scholarly journals Apohemoglobin-haptoglobin complexes attenuate the hypertensive response to low-molecular-weight polymerized hemoglobin

2020 ◽  
Vol 4 (12) ◽  
pp. 2739-2750
Author(s):  
Donald A. Belcher ◽  
Carlos Munoz ◽  
Ivan S. Pires ◽  
Alexander T. Williams ◽  
Pedro Cabrales ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Molecular Weight ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Capillary Density ◽  
Functional Capillary Density ◽  
Systemic Hypertension ◽  
Low Molecular Weight ◽  
Potential Candidate ◽  
Polymerized Hemoglobin

Abstract Polymerized hemoglobin (PolyHb) is a promising hemoglobin (Hb)-based oxygen carrier currently undergoing development as a red blood cell substitute. Unfortunately, commercially developed products are composed of low-molecular-weight (LMW) PolyHb molecules, which extravasate, scavenge nitric oxide, and result in vasoconstriction and hypertension. The naturally occurring Hb-scavenging species haptoglobin (Hp), combined with the purified heme-scavenging species apohemoglobin (apoHb), is a potential candidate to alleviate the pressor effect of PolyHb. This study evaluated the protective activity of administering the apoHb-Hp complex to mitigate the vasoactive response induced by the transfusion of LMW PolyHb. Hp binding to PolyHb was characterized in vitro. The effectiveness of apoHb–Hp administration on reducing the vasoconstriction and pressor effects of PolyHb was assessed by measuring systemic and microcirculatory hemodynamics. Transfusion of LMW PolyHb to vehicle control pretreated animals increased mean arterial pressure while decreasing arteriole diameter and functional capillary density. However, transfusion of LMW PolyHb to apoHb–Hp pretreated animals prevented changes in mean arterial pressure, heart rate, arteriole diameter, blood flow, and functional capillary density relative to before transfusion. These results indicate that the increased size of PolyHb after binding to the apoHb-Hp complex may help compartmentalize PolyHb in the vascular space and thus reduce extravasation, nitric oxide scavenging, and toxicity responsible for vasoconstriction and systemic hypertension.

Recombinant Human Hemoglobin with Reduced Nitric Oxide–scavenging Capacity Restores Effectively Pancreatic Microcirculatory Disorders in Hemorrhagic Shock

2004 ◽  
Vol 100 (6) ◽  
pp. 1484-1490 ◽  
Author(s):  
Ernst von Dobschuetz ◽  
Joerg Hutter ◽  
Tomas Hoffmann ◽  
Konrad Messmer
Keyword(s):  
Nitric Oxide ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Hemorrhagic Shock ◽  
Hydroxyethyl Starch ◽  
Capillary Density ◽  
Functional Capillary Density ◽  
Human Hemoglobin ◽  
Scavenging Capacity ◽  
Area Functional

Background Scavenging of nitric oxide by hemoglobin-based oxygen carriers could aggravate microcirculatory failure in splanchnic organs after hemorrhagic shock as a consequence of vasoconstrictive side effects. The aim of this study was to compare the effects of two recombinant human hemoglobin solutions, a second-generation product bearing reduced nitric oxide-scavenging properties (rHb2.0) due to site directed mutagenesis of the heme pocket and a first-generation recombinant hemoglobin (rHb1.1) with scavenging capacity similar to native hemoglobin, on the pancreatic microcirculation after hemorrhagic shock. Methods Twenty-eight pentobarbital-anesthetized rats were bled to a mean arterial pressure of 40 mmHg and maintained at this level for 1 h. Using an intravital microscope, the length of erythrocyte-perfused pancreatic capillaries per observation area (functional capillary density) were measured in animals resuscitated by volumes of hydroxyethyl starch, rHb1.1, or rHb2.0 equivalent to the shed blood volume. Animals without shock induction served as control. Results As compared with control (438 +/- 10 cm(-1)), animals treated with hydroxyethyl starch (315 +/- 44 cm(-1)) and rHb1.1 (288 +/- 67 cm(-1)) showed a significant reduction of functional capillary density after 2 h of resuscitation. rHb2.0 was able to restore functional capillary density (410 +/- 42 cm(-1)) and mean arterial pressure to baseline values. Conclusion rHb2.0 was effectively able to restore pancreatic microcirculation after hemorrhagic shock. This may be related to the compound's effective lack of nitric oxide-scavenging properties. This hemoglobin solution or ones similar to it might be uniquely valuable for resuscitation from hemorrhagic shock.

