ischemia, did not affect flow to brain or other major organs. CONCLUSIONS An intermediate size range of polymerized bovine hemoglobin possessing high oxygen affinity appears optimal for rescuing mouse brain from transient focal cerebral ischemia. A minimum concentration of a 6% solution is required, the rescue is superior to that obtained with crosslinked tetrameric hemoglobin possessing normal oxygen affinity, and tissue salvage is not associated with increased blood flow. This polymer solution avoids the adverse effects of severe renal and splanchnic vasoconstriction seen with crosslinked tetrameric hemoglobin.
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Affiliation(s)
- Toshiaki Mito
- Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Blalock 1404, Baltimore, MD 21287, USA
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Sakai H, Tsuchida E. Hemoglobin-vesicles for a Transfusion Alternative and Targeted Oxygen Delivery. J Liposome Res 2008; 17:227-35. [DOI: 10.1080/08982100701529904] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Towards a novel haemoglobin-based oxygen carrier: Euro-PEG-Hb, physico-chemical properties, vasoactivity and renal filtration. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2008; 1784:1402-9. [DOI: 10.1016/j.bbapap.2008.03.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2007] [Revised: 03/08/2008] [Accepted: 03/08/2008] [Indexed: 11/17/2022]
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Koehler RC, Fronticelli C, Bucci E. Insensitivity of cerebral oxygen transport to oxygen affinity of hemoglobin-based oxygen carriers. BIOCHIMICA ET BIOPHYSICA ACTA 2008; 1784:1387-94. [PMID: 18230370 PMCID: PMC2562895 DOI: 10.1016/j.bbapap.2008.01.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/09/2007] [Revised: 12/27/2007] [Accepted: 01/02/2008] [Indexed: 10/22/2022]
Abstract
The cerebrovascular effects of exchange transfusion of various cell-free hemoglobins that possess different oxygen affinities are reviewed. Reducing hematocrit by transfusion of a non-oxygen-carrying solution dilates pial arterioles on the brain surface and increases cerebral blood flow to maintain a constant bulk oxygen transport to the brain. In contrast, transfusion of hemoglobins with P50 of 4-34 Torr causes constriction of pial arterioles that offsets the decrease in blood viscosity to maintain cerebral blood flow and oxygen transport. The autoregulatory constriction is dependent on synthesis of 20-HETE from arachidonic acid. This oxygen-dependent reaction is apparently enhanced by facilitated oxygen diffusion from the red cell to the endothelium arising from increased plasma oxygen solubility in the presence of low or high-affinity hemoglobin. Exchange transfusion of recombinant hemoglobin polymers with P50 of 3 and 18 Torr reduces infarct volume from experimental stroke. Cell-free hemoglobins do not require a P50 as high as red blood cell hemoglobin to facilitate oxygen delivery.
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Affiliation(s)
- Raymond C Koehler
- Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, Baltimore, Maryland 21287, USA.
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Irwin DC, Foreman B, Morris K, White M, Sullivan T, Jacobs R, Monnet E, Hackett T, TissotvanPatot MC, Hamilton KL, Gotshall RW. Polymerized bovine hemoglobin decreases oxygen delivery during normoxia and acute hypoxia in the rat. Am J Physiol Heart Circ Physiol 2008; 295:H1090-H1099. [PMID: 18567708 DOI: 10.1152/ajpheart.00303.2008] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Hemoglobin-based oxygen carriers (HBOC) have been primarily studied for blood loss treatment. More recently infusions of HBOC in euvolemic subjects have been proposed for a wide variety of potential therapies in which increased tissue oxygenation would be beneficial. However, compared with the exchange transfusion models to study blood loss, less is known about HBOC oxygen delivery and vasoacitvity when it is infused in euvolemic subjects. We hypothesized that HBOC [polymerized bovine hemoglobin (PBvHb)] infusion creating hypervolemia would increase oxygen delivery to tissues during acute global hypoxia. Vascular oxygen content and hemodynamics were determined after euvolemic rats were infused with 3 ml of either lactated Ringer or PBvHb solution (13 g/dl, 1.3 g/kg) during acute hypoxia (FIO2 = 10%, 4 h) or normoxia (FIO2 = 21%) exposure. Our data demonstrated that compared with Ringer-infused animals, in hypoxia and normoxia, PBvHb treatment improved oxygen content but raised mean arterial pressure, lowered stroke volume, heart rate, and cardiac index, which resulted in a net reduction in blood flow and oxygen delivery to the tissues. The PBvHb vasoactive effect was similar in magnitude and direction as to the Ringer-infused animals treated with a nitric oxide synthase inhibitor nitro-l-arginine, suggesting the PBvHb effect is mediated via nitric oxide scavenging. We conclude that infusion of PBvHb is not likely to be useful in treating global hypoxia under these conditions.
