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.

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.

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.

scholarly journals Resuscitation with Recombinant Hemoglobin rHb2.0 in a Rodent Model of Hemorrhagic Shock

2007 ◽  
Vol 107 (2) ◽  
pp. 273-280 ◽  
Author(s):  
Joerg Hermann ◽  
Carlos Corso ◽  
Konrad F. Messmer
Keyword(s):  
Nitric Oxide ◽  
Metabolic Acidosis ◽  
Hemorrhagic Shock ◽  
Capillary Density ◽  
Volume Effect ◽  
Wild Type ◽  
Shed Blood ◽  
Baxter Healthcare ◽  
Scavenging Capacity ◽  
Oxygen Carrying Capacity

Background Hemoglobin solutions combine volume effect, oxygen-carrying capacity, and vasoactive properties, the latter facilitating restoration of global hemodynamics but endangering microvascular resuscitation. Hemoglobin-evoked vasoconstriction probably is due to nitric oxide scavenging, which can be reduced by genetic modifications of the heme pocket. This study compares resuscitation with a nonhemoglobin colloid and two recombinant hemoglobin solutions with wild-type and reduced nitric oxide-scavenging capacity. Methods Twenty-seven awake Syrian golden hamsters fitted with dorsal skinfold chambers underwent a 30 min-hemorrhagic shock (mean arterial pressure [MAP] 30-35 mmHg) and resuscitation with shed blood volume of either 6% dextran 60 (Biophausia, Uppsala, Sweden), recombinant hemoglobin 1.1 (rHb1.1; wild-type nitric oxide-scavenging capacity; 10 g/dl), or recombinant hemoglobin 2.0 (rHb2.0; reduced nitric oxide-scavenging capacity; 10 g/dl; both Baxter Healthcare, Boulder, CO). Macrohemodynamic and laboratory parameters were assessed; microvascular parameters in the skinfold chamber were analyzed by intravital microscopy. Results Hemorrhagic shock reduced functional capillary density (FCD) by 70% and caused significant metabolic acidosis. Colloid resuscitation led to incomplete recovery of MAP and FCD. Infusion of rHb1.1 completely restored MAP but not FCD, with the smallest arteriolar diameters found in this group. FCD was restored best by resuscitation with rHb2.0, although MAP was lower than in rHb1.1-treated animals. Metabolic acidosis was resolved by both hemoglobin solutions, but not by dextran. Conclusion After resuscitation with rHb1.1, arteriolar vasoconstriction quickly restored MAP, but this was achieved at the expense of FCD. In contrast, after resuscitation with rHb2.0, the recovery of MAP could be translated into a significantly improved FCD.

scholarly journals Resuscitation with Hydroxyethyl Starch Maintains Hemodynamic Coherence in Ovine Hemorrhagic Shock

2020 ◽  
Vol 132 (1) ◽  
pp. 131-139 ◽  
Author(s):  
Philip-Helge Arnemann ◽  
Michael Hessler ◽  
Tim Kampmeier ◽  
Laura Seidel ◽  
Youssef Malek ◽  
...  
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Hemorrhagic Shock ◽  
Hydroxyethyl Starch ◽  
Fluid Resuscitation ◽  
Saline Group ◽  
Vessel Density ◽  
Flow Index ◽  
Microvascular Flow Index ◽  
Microvascular Flow

