Colloid osmotic properties of modified hemoglobins: chemically cross-linked versus polyethylene glycol surface-conjugated

Vandegriff, Kim D.; McCarthy, Michael; Rohlfs, Ronald J.; Winslow, Robert M.

doi:10.1016/s0301-4622(97)00079-3

Cited by 89 publications

(70 citation statements)

References 14 publications

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“…The Enzon PEG5K-bovine Hb that was observed previously to be nonhypertensive (15)(16)(17) was generated by the active ester chemistry (18) which results in the loss of the net positive charge of the protein, and has been suggested to carry an average of ten PEG-5K chains/Hb. The results of the present study suggest that the conservation of the net surface charge of the parent Hb is not crucial to generate a nonhypertensive Hb and that the nonhypertensive property can be endowed to Hb with less than ten PEG5K…”

Section: Discussionmentioning

confidence: 99%

“…The other approach involves enhancement of the molecular size of Hb to reduce or possibly prevent the extravasation of Hb, based on the concept that the vasoactivity of acellular Hb is due to its extravasation into the interstitial spaces and trapping of NO (14). However, the recent studies of Winslow and co-workers (15)(16)(17) utilizing Hb preparations varying in molecular size namely, oligomerized Hb, polymerized Hb and PEGylated Hb have suggested a lack of correlation between their NO binding activity and pressor effect. These studies also suggested that PEGylation modulates the Hb induced hypertension and thus could be an efficient approach to reduce the vasoactivity of Hb.…”

Section: Introductionmentioning

confidence: 99%

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WITHDRAWN: PEGylated hemoglobin: Role of surface configuration of PEG for the modulation of hemoglobin vasoactivity

Manjula

2004

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: PEGylated hemoglobin: Role of surface configuration of PEG for the modulation of hemoglobin vasoactivity

Manjula

2004

Journal of Biological Chemistry

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“…Colloid oncotic pressure was measured with the use of a colloid osmometer (model 4420, Wescor; Logan, UT) (34). O 2 equilibrium curves of MP4 and of freshly collected hamster red blood cells were measured as described previously (37) in 100 mM phosphate buffer, pH 7.4.…”

Section: Methodsmentioning

confidence: 99%

Targeted O₂delivery by low-P₅₀hemoglobin: a new basis for O₂therapeutics

Tsai¹,

Vandegriff²,

Intaglietta³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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135

179

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To assess O2 delivery to tissue by a new surface-modified, polyethylene glycol-conjugated human hemoglobin [MP4; PO2 at 50% saturation of hemoglobin (P50); 5.4 mmHg], we studied microcirculatory hemodynamics and O2 release in golden Syrian hamsters hemodiluted with MP4 or polymerized bovine hemoglobin (PolyBvHb; P50 54.2 mmHg). Comparisons were made with the animals' hemodiluted blood with a non-O2 carrying plasma expander with similar solution properties (Dextran-70). Systemic hemodynamics (arterial blood pressure and heart rate) and acid-base parameters were not correlated with microhemodynamics (arteriolar and venular diameter, red blood cell velocity, and flow). Microscopic measurements of PO2 and the O2 equilibrium curves permitted analysis of O2 release in precapillary and capillary vessels by red blood cells and plasma hemoglobin separately. No significant differences between the groups of animals with respect to arteriolar diameter, flow, or flow velocity were observed, but the functional capillary density was significantly higher in the MP4-treated animals (67%) compared with PolyBvHbtreated animals (37%; P Ͻ 0.05) or dextran-treated animals (53%). In the PolyBvHb-treated animals, predominant O2 release (both red blood cells and plasma hemoglobin) occurred in precapillary vessels, whereas in MP4 animals most of the O2 was released from both red blood cells and plasma hemoglobin in capillaries. Base excess correlated directly with capillary O2 release but not systemic O2 content or total O2 release. Higher O2 extraction of both red blood cell and plasma hemoglobin in capillaries represents a new mechanism of action of cell-free hemoglobin. High O2 affinity appears to be an important property for cell-free hemoglobin solutions. blood substitutes; microcirculation; polyethylene glycol ARTERIOLAR VASOCONSTRICTION limits tissue perfusion by some early-generation hemoglobin-based O 2 carriers, increasing vascular resistance, which may be manifest as systemic hypertension, offsetting potential efficacy (40). Although the mechanism of vasoactivity has been disputed, one popular explanation is that nitric oxide (NO) is scavenged by cell-free hemoglobin (9), either directly in the lumen of the vessel or in the interstitial space after extravasation. We observed, however, that derivatized hemoglobins with different hypertensive effects have nearly identical NO binding constants (26). An alternative (or additional) mechanism is the involvement of autoregulation, by which vasoconstriction results from an oversupply of O 2 to vascular walls, particularly in arterioles, which regulate the entry of blood into capillary networks (23). An O 2 oversupply would result from facilitated diffusion of O 2 as oxyhemoglobin in plasma. Oxyhemoglobin diffusion is a function of molecular size, viscosity, and O 2 affinity, and manipulation of these three parameters offers strategies for potentially overcoming autoregulatory vasoconstriction. We explored these ideas in an artificial capillary system and concluded that the O 2 deliver...