Intracarotid Nitroprusside Does Not Augment Cerebral Blood Flow in Human Subjects

2002 ◽  
Vol 96 (1) ◽  
pp. 60-66 ◽  
Author(s):  
Shailendra Joshi ◽  
William L. Young ◽  
Huang Duong ◽  
Beverly A. Aagaard ◽  
Noeleen D. Ostapkovich ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Repeated Measures ◽  
Human Subjects ◽  
Systemic Hypertension ◽  
Cerebrovascular Resistance ◽  
Post Hoc

Background The recent resurgence of interest in the cerebrovascular effects of nitroprusside can be attributed to the possibility of using nitric oxide donors in treating cerebrovascular insufficiency. However, limited human data suggest that intracarotid nitroprusside does not directly affect cerebrovascular resistance. In previous studies, physiologic or pharmacologic reactivity of the preparation was not tested at the time of nitroprusside challenge. The authors hypothesized that if nitric oxide is a potent modulator of human cerebral blood flow (CBF), then intracarotid infusion of nitroprusside will augment CBF. Methods Cerebral blood flow was measured (intraarterial (133)Xe technique) in sedated human subjects undergoing cerebral angiography during sequential infusions of (1) intracarotid saline, (2) intravenous phenylephrine to induce systemic hypertension, (3) intravenous phenylephrine with intracarotid nitroprusside (0.5 microg x kg(-1) x min(-1)), and (4) intracarotid verapamil (0.013 mg x kg(-1) x min(-1)). Data (mean +/- SD) were analyzed by repeated-measures analysis of variance and post hoc Bonferroni-Dunn test. Results Intravenous phenylephrine increased systemic mean arterial pressure (from 83 +/- 12 to 98 +/- 6 mmHg; n = 8; P < 0.001), and concurrent infusion of intravenous phenylephrine and intracarotid nitroprusside reversed this effect. However, compared with baseline, CBF did not change with intravenous phenylephrine or with concurrent infusions of intravenous phenylephrine and intracarotid nitroprusside. Intracarotid verapamil increased CBF (43 +/- 9 to 65 +/- 11 ml x 100 g(-1) x min(-1); P < 0.05). Conclusions The authors conclude that, in humans, intracarotid nitroprusside sufficient to decrease mean arterial pressure during recirculation, does not augment CBF. Failure of intracarotid nitroprusside to augment CBF despite demonstrable autoregulatory vasoconstriction and pharmacologic vasodilation questions the significance of nitric oxide-mediated vasodilation in human cerebral circulation.

Diaspirin Cross-linked Hemoglobin Effectively Restores Pancreatic Microcirculatory Failure in Hemorrhagic Shock 

1999 ◽  
Vol 91 (6) ◽  
pp. 1754-1754 ◽  
Author(s):  
Ernst von Dobschuetz ◽  
Tomas Hoffmann ◽  
Konrad Messmer
Keyword(s):  
Lipid Peroxidation ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Hemorrhagic Shock ◽  
Whole Blood ◽  
Capillary Density ◽  
Pancreatic Tissue ◽  
Functional Capillary Density ◽  
Reactive Material ◽  
Area Functional

