Mechanisms and implications of capillary endothelial swelling and luminal narrowing in low-flow ischemias

Decreased functional capillary density (FCD) is a characteristic of low-flow ischemia which often persists on reperfusion of a tissue even though supply blood flow is reestablished. Capillary narrowing is a possible mechanism for the reduced blood reflow through an increase of the hydraulic resistance of the capillary network. We attribute the narrowing to swollen endothelial cells, a condition that could be observed directly and was found to develop with blood acidosis in both hemorrhagic shock and intentional acid infusion. A computer model of blood flow in skeletal muscle was used to predict the impact of a 21% decrease in capillary luminal diameter on flow and leukocyte transit through the network. For hemorrhagic shock, reduction in blood flow due to capillary narrowing and lowered systemic pressure was offset by hemodilution causing a low-flow state. On reperfusion, flow could be restored if the narrowing was rectified by infusion of a hypertonic saline-dextran solution. Reinfusion with conventional Ringer's lactate only partially restored flow because of a persistent capillary narrowing. The rheological contribution of passive leukocytes added only a few percent to network resistance even with shock-narrowed capillaries. With leukocyte activation increased cell cytoplasmic viscosity caused prolonged transit times for leukocytes in the network with a concomitant elevation in resistance. We conclude that capillary narrowing is a mechanism of FCD reduction in reperfusion after low-flow ischemia, either by a direct effect on flow or by enhancing the transient plugging of leukocytes. Therapeutic strategies should aim to ameliorate or prevent capillary endothelial cell swelling, and to minimize the level of activated circulating leukocytes.