Effects of polymerization on the hypertensive action of diaspirin cross-linked hemoglobin in rats

Abassi, Zaid; Kotob, Shaban; Pieruzzi, Federico; Abouassali, Majd; Keiser, Harry R.; Fratantoni, Joseph C.; Alayash, Abdu I.

doi:10.1016/s0022-2143(97)90194-3

Cited by 81 publications

(63 citation statements)

References 13 publications

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“…One possible explanation for our data is that glutaraldehyde treatment reduced the reactive heme concentration at the site of NO scavenging. Whereas the specific site of NO scavenging important for vasoconstriction is unknown, several investigators have suggested that it lies outside of the vascular compartment (22)(23)(24). Although there is little or no direct evidence available to support the hypothesis that extravasation is required for the hemoglobin-induced hypertensive response, our results and those of others (22,27,44) with polymerized hemoglobin are consistent with an obligatory role for hemoglobin extravasation.…”

Section: Discussionmentioning

confidence: 99%

“…Whereas the specific site of NO scavenging important for vasoconstriction is unknown, several investigators have suggested that it lies outside of the vascular compartment (22)(23)(24). Although there is little or no direct evidence available to support the hypothesis that extravasation is required for the hemoglobin-induced hypertensive response, our results and those of others (22,27,44) with polymerized hemoglobin are consistent with an obligatory role for hemoglobin extravasation. If polymerized hemoglobin such as poly-glxrHb is less able to leave the vasculature, the interstitial concentrations will be lower than those for smaller hemoglobin molecules (e.g.…”

Section: Discussionmentioning

confidence: 99%

“…intravascular or interstitial) is unknown. Several researchers have suggested that hemoglobin must leave the vascular space to cause constriction through an NO-mediated mechanism (22)(23)(24). Direct evidence supporting this hypothesis is scant.…”

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confidence: 99%

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Glutaraldehyde Modification of Recombinant Human Hemoglobin Alters Its Hemodynamic Properties

Doyle

Apostoł

Kerwin

1999

Journal of Biological Chemistry

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Many cell-free hemoglobin solutions designed as oxygen-carrying therapeutics produce a hypertensive effect in animals. The response is likely due to oxidation of nitric oxide by hemoglobin. Since the site of oxidation may lie outside the vascular compartment, we tested the hypothesis that polymerization of hemoglobin, rHb1.1, by glutaraldehyde would attenuate the hypertensive response. Two products of the cross-linking reaction were isolated, a glutaraldehyde-derivatized monomer (monoglxrHb) and a glutaraldehyde cross-linked polymer (poly-glxrHb), and evaluated for their effects on systemic hemodynamics in conscious rats. Administration of rHb1.1 caused a mean arterial pressure elevation of approximately 20 mm Hg and an increase in total peripheral resistance of approximately 30%. Administration of mono-glxrHb induced changes in mean arterial pressure and vascular resistance that were significantly diminished relative to those observed with rHb1.1. PolyglxrHb elicited a mean arterial pressure response that was further reduced compared with that obtained with mono-glxrHb and a change in vascular resistance that was the same as the response to mono-glxrHb. These results suggest that rHb peripheral vasoconstriction elicited by rHb1.1 is significantly attenuated by glutaraldehyde modification of the hemoglobin monomer and that the effect of glutaraldehyde polymerization is likely due to surface modification and/or intramolecular cross-linking, rather than an increase in molecular size.As reviewed elsewhere (1-3), the search for a safe and efficacious oxygen-delivering therapeutic has been ongoing for many years. Limitations to the use of hemoglobin solutions as therapeutics have included renal toxicities due to the presence of stromal elements (4, 5), dissociation into ␣␤ dimers (6), high oxygen affinities (7), and short intravascular retention times (1). Multiple approaches have been taken to modify hemoglobins to address these limitations (1, 3), including chemical cross-linking of purified human or bovine hemoglobin to prevent dissociation and chemical modification to increase the P 50 to a physiologically suitable level (approximately 25-35 mm Hg, (7)). Recombinant technology was employed to genetically cross-link the ␣-globins to form a di-␣-globin and thereby prevent dissociation. In addition, the P 50 was increased by substitution of Lys for Asn at the ␤108 position. The resultant hemoglobin molecule, rHb1

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Glutaraldehyde Modification of Recombinant Human Hemoglobin Alters Its Hemodynamic Properties

Doyle

Apostoł

Kerwin

1999

Journal of Biological Chemistry

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“…The increased ability of cell-free Hb to scavenge NO has been widely attributed to the hypertension, increased systemic and pulmonary vascular resistance, and morbidity and mortality associated with administration of hemoglobin-based oxygen carriers (HBOCs or "blood substitutes") [53][54][55][56][57][58][59][60][61][62][63][64][65][66][67]. More recently, the importance of intravascular hemolysis on NO bioavailability in diseased states including hemolytic anemias like sickle cell disease and paroxysmal nocturnal hemoglobinuria (PNH), thalassemia intermedia, malaria, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome and cardiopulmonary bypass has been elucidated [17][18][19][68][69][70][71][72][73].…”

