Effects of polymerization on the hypertensive action of diaspirin cross-linked hemoglobin in rats.
It is believed that the hypertensive effect of diaspirin crosslinked hemoglobin, a viable blood substitute, can be resolved by polymerization, which reduces the diffusion of this derivative into the interstitial space between nitric oxide-producing endothelium and the target vascular smooth muscle. We studied the systemic and renal responses to infusion of three cell-free human hemoglobins in anesthetized isovolemic rats: unmodified (HbA0), crosslinked (alpha-DBBF), and polymerized crosslinked (poly alpha-DBBF). HbA0 produced a significant increase in mean arterial blood pressure (MAP) throughout the 60-minute infusion. alpha-DBBF, on the other hand, produced a more marked and prolonged increase in MAP over 120 minutes. Only a moderate increase in MAP was observed in rats after a 30-minute infusion with poly alpha-DBBF. The extent of renal insufficiency produced by these proteins, as determined by the glomerular filtration rate, was in the following order: HbA0 > poly alpha-DBBF > alpha-DBBF. Infusion of poly alpha-DBBF, under hypovolemic but not isovolemic conditions in rats, produced an increase in heart rate, cardiac output, and stroke volume and a decrease in total peripheral resistance after 60 minutes. Chemical polymerization to increase the size of alpha-DBBF does not appear to improve its hemodynamic properties in rats, especially under partial exchange transfusion, a more clinically relevant indication for a hemoglobin-based blood substitute.
Abassi
Z
Z
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
Kotob
S
S
Pieruzzi
F
F
Abouassali
M
M
Keiser
H R
HR
Fratantoni
J C
JC
Alayash
A I
AI
D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D001241:Aspirin / Q000031:analogs & derivatives*; D001794:Blood Pressure / Q000187:drug effects*; D001802:Blood Substitutes / Q000633:toxicity*; D002302:Cardiac Output / Q000187:drug effects; D003432:Cross-Linking Reagents; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D004790:Enzyme Induction; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006454:Hemoglobins / Q000302:isolation & purification / Q000633:toxicity*; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D011092:Polyethylene Glycols; D011188:Potassium / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000652:urine; D013318:Stroke Volume / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D001802:Blood Substitutes; D003432:Cross-Linking Reagents; D006454:Hemoglobins; C021630:bis(3,5-dibromosalicyl)fumarate; D011092:Polyethylene Glycols; C030830:succinyldisalicylic acid; D012964:Sodium; D019001:Nitric Oxide Synthase; D001241:Aspirin; D011188:Potassium; D019331:NG-Nitroarginine Methyl Ester