Exchange Transfusion with Albumin-Heme as an Artificial O₂-Infusion into Anesthetized Rats:  Physiological Responses, O₂-Delivery, and Reduction of the Oxidized Hemin Sites by Red Blood Cells

Abstract

Human serum albumin (HSA) incorporating synthetic hemes, the tetrakis(o-pivalamido)phenylporphinatoiron(II) derivative (FeP), is an artificial hemoprotein (HSA-FeP) which is able to reversibly bind and release dioxygen under physiological conditions (in aqueous media, pH 7.4, 37 degrees C) like hemoglobin and myoglobin. Physiological responses to exchange transfusion with HSA-FeP solution [[HSA], 5 g/dL; FeP/HSA, 4 (mol/mol)] into rats after hemodilution and hemorrhage (Hct, about 10%) has been evaluated. The declined mean arterial pressure (MAP) and blood flow after a 70% exchange with HSA and the further 40% bleeding of blood were significantly recovered up to about 90% of the baseline values by the injection of HSA-FeP. Furthermore, the renal cortical O(2)-tensions and skeletal tissue O(2)-tensions were also increased, indicating the in vivo O(2)-delivery of HSA-FeP. Autoxidation of ferrous Fe(II)P to ferric Fe(III)P was retarded in the blood stream; the half-lifetime of the dioxygenated FeP [tau(1/2)(O(2))] in vivo was 4.1 h [cf. 1.0 h (in vitro)]. It has been found that autooxidized Fe(III)P was certainly reduced in the whole blood suspension. Physiological concentrations of ascorbic acid continuously provided by red blood cells probably rereduces Fe(III)P, leading to the apparent long lifetime of the dioxygenated species of FeP.

Superior Plasma Retention of a Cross-Linked Human Serum Albumin Dimer in Nephrotic Rats as a New Type of Plasma Expander

“…HSA-FeP reversibly binds and releases O 2 under physiological conditions, the same as hemoglobin (Komatsu et al, 1999). An in vivo study using hemorrhagic shocked rats revealed that the renal cortical O 2 -tensions and skeletal tissue O 2 -tensions were increased when HSA-FeP was injected (Tsuchida et al, 2000;Komatsu et al, 2004b). An artificial oxygen carrier is also required to maintain high blood circulation, because it must temporarily function until a blood transfusion is available or until autologous blood is recovered after a massive hemorrhage.…”

Human serum albumin incorporating synthetic heme: Red blood cell substitute without hypertension by nitric oxide scavenging

“…12 Furthermore, rHSA is now manufactured on a large scale by expression in the methylotropic yeast Pichia pastoris as a host cell, and is expected to reach the market within a few years. 13 Our only source of concern was that the small rHSA-FeP molecules (8 × 3 nm) injected into the blood vessels would be eliminated from the circulation and contribute to the significant consumption of NO in the interstitial space between the endothelium and vascular smooth muscle.…”

Crystal Structure Analysis of Warfarin Binding to Human Serum Albumin

“…To understand the molecular basis of these effects, structural information is required to fully delineate the binding sites for drugs and endogenous ligands. Such information will also be invaluable to efforts to exploit the carrier properties of HSA in the development of novel therapeutic reagents for drug targeting (8) or oxygen transport (9).…”