Section: Introductionmentioning

confidence: 99%

The potential of Angeli's salt to decrease nitric oxide scavenging by plasma hemoglobin

Azarov

Jeffers

et al. 2008

Free Radical Biology and Medicine

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Release of hemoglobin from the erythrocyte during intravascular hemolysis contributes to the pathology of a variety of diseased states. This effect is partially due to the enhanced ability of cellfree plasma hemoglobin, which is primarily found in the ferrous, oxygenated state, to scavenge nitric oxide. Oxidation of the cell-free hemoglobin to methemoglobin, which does not effectively scavenge nitric oxide, using inhaled nitric oxide has been shown to be effective in limiting pulmonary and systemic vasoconstriction. However, the ferric heme species may be reduced back to ferrous hemoglobin in plasma and has the potential to drive injurious redox chemistry. We propose that compounds that selectively convert cell-free hemoglobin to ferric, and ideally iron-nitrosylated heme species that do not actively scavenge nitric oxide would effectively treat intravascular hemolysis. We show here that nitroxyl, generated by Angeli's salt (Sodium α-oxyhyponitrite, Na 2 N 2 O 3 ), preferentially reacts with cell-free hemoglobin compared to that encapsulated in the red blood cell under physiologically relevant conditions. Nitroxyl oxidizes oxygenated ferrous hemoglobin to methemoglobin and can convert the methemoglobin to a more stable, less toxic species, iron-nitrosyl hemoglobin. These results support the notion that Angeli's salt or a similar compound could be used to effectively treat conditions associated with intravascular hemolysis.

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“…The Bohr effect has also been shown to be more pronounced in bovine Hb, which allows an even better O 2 delivery at lower pH values. It has also been shown that this blood substitute does not change hemodynamics with respect to PCO 2 and pH (1,6,12,17,19,23). HBOC-201 is modified by cross-linking of the ␣,␤-dimers to form a tetrameric structure that does not dissociate as rapidly as free Hb (14).…”

mentioning

confidence: 95%

A novel hemoglobin-based blood substitute protects against myocardial reperfusion injury

Caswell¹,

Strange²,

Rimmer³

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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. A novel hemoglobin-based blood substitute protects against myocardial reperfusion injury. Am J Physiol Heart Circ Physiol 288: H1794 -H1801, 2005 doi:10.1152/ajpheart.00905.2004 Cambridge, MA) is a glutaraldehyde-polymerized bovine hemoglobin (Hb) solution that is stroma free, has lower viscosity than blood, and promotes O 2 unloading. We investigated the effects of HBOC-201 in a canine model of myocardial ischemia-reperfusion injury. Dogs were anesthetized and subjected to 90 min of regional myocardial ischemia and 270 min of reperfusion. HBOC-201 or 0.9% saline vehicle equivalent to 10% total blood volume was infused 30 min before myocardial ischemia. Hemodynamic data and peripheral blood samples were taken at baseline, 1 h of myocardial ischemia, and 1, 2, and 4 h of reperfusion. At 270 min of reperfusion, the area at risk (AAR) per left ventricle and the area of infarction (Inf) per AAR were determined. The myocardial AARs in the two study groups were similar. In addition, myocardial blood flow (as measured by radioactive microspheres) in the ischemic zone was similar between the vehicle and HBOC-201 groups. HBOC-201-infused dogs demonstrated a significant (P Ͻ 0.01) 56% reduction in Inf/AAR. Analysis of blood samples taken at 4 h of reperfusion showed a significant (P Ͻ 0.05) reduction in creatine kinase MB isoform for the HBOC-201 group. Histological analysis of the myocardium demonstrated significant (P Ͻ 0.01) reductions in neutrophil infiltration in the HBOC-201 group. These data indicate that treatment with HBOC-201 before myocardial ischemia-reperfusion reduces the extent of myocardial inflammation and ischemia-reperfusion injury in the canine myocardium.

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Effects of polymerization on the hypertensive action of diaspirin cross-linked hemoglobin in rats

Cited by 81 publications

References 13 publications

Glutaraldehyde Modification of Recombinant Human Hemoglobin Alters Its Hemodynamic Properties

Glutaraldehyde Modification of Recombinant Human Hemoglobin Alters Its Hemodynamic Properties

The potential of Angeli's salt to decrease nitric oxide scavenging by plasma hemoglobin

A novel hemoglobin-based blood substitute protects against myocardial reperfusion injury

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