Effect of red blood cell rigidity on tumor blood flow: increase in viscous resistance during hyperglycemia

Elevated glucose level and low pH have been shown to increase red blood cell (RBC) rigidity. This increased rigidity has been proposed as one factor which mediates the tumor blood flow (TBF) reduction during hyperglycemia by (a) causing RBC entrapment and hence increasing geometric resistance and (b) increasing viscous resistance to blood flow. However, due to the inability to measure these resistances in vivo in tumors directly, the relative contribution of RBC rigidity in TBF reduction has not been quantified. In the present study, blood flow resistance was measured in "tissue-isolated" mammary adenocarcinoma R3230AC perfused ex vivo with (a) normally deformable, (b) glutaraldehyde-hardened, and (c) glucose-incubated RBC suspensions. Flow resistance measured during tumor perfusion with Krebs-Henseleit buffer prior to and following perfusion with the glutaraldehyde-hardened RBC suspensions showed no significant change, suggesting constant geometric resistance and lack of RBC entrapment. Instead, our measurements indicated increased viscous resistance with loss of deformability due to glutaraldehyde and glucose incubation even though glucose incubation did not significantly alter the apparent blood viscosity measured in vitro. Thus, the TBF reduction during hyperglycemia may be due to subtle changes in RBC deformability. These results suggest the development of strategies to increase the delivery of drugs or oxygen must take into account any changes in intratumor viscous resistance. For example, the increase in the oxygen-carrying capacity of blood using RBC transfusion or fluorocarbon emulsions may be offset by the increase in viscous resistance and the corresponding reduction in TBF.