Transvascular flux and tissue accrual of Evans blue: Effects of endotoxin and histamine

We investigated the relationship between the pharmacokinetics of exogenous molecules and transcapillary flux by studying the intravascular and tissue content and the histologic distribution of Evans blue in guinea pigs. Pharmacokinetic analysis demonstrated that 87% of the decline in intravascular Evans blue during the first 3 hours after administration was a result of transvascular flux to tissue compartments. Rapidly and slowly equilibrating compartments were identified. Greater than 90% of the clearances in lung and heart were rapid compartment clearances. Histologically, the distribution of Evans blue in these tissues was predominantly extracellular and similar to the distribution of fluorescein-labeled dextran. By contrast, the accumulation in kidney and liver was kinetically similar to characteristics of the slowly equilibrating compartment. This corresponded histologically to the predominent intracellular uptake of Evans blue in these tissues. Generalized increases in capillary permeability were produced by endotoxin or histamine infusion. Both treatments were associated with a more rapid initial decline in intravascular content of Evans blue than was found in control animals. Although the histologic distribution of Evans blue in tissues was not altered, endotoxin was associated with a more rapid appearance of Evans blue in the lung and heart than was seen in controls. We conclude that the initial decline in intravascular content of Evans blue corresponds to the intercompartmental clearance and to transcapillary macromolecular flux. The initial decline in serum concentrations may therefore be useful in studying disorders of generalized capillary permeability. Furthermore, the initial accrual of Evans blue in the lung and heart may be used as a marker of transcapillary macromolecular flux in those tissues.