Background Microvascular reperfusion failure of splanchnic organs is a crucial hallmark in organ damage induced by hemorrhagic shock, which should be prevented by a resuscitation solution. Because the vasoactive properties of the hemoglobin-based oxygen carrier diaspirin cross-linked hemoglobin (DCLHb) could adversely influence restoration of pancreatic capillary perfusion during resuscitation, the authors investigated its effects on the microcirculation of the rat pancreas in comparison with whole blood and 6% hydroxyethylstarch resuscitation from severe hemorrhagic shock. Methods Twenty-eight pentobarbital-anaesthetized rats were bled to a mean arterial pressure (MAP) of 40 mmHg and maintained at this level for 1 h. Using an intravital microscope, mean arterial pressure, the length of erythrocyte-perfused pancreatic capillaries per observation area (functional capillary density), the adherence of leukocytes in postcapillary venules, and pancreatic lipid peroxidation, measured as thiobarbituric acid-reactive material in pancreatic tissue, were determined in animals resuscitated by volumes of hydroxyethylstarch, DCLHb, and whole blood (WB) equivalent to the shed blood volume or in control animals without shock induction for a period of 2 h after resuscitation. Results Compared with control animals (366+/-28 cm(-1)), animals resuscitated with DCLHb (294+/-45 cm(-1)), WB (306+/-11 cm(-1)), and hydroxyethylstarch (241+/-34 cm(-1)) showed a significant reduction of functional capillary density after 2 h of resuscitation. DCLHb was as effective as WB and superior to hydroxyethylstarch in restoring functional capillary density and mean arterial pressure. Leukocyte adherence in postcapillary venules was not enhanced by DCLHb (369+/-148/mm2) infusion when compared with hydroxyethylstarch- (615+/-283/mm2) and WB-treated (510+/-415/mm2) animals. Lipid peroxidation of pancreatic tissue was significantly elevated after treatment with both oxygen-carrying solutions compared with hydroxyethylstarch. Conclusion DCLHb is as effective as WB for preservation of the pancreatic microcirculation.

Abstract 316: Effects of Inhibiting of Inducible Nitric Oxide Synthase in the Pathophysiology of Experimental Preeclampsia

Hypertension ◽  
2012 ◽  
Vol 60 (suppl_1) ◽  
Author(s):  
Lorena M Amaral ◽  
Ana Carolina T Palei ◽  
Lucas C Pinheiro ◽  
Jonas T Sertorio ◽  
Danielle A Guimaraes ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Inducible Nitric Oxide Synthase ◽  
Inos Expression ◽  
Oxygen Species ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

The pathophysiology of preeclampsia (PE) is not entirely known. However, increased oxidative stress possibly leading to impaired nitric oxide activity has been implicated in the critical condition. Increased oxidative stress with increased levels of highly reactive species including superoxide may generate peroxynitrite. We examined the role of inducible nitric oxide synthase (iNOS) and oxidative stress in the reduced uterine perfusion pressure (RUPP) preeclampsia experimental model. METHODS: RUPP was induced in wistar rats. Pregnant rats in the RUPP group had their aortic artery clipped at day 14 of gestation. After a midline incision, a silver clip (0.203 mm) was placed around the aorta above the iliac bifurcation; silver clips (0.100 mm) were also placed on branches of both the right and left ovarian arteries that supply the uterus. Sham-operated (pregnant control rats) and RUPP rats were treated with oral vehicle or 1 mg/kg/day 1400W (iNOS inhibitor) for 5 days. Mean arterial pressure (MAP) and plasma levels of thiobarbituric acid-reactive species (TBARS) and total radical-trapping antioxidant potential (TRAP) were measured determined. Aortic iNOS expression (Western blotting) and reactive oxygen species (ROS; assessed by fluorescence microscopy with dihydroethidium-DHE) were measured. We found increased mean arterial pressure in RUPP compared with pregnant control rats (MAP= 128±1 vs. 100±1.8 mmHg, respectively; P<0.05) and 1400W exerted antihypertensive effects (MAP= 114±2 vs.128±1 mmHg in RUPP treated and untreated rats, respectively; P<0.05). Higher reactive oxygen species (ROS) concentrations were found in RUPP compared with pregnant control rats (7.1±0.5 vs. 5.1±0.5 arbitrary units (A.U.), respectively; P<0.05) and 1400W decreased ROS production to 5.8±0.02 A.U. in RUPP treated rats, P<0.05. In addition, 1400W attenuated iNOS expression in RUPP rats (0.29±0.02 vs. 0.55±0.8 A.U. in RUPP treated and untreated rats, respectively; P<0.01) and had no effects on plasma TBARS and TRAP levels. Our results suggest that 1400w exerts antihypertensive effects in the RUPP model and suppresses ROS formation. Supported by FAPESP,Cnpq.