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Affiliation(s)
- David C Irwin
- Cardiovascular Pulmonary Research Group, School of Medicine, University of Colorado Health Science Center, 4200 E 9Ave., Denver, CO 80262, USA.
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Haemoglobin, oxygen carriers and perioperative organ perfusion. Best Pract Res Clin Anaesthesiol 2008; 22:63-80. [DOI: 10.1016/j.bpa.2007.10.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
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Lenz C, Rebel A, Waschke KF, Koehler RC, Frietsch T. Blood viscosity modulates tissue perfusion: sometimes and somewhere. TRANSFUSION ALTERNATIVES IN TRANSFUSION MEDICINE : TATM 2008; 9:265-272. [PMID: 19122878 PMCID: PMC2519874 DOI: 10.1111/j.1778-428x.2007.00080.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Each organ possesses specific properties for controlling microvascular perfusion. Such specificity provides an opportunity to design transfusion fluids that target thrombo-embolic or vasospasm-induced ischemia in a particular organ or that optimize overall perfusion from systemic shock. The role of viscosity in the design of these fluids might be underestimated, because viscosity is rarely monitored or considered in critical care decisions. Studies linking viscosity-dependent changes of microvascular perfusion to outcome-relevant data suggest that whole blood viscosity is negligible as a determinant of microvascular perfusion under physiological conditions when autoregulation is effective. Because autoregulation is driven to maintain oxygen supply constant, the organism will compensate for changes in blood viscosity to sustain oxygen delivery. In contrast, under pathological conditions in the brain and elsewhere, increases of overall viscosity should be avoided - including all the situations where vascular autoregulatory mechanisms are inoperative due to ischemia, structural damage or physiologic dysfunction. As latter conditions are not to identify with high certainty, the risks that accompany therapeutic correction of blood viscosity are outweighing the benefits. The ability to bedside monitor blood viscosity and to link changes in viscosity to outcome parameters in various clinical conditions would provide more solid foundation for evidence-based clinical management.
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Affiliation(s)
- C Lenz
- Clinic of Anesthesiology and Critical Care Medicine, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany
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Abstract
Oxygen-carrying plasma expanders (blood substitutes) have been sought for over a century. Development of current products is a result of evolution in the understanding of proteins in general, of hemoglobin in particular, and of how cell-free hemoglobin interacts with the control of local blood flow to ensure adequate tissue oxygenation. Hemoglobin-based products are considered in four "generations" corresponding to major improvements. First-generation products consisted of hemoglobin, freed of red cell membranes (stroma-free hemoglobin [SFH]), which was renal toxic and vasoactive. Second-generation products were polymerized with aldehyde reagents to reduce or eliminate the renal toxicity, but the products were heterogeneous and still vasoactive. Third-generation products employed more specific intramolecular crosslinking to eliminate polymerization and promote homogeneity, but they also remained vasoactive. Fourth-generation products are based on a new understanding of the way in which microvascular blood flow is controlled and the influence of O(2) delivery to vascular walls. After more than a century of research, one of these new solutions should find use as an alternative to red cells for transfusion in certain clinical settings.
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Affiliation(s)
- Robert M Winslow
- Sangart, Inc, and Department of Bioengineering, University of California, San Diego, CA 92121, USA.
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