Abstract Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Fluid resuscitation in hemorrhagic shock aims to restore hemodynamics and repair altered microcirculation. Hemodynamic coherence is the concordant performance of macro- and microcirculation. The present study on fluid therapy in hemorrhagic shock hypothesized that the choice of fluid (0.9% sodium chloride [saline group] or balanced 6% hydroxyethyl starch 130/0.4 [hydroxyethyl starch group]) impacts on hemodynamic coherence. Methods After instrumentation, 10 sheep were bled up to 30 ml/kg body weight of blood stopping at a mean arterial pressure of 30 mmHg to establish hemorrhagic shock. To reestablish baseline mean arterial pressure, they received either saline or hydroxyethyl starch (each n = 5). Hemodynamic coherence was assessed by comparison of changes in mean arterial pressure and both perfused vessel density and microvascular flow index. Results Bleeding of 23 ml/kg blood [21; 30] (median [25th; 75th percentile]) in the saline group and 24 ml/kg [22; 25] (P = 0.916) in the hydroxyethyl starch group led to hemorrhagic shock. Fluid resuscitation reestablished baseline mean arterial pressure in all sheep of the hydroxyethyl starch group and in one sheep of the saline group. In the saline group 4,980 ml [3,312; 5,700] and in the hydroxyethyl starch group 610 ml [489; 615] of fluid were needed (P = 0.009). In hemorrhagic shock perfused vessel density (saline from 100% to 83% [49; 86]; hydroxyethyl starch from 100% to 74% [61; 80]) and microvascular flow index (saline from 3.1 [2.5; 3.3] to 2.0 [1.6; 2.3]; hydroxyethyl starch from 2.9 [2.9; 3.1] to 2.5 [2.3; 2.7]) decreased in both groups. After resuscitation both variables improved in the hydroxyethyl starch group (perfused vessel density: 125% [120; 147]; microvascular flow index: 3.4 [3.2; 3.5]), whereas in the saline group perfused vessel density further decreased (64% [62; 79]) and microvascular flow index increased less than in the hydroxyethyl starch group (2.7 [2.4; 2.8]; both P < 0.001 for saline vs. hydroxyethyl starch). Conclusions Resuscitation with hydroxyethyl starch maintained coherence in hemorrhagic shock. In contrast, saline only improved macro- but not microcirculation. Hemodynamic coherence might be influenced by the choice of resuscitation fluid.

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.

Evidence for enhanced uptake of ATP by liver and kidney in hemorrhagic shock

1977 ◽  
Vol 233 (3) ◽  
pp. R83-R88 ◽  
Author(s):  
I. H. Chaudry ◽  
M. M. Sayeed ◽  
A. E. Baue
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Beneficial Effect ◽  
Hemorrhagic Shock ◽  
Kidney Slices ◽  
Atp Levels ◽  
Salutary Effect ◽  
Liver And Kidney ◽  
In Vitro Uptake

It has been shown that infusion of ATP-MgCl2 proved beneficial in the treatment of shock; however, it is not known whether this effect is due to improvement in the microcirculation or direct provision of energy or a combination of the above or other effects. To elucidate the mechanism of the salutary effect of ATP-MgCl2, we have now examined the in vitro uptake of ATP by liver and kidney of animals in shock. Rats were bled to a mean arterial pressure of 40 Torr and so maintained for 2 hrs. After the rats were killed, liver and kidney were removed and slices of tissue (0.3-0.5 mm thick) were incubated for 1 h in 1.0 ml of Krebs-HCO3 buffer containing 10 mM glucose, 5 mM MgCl2, and 5 mM [8-14C]ATP or 5 mM [8-14C]ADP, or 5 mM [8-14C]AMP, or 5 mM [8-14C]adenosine in 95% O2-5% CO2 and then homogenized. Tissue and medium samples were subjected to electrophoresis to separate and measure the various nucleotides. The uptake of [14C]ATP but not that of [14C]ADP or [14C]adenosine by liver and kidney slices from animals in shock was 2.5 times greater than the corresponding uptake by control slices. Thus, the beneficial effect of ATP-MgCl2 in shock could be due to provision of energy directly to tissue in which ATP levels were lowered.

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.

Hemorrhagic Shock in Swine: Nitric Oxide and Potassium Sensitive Adenosine Triphosphate Channel Activation

2004 ◽  
Vol 101 (2) ◽  
pp. 399-408 ◽  
Author(s):  
Jeffrey B. Musser ◽  
Timothy B. Bentley ◽  
Scott Griffith ◽  
Pushpa Sharma ◽  
John E. Karaian ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Mean Arterial Pressure ◽  
Nitric Oxide Synthase ◽  
Hemorrhagic Shock ◽  
Inducible Nitric Oxide Synthase ◽  
Katp Channel ◽  
Channel Activation ◽  
Oxide Synthase ◽  
Nitric Oxide Synthase Activity ◽  
Inducible Nitric Oxide