S-nitroso-albumin carries a thiol-labile pool of nitric oxide, which causes venodilation in the rat

2005 ◽  
Vol 289 (2) ◽  
pp. H916-H923 ◽  
Author(s):  
Nelson N. Orie ◽  
Patrick Vallance ◽  
Dean P. Jones ◽  
Kevin P. Moore
Keyword(s):  
Nitric Oxide ◽  
Molecular Weight ◽  
Blood Flow ◽  
Vascular Function ◽  
Low Molecular Weight ◽  
Aortic Blood Flow ◽  
Hemodynamic Effects ◽  
Rapid Decomposition ◽  
Aortic Blood

It is now established that S-nitroso-albumin (SNO-albumin) circulates at low nanomolar concentrations under physiological conditions, but concentrations may increase to micromolar levels during disease states (e.g., cirrhosis or endotoxemia). This study tested the hypothesis that high concentrations of SNO-albumin observed in some diseases modulate vascular function and that it acts as a stable reservoir of nitric oxide (NO), releasing this molecule when the concentrations of low-molecular-weight thiols are increased. SNO-albumin was infused into rats to increase the plasma concentration from <50 nmol/l to ∼4 μmol/l. This caused a 29 ± 6% drop in blood pressure, 20 ± 4% decrease in aortic blood flow, and a 25 ± 14% reduction of renal blood flow within 10 min. These observations were in striking contrast to those of an infused arterial vasodilator (hydralazine), which increased aortic blood flow, and suggested that SNO-albumin acts primarily as a venodilator in vivo. This was confirmed by the observations that glyceryl trinitrate (a venodilator) led to similar hemodynamic changes and that the hemodynamic effects of SNO-albumin are reversed by infusion of colloid. Infusion of N-acetylcysteine into animals with artificially elevated plasma SNO-albumin concentrations led to the rapid decomposition of SNO-albumin in vivo and reproduced the hemodynamic effects of SNO-albumin infusion. These data demonstrate that SNO-albumin acts primarily as a venodilator in vivo and represents a stable reservoir of NO that can release NO when the concentrations of low-molecular-weight thiols are elevated.

Characterization of acute reversible systemic hypertension in a model of heme protein-induced renal injury

1999 ◽  
Vol 277 (1) ◽  
pp. F58-F65 ◽  
Author(s):  
David H. Warden ◽  
Anthony J. Croatt ◽  
Zvonimir S. Katusic ◽  
Karl A. Nath
Keyword(s):  
Nitric Oxide ◽  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Sodium Nitroprusside ◽  
Vessel Wall ◽  
Heme Proteins ◽  
Blood Vessel Wall ◽  
Vasodilatory Response

In the glycerol model of renal injury we describe an acute rise in systemic arterial pressure which is attended by a reduced vasodilatory response to acetylcholine in vivo; vasodilatory responses to verapamil, however, were not impaired. Neither arginine nor sodium nitroprusside diminished this rise in blood pressure; N ω-nitro-l-arginine methyl ester (l-NAME) elevated basal mean arterial pressure and markedly blunted the rise in mean arterial pressure following the administration of glycerol. Aortic rings from the glycerol-treated rat demonstrate an impaired vasodilatory response to acetylcholine, an effect not repaired by arginine; the vasodilatory responses to nitric oxide donors, sodium nitroprusside and SIN-1, were also impaired; 8-bromo-cGMP, at higher doses, evinced a vasodilatory response comparable to that observed in the control rings. This pattern of responses was not a nonspecific effect of aortic injury, since aortic rings treated with mercuric chloride, a potent oxidant, displayed an impaired vasodilatory response to acetylcholine but not to sodium nitroprusside. We conclude that in the glycerol model of heme protein-induced tissue injury, there is an acute elevation in mean arterial pressure attended by impaired endothelium-dependent vasodilatation in vitro and in vivo. We suggest that the acute scavenging of nitric oxide by heme proteins depletes the blood vessel wall of its endogenous vasodilator and permeation of heme proteins into the blood vessel wall may contribute to such sustained effects as observed in vitro.

