Facilitated Oxygen Transport And Vasoconstriction

The rates of oxygen transport in the artificial capillary apparatus described above (see Figure 5.1) showed a direct correlation with the mean arterial blood pressure in rats in response to exchange transfusion with the hemoglobins studied (McCarthy et al., 2001). Both aa-Hb and HbA0, which gave higher calculated values for the diffusion transport parameter compared to RBCs and PEG-Hb, exhibited hypertension in the rat model, while the PEG-Hb did not.

The autoregulatory theory of hemoglobin-induced vasoconstriction predicts that the pressor effect can be reduced or eliminated by controlling the rate of oxygen transport by the cell-free hemoglobin. If the rate of oxygen transport is similar to that of red blood cells, then compensatory mechanisms will respond normally to changes in oxygen delivery. From Equation 5.6, the overall flux of oxygen can be controlled by changing the oxyhemoglobin diffusion constant (DHbO2) and/or the hemoglobin saturation gradient, AY[Hb]/dx. As described by the Stokes-Einstein equation (Equation 5.3), the macromolecular diffusion inversely proportional to the viscosity of the macromolecular solution and the radius of the macromolecule (r). A Y[Hb]T/Ax is the critical parameter in Equation 5.6 that determines the amount of oxygen that will be offloaded over a given APO2, which is a function of the hemoglobin-oxygen equilibrium curve.

From Equation 5.6, diffusive oxygen transport also can be limited by the oxygen-carrying capacity of the cell-free hemoglobin, i.e., [Hb]. However, there must be a lower limit of [Hb] for survival. To evaluate this, a total exchange transfusion was performed in rats to compare a high-oxygen affinity, non-vasoactive cell-free oxygen carrier, maleimide-PEG-conjugated hemoglobin (MP4)

(Vandegriff et al., 2003), with two non-oxygen carrying solutions: PEG-modified albumin (MPA), prepared using the same chemistry as for MP4, and 10 per cent pentastarch (PS) to match the PEG-modified proteins for oncotic activity and viscosity but without PEG (Winslow et al., 2004). Continuous exchange transfusions were carried out such that the final hematocrit in all animals was between 0 and 5 per cent. All animals in the MP4 group survived (n = 5 for each group) over the 60 minutes of exchange followed by a 70-minute observation period. None of the animals that received either PS or MPA survived for more than 90 minutes. Lactic acid began to rise at ~15 per cent hematocrit in the PS and MPA groups, but at lower hematocrit (~7.5 per cent) in the MP4 group. At these points, the total [Hb] was ~5g/dl in all groups. This defines a lower limit of oxygen-carrying capacity of 5 g/dl with either red blood cell hemoglobin alone or red blood cells plus an acellular, non-vasoactive, high-oxygen affinity hemoglobin. In the MP4 group, ~2.5 of the 5 g/dl were present as plasma hemoglobin, which decreased the critical hematocrit in half and provided equivalent functional oxygen delivery as red blood cells gram-for-gram of hemoglobin.

The mechanism behind hemoglobin-induced vasoconstriction has been investigated in the microcirculation during extreme hemodilution in hamsters. In those experiments, high-oxygen affinity MP4 (4.2 g/dl; P50 = 5 mmHg) (Vandegriff et al., 2003) was compared with a low-oxygen affinity polymerized bovine veterinary product Oxyglobin™ (PolyBvHb) (13.1 g/dl P50 = 54 mmHg). After hemodilution, plasma hemoglobin concentrations were 1.1 and 3.7 g/dl for MP4 and PolyBvHb, respectively. The PolyBvHb solution and the red blood cells in circulation with PolyBvHb offloaded more oxygen in the systemic, arterial circulation so that by the time these oxygen carriers reached the capillary circulation, both the cellular and acellular hemoglobins were significantly more desaturated compared to MP4, or to red blood cells in circulation with MP4. MP4 preserved its oxygen saturation and that of the red blood cells in the arteries and arterioles and provided greater oxygen delivery to the capillary beds (Tsai et al., 2004b). This observation describes the importance not just of oxygen-carrying capacity but of regional oxygen delivery in the microcirculation where blood flow is regulated at pre-capillary arterioles by innervated smooth muscle that controls the diameter of the vessels (Ping and Johnson, 1994).

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