Background To determine the role of nitric oxide and adenosine triphosphate-sensitive potassium (KATP) vascular channels in vascular decompensation during controlled hemorrhagic shock in swine. Methods Thirty instrumented, anesthetized adolescent Yorkshire swine were subjected to controlled isobaric hemorrhage to a mean arterial pressure of 40 mmHg for 2 h (n = 6) or 4 h (n = 10) or 50 mmHg for 4 h (n = 8). An additional six animals were used as anesthetized instrumented time controls. During controlled hemorrhage, plasma and tissue samples were obtained every 30 to 60 min. Before euthanasia, tissue (carotid artery, lung, liver, and aorta) was obtained for analysis of nitrate concentrations and nitric oxide synthase activity. Isolated carotid artery ring reactivity to norepinephrine was also determined with and without glibenclamide. Results Animals hemorrhaged to 40 mmHg decompensated earlier than animals hemorrhaged to 50 mmHg. Plasma nitrate concentrations and nitric oxide synthase activity rose consistently throughout hemorrhage in both groups. However, they were substantially higher in the mean arterial pressure 40 group. Constitutive nitric oxide synthase activity was the major contributor to total nitric oxide synthase activity throughout the protocol with only the animals maintained at 40 mmHg for 4 h showing evidence of inducible nitric oxide synthase activity. Profound KATP channel activation and hyporeactivity of isolated vessel rings to norepinephrine was not observed until 4 h after the initiation of hemorrhagic shock. Only those animals with inducible nitric oxide synthase activity showed a decreased response to norepinephrine, and this hyporeactivity was reversed with the KATP channel inhibitor, glibenclamide. Conclusions The data indicate that profound KATP activation associated with increased nitric oxide concentrations and inducible nitric oxide synthase induction is a key factor in vascular smooth muscle hyporeactivity characteristic of the late decompensatory phase of hemorrhagic shock in swine.

scholarly journals Responsiveness to different volume therapies following hemodilution and hemorrhagic shock: a comparative experimental study in rats

2007 ◽  
Vol 22 (5) ◽  
pp. 355-360 ◽  
Author(s):  
Riad Naim Younes ◽  
Fernanda Deutsch ◽  
Mario Itinoshe ◽  
Belchor Fontes ◽  
Renato Poggetti ◽  
...  
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Hemorrhagic Shock ◽  
Hypertonic Saline ◽  
Hypovolemic Shock ◽  
Isotonic Saline ◽  
High Volume ◽  
Subsequent Treatment ◽  
Volume Replacement ◽  
Trauma Patients

Guidelines for volume replacement for acutely hemorrhaged and hemodiluted trauma patients have not been well established. Purpose: To evaluate the effects of acute hemodilution on mean arterial pressure (MAP), and responsiveness of acutely hemodiluted and subsequently hemorrhaged rats to different volume therapies. Methods: 180 rats were hemodiluted to simulate hemorrhaged trauma patients with persistent bleeding after high volume replacement with isotonic solutions. Thirty hemodiluted [Anemia (ANE) group] animals received no further treatment. The remaining 150 animals were subjected to hypovolemic shock and randomized into five groups, according to the treatment option employed: Control (CTL) animals did not receive subsequent treatment after hemorrhagic hypovolemia, SAL4 animals received isotonic saline 4 mL/kg, SAL32 animals received isotonic saline 32 mL/kg, HS animals received hypertonic saline 4 mL/kg and BLD animals received re-infusion of drawn blood. Results: Highest mean arterial pressure (MAP) was achieved by BLD, followed by SAL32 and HS. MAP after treatment of BLD, HS, SAL32 and ANE were higher than CTL (p=0.036). At 85 and 95 minutes of experiment, SAL4, SAL32 and HS presented the lowest hematocrit levels (p<0.01). At day 3, ANE, CTL and HS had the highest hematocrit. SAL4 and CTL groups presented the highest mortality rates. Conclusion: Hypertonic saline is an effective and safe initial therapy for hemodiluted rats undergoing hemorrhagic shock, with an overall outcome comparable to blood replacement or high volume isotonic saline administration.

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