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“…23 The methemoglobin (MetHb) levels were measured spectrophotometrically (Lamda 20; Perkin-Elmer, Foster City, CA) to insure that they were less than 5%. Experimental groups were as follows: (1) 0.9% NaCl (saline): saline infusion was the no-treatment group used to assess the effect of the experimental protocol; (2) ␣␣ cross-linked Hb (␣␣Hb): human Hb cross-linked between the ␣ chains with 3,5-bis(dibromosalicyl)fumarate under deoxy conditions and purified by ion exchange chromatography following previously described techniques.…”

Section: Scavenging By Cell-free Hemoglobin Protocolmentioning

confidence: 99%

Dissociation of local nitric oxide concentration and vasoconstriction in the presence of cell-free hemoglobin oxygen carriers

Tsai

Cabrales

Manjula

et al. 2006

Blood

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126

108

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Cell-free hemoglobin's (CFH) high affinity for nitric oxide (NO) could limit CFH's use as an oxygen-carrying blood replacement fluid because it scavenges NO, causing vasoconstriction and hypertension. However, the extent to which perivascular NO levels change following intravascular administration of hemoglobin (Hb) with different molecular dimensions correlates with vasoconstrictive responses in the microcirculation is unknown. The study objective was to determine vasoconstrictive effects following bolus infusions of (1) ␣␣ cross-linked Hb; (2) polymerized bovine Hb; or (3) polyethylene glycol-decorated Hb (PEG-Hb), by measurements of in vivo microvessel diameter, blood flow, perivascular NO concentration, and systemic hemodynamic parameters. All CFHs caused reductions in perivascular NO levels, not correlated to microvascular responses. PEG-Hb (largest molecular volume) maintained blood flow, while the others caused vasoconstriction and reduced perfusion. All solutions increased mean arterial pressure due to vasoconstriction and blood volume expansion, except for PEGHb, which increased blood pressure due to blood volume expansion and maintenance of cardiac output. In conclusion, perivascular NO reduction is similar for all Hb solutions because NO binding affinities are similar; however, effects on vascular resistance are related to the type of molecular modification, molecular volume, and oxygen affinity.

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Colloid osmotic properties of modified hemoglobins: chemically cross-linked versus polyethylene glycol surface-conjugated

Cited by 89 publications

References 14 publications

WITHDRAWN: PEGylated hemoglobin: Role of surface configuration of PEG for the modulation of hemoglobin vasoactivity

WITHDRAWN: PEGylated hemoglobin: Role of surface configuration of PEG for the modulation of hemoglobin vasoactivity

Targeted O₂delivery by low-P₅₀hemoglobin: a new basis for O₂therapeutics

Dissociation of local nitric oxide concentration and vasoconstriction in the presence of cell-free hemoglobin oxygen carriers

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Colloid osmotic properties of modified hemoglobins: chemically cross-linked versus polyethylene glycol surface-conjugated

Cited by 89 publications

References 14 publications

WITHDRAWN: PEGylated hemoglobin: Role of surface configuration of PEG for the modulation of hemoglobin vasoactivity

WITHDRAWN: PEGylated hemoglobin: Role of surface configuration of PEG for the modulation of hemoglobin vasoactivity

Targeted O2delivery by low-P50hemoglobin: a new basis for O2therapeutics

Dissociation of local nitric oxide concentration and vasoconstriction in the presence of cell-free hemoglobin oxygen carriers

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Targeted O₂delivery by low-P₅₀hemoglobin: a new basis for O₂therapeutics