Renal response to hemodilution with albumin or crosslinked bovine hemoglobin: Role of nitric oxide

Matheson, Barbara; Razynska, Anna; O'Hearne, Michael; Bucci, Enrico

doi:10.1016/s0022-2143(98)90024-5

Cited by 10 publications

(4 citation statements)

References 16 publications

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“…At present, the prevailing hypothesis is that vasoconstriction is produced because infused hemoglobin scavenge endothelial-derived NO, leading to decreased NO-dependent relaxation of arteriolar smooth muscle. Evidence supporting this hypothesis includes the observation that a very similar pressor response can be produced by inhibiting the NO synthase (17), that inhibiting NO synthase after tetrameric hemoglobin transfusion produces little additional peripheral vasoconstriction (26), and that administration of the NO synthase substrate L-arginine attenuates the peripheral vasoconstrictor response to tetrameric hemoglobin transfusion (23).…”

Section: Discussionmentioning

confidence: 98%

“…Presumably because of the large pores, stabilized hemoglobin tetramers extravasate across postglomerular capillary beds and appear in the hilar lymph (16). It is likely that extravasation across the large pores of capillary beds accounts for the short half time of nondissociable tetramers [near 4 h vs. the 6 h for equal-size serum albumin (3,17)].…”

mentioning

confidence: 99%

“…The mechanism for the pressor response is thought to be the scavenging of the vasodilating agent nitric oxide (NO) by cell-free hemoglobin (17). It has also been suggested that decreased blood viscosity would decrease the shear-induced production of NO (28).…”

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confidence: 99%

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Vascular response to infusions of a nonextravasating hemoglobin polymer

Matheson

Kwansa

Bucci

et al. 2002

Journal of Applied Physiology

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129

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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 A 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.

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Section: Discussionmentioning

confidence: 98%

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confidence: 99%

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Vascular response to infusions of a nonextravasating hemoglobin polymer

Matheson

Kwansa

Bucci

et al. 2002

Journal of Applied Physiology

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129

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“…Peptide fragments were separated using gradients of acetonitrile from 0% to 100% with 0.1% THF as the developer . The peaks for peptide fragments were labeled based upon the MALDI-TOF MASS analysis results of hydrolysates and reference data , . The effluents were monitored at 220 nm for all peptide fragments and 258 nm for phthalates .…”

Section: Methodsmentioning

confidence: 99%

Functional Cross-Linked Hemoglobin Bis-tetramers: Geometry and Cooperativity

Kluger

2008

Biochemistry

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Hemoglobin-based oxygen carriers have been sought as stable, sterile alternatives to red cells in transfusions. Problems in clinical trials using cross-linked tetramers have led to proposals that larger assemblies of tetramers may alleviate some of the problems. A study of such assemblies requires materials with defined structures and physical properties. Evaluation of cross-linked bis-tetramers with inflexible linear links between the tetramers revealed that these have very low cooperativity in oxygen binding and would thus be inefficient as oxygen carriers. New, more flexible reagents were designed to cross-link and connect tetramers in two modes: with angular connectors that permit torsional movement (1-3) and with linear connectors that resemble previously studied systems (4-6). The resulting cross-linked bis-tetramers were produced in high yield and were isolated and characterized. Digest mapping showed that modifications were specifically introduced as expected at amino groups in the 2,3-bisphosphoglycerate binding sites within beta subunits. Circular dichroism showed that the secondary structure of the globin chains is maintained while the microenvironment of the hemes is altered. The bis-tetramers derived from 1-3 have oxygen affinity (P(50) = 3.6-4.7) and cooperativity (n(50) = 2.2-2.7) that appear to be suitable for efficient oxygen delivery to hypoxic regions along with increased mass that is expected to minimize extravasation.

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