Functional properties of MP4

Early in the development of our theoretical conceptualization of the mechanism of vasoactivity induced by cell-free hemoglobin, we measured the NO reaction rate constant for all three classes of compounds and found them to be the same (Rohlfs et al, 1998). Furthermore, the NO binding kinetics did not correlate with blood pressure measured in the rat when these solutions were infused. These kinetic NO binding experiments have been repeated using the current formulation of MP4 (Table 40.2).The rates of NO association to the deoxyhemoglobins and for NO oxidation of the oxyhemoglobins were identical for MalPEG-Hb and SFH.

The diffusive properties of representative modified hemoglobins were measured using a specially-constructed apparatus to simulate an arteriole (McCarthy et al, 2001). The study compared aa-Hb, a PEG-modified bovine hemoglobin (PEG-BvHb), hemoglobin A0, and a suspension of human red blood cells. The hemoglobin solutions were first equilibrated with air, then passed through the capillary and collected at the outlet to be analyzed for O2 content. The gas outside of the capillary was pure N2.

As the solution flows through the capillary, no O2 is lost if the flow rate is high enough. If the flow is very slow, all the O2 is lost, as the solution inside comes to equilibrium with the N2 on the outside. At intermediate flow rates, the exit rate of O2 depends on the diffusion of O2 in the liquid, the oxygen affinity of the hemoglobin and the diffusion of hemoglobin itself ('facilitated diffusion').The first two of these factors, O2 diffusion and oxygen affinity, are known, and so differences in the behavior of the solutions that cannot be accounted for must be attributable to facilitated diffusion.

The results of the study showed that the overall transfer of O2 by red blood cells was most nearly approximated by PEG-BvHb. In contrast, O2 was delivered much more readily by aa-Hb compared to either red blood cells or PEG-BvHb. Oxygen

Table 40.2 NO association (k') and oxidation (kox) rate constants for stroma-free hemoglobin (SFH) and MalPEG-Hb (Vandegriff et a/., 2004)

SFH 21 18

MalPEG-Hb 22 23

release by hemoglobin A0was very similar to that of aa-Hb. These results can only be explained if the facilitated diffusion of the PEG-BvHb was attenuated compared to the smaller aa-Hb and hemoglobin A0.The data support the concept that small hemoglobin molecules greatly increase the availability of O2 to vessel walls.

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