Vascular response to infusions of a nonextravasating hemoglobin polymer

2002 ◽  
Vol 93 (4) ◽  
pp. 1479-1486 ◽  
Author(s):  
Barbara Matheson ◽  
Herman E. Kwansa ◽  
Enrico Bucci ◽  
Annette Rebel ◽  
Raymond C. Koehler
Keyword(s):  
Molecular Weight ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Arterial Pressure ◽  
Exchange Transfusion ◽  
Pressor Response ◽  
Low Molecular Weight ◽  
Bovine Hemoglobin ◽  
Pial Arterioles ◽  
Awake Cats

The clinical utility of cross-linked tetrameric hemoglobin solutions is limited by peripheral vasoconstriction thought to be due to scavenging of nitric oxide. In addition, transfusion of crude preparations of hemoglobin polymers can cause arterial hypertension. We tested the hypothesis that eliminating low-molecular-weight components from the polymer solution would prevent extravasation and its associated pressor response. A zero-link polymer of bovine hemoglobin was developed without chemical linkers left between the tetramers. Transfusion of unprocessed preparations of these polymers in rats resulted in appearance of the polymer in the renal hilar lymph. However, eliminating the low-molecular-weight components with a 300-kDa diafiltration resulted in an average hydrodynamic radius of 250 Å and in undetectable levels of polymer in hilar lymph. Exchange transfusion in anesthetized rats and cats and in awake cats produced no increase in arterial pressure. In anesthetized cats, exchange transfusion with an albumin solution reduced hematocrit from 30 to 18%, increased cerebral blood flow, and dilated pial arterioles. In contrast, reducing hematocrit by transfusing the diafiltered polymer did not increase cerebral blood flow as pial arterioles constricted. These results are consistent with the hypothesis that the increase in arterial pressure associated with cell-free hemoglobin transfusion depends on hemoglobin extravasation. Constriction observed in the cerebrovascular bed with a nonextravasating hemoglobin polymer at low hematocrit is presumably a regulatory response to prevent overoxygenation at low blood viscosity.

scholarly journals Immunomodulatory Activity of Low Molecular-Weight Peptides from Nibea japonica in RAW264.7 Cells via NF-κB Pathway

Marine Drugs ◽  
2019 ◽  
Vol 17 (7) ◽  
pp. 404 ◽  
Author(s):  
Zhuangwei Zhang ◽  
Xuyang Hu ◽  
Lin Lin ◽  
Guofang Ding ◽  
Fangmiao Yu
Keyword(s):  
Nitric Oxide ◽  
Molecular Weight ◽  
Cell Cycle Progression ◽  
Protein Hydrolysate ◽  
Raw264.7 Cells ◽  
Immunomodulatory Activity ◽  
Low Molecular Weight ◽  
Phagocytic Capacity ◽  
Activated State ◽  
Factor Α

In this study, a low molecular-weight (Mw) peptide named NJP (<1 kDa), was purified from a protein hydrolysate of Nibea japonica by ultrafiltration, and its immunomodulatory effect on RAW264.7 cells was evaluated. The lactate dehydrogenase (LDH) and MTT assays were performed to explore the cytotoxicity of NJP. The results showed that NJP promoted cell proliferation and had no significant toxic effects on RAW264.7 cells. Moreover, the cells formed multiple pseudopodia indicating that they were in activated state. Further tests showed that NJP significantly promoted phagocytic capacity, and the secretion of proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β). It also increased the synthesis of nitric oxide (NO) by upregulating inducible nitric oxide synthase (iNOS) protein level. Flow cytometry revealed that NJP promoted cell cycle progression and increased the percentage of cells in G0/G1 phase. NJP promoted IκBα degradation, p65 and nuclear factor (NF)-κB activation and translocation by up-regulating IKKα/β protein expression. In conclusion, these results indicated that NJP exerts immunomodulatory effects on RAW264.7 cells through the NF-κB signaling pathway. Therefore, NJP can be incorporated in the production of functional foods or nutraceuticals.

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