O-raffinose cross-linking markedly reduces systemic and renal vasoconstrictor effects of unmodified human hemoglobin

Citation
W. Lieberthal et al., O-raffinose cross-linking markedly reduces systemic and renal vasoconstrictor effects of unmodified human hemoglobin, J PHARM EXP, 288(3), 1999, pp. 1278-1287
Citations number
42
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
0022-3565 → ACNP
Volume
288
Issue
3
Year of publication
1999
Pages
1278 - 1287
Database
ISI
SICI code
0022-3565(199903)288:3<1278:OCMRSA>2.0.ZU;2-B
Abstract
The hemodynamic effects of a 20% exchange-transfusion with different soluti ons of highly purified human hemoglobin A-zero (A(0)) were evaluated. We co mpared unmodified hemoglobin with hemoglobin cross-linked with O-raffinose. Unmodified hemoglobin increased systemic vascular resistance and mean arte rial pressure more than the O-raffinose cross-linked hemoglobin solution (b y similar to 45% and similar to 14%, respectively). Unmodified hemoglobin m arkedly reduced cardiac output (CO) by similar to 21%, whereas CO was unaff ected by the O-raffinose crosslinked hemoglobin solution. Unmodified and O- raffinose crosslinked hemoglobin solutions increased mean arterial pressure to comparable extents (similar to 14% and similar to 9%, respectively). Un modified hemoglobin increased renal vascular resistance 2-fold and reduced the glomerular filtration rate by 58%. In marked contrast, the O-raffinose cross-linked hemoglobin had no deleterious effect on the glomerular filtrat ion rate, renal blood flow, or renal Vascular resistance. The extents to wh ich unmodified and O-raffinose cross-linked hemoglobin solutions inactivate d nitric oxide also were compared using three separate in vitro assays: pla telet nitric oxide release, nitric oxide-stimulated platelet cGMP productio n, and endothelium-derived relaxing factor-mediated inhibition of platelet aggregation. Unmodified hemoglobin inactivated or oxidized nitric oxide to a greater extent than the O-raffinose cross-linked hemoglobin solutions in all three assays. In summary, O-raffinose cross-linking substantially reduc ed the systemic vasoconstriction and the decrease in CO induced by unmodifi ed hemoglobin and eliminated the deleterious effects of unmodified hemoglob in on renal hemodynamics and function. We hypothesize that O-raffinose cros s-linking reduces the degree of oxidation of nitric oxide and that this con tributes to the reduced vasoactivity of this modified hemoglobin.