TxA₂ receptor activation elicits organ-specific increases in microvascular permeability in the rat

We investigated whether the stable thromboxane A₂ (TxA₂) analogue U- 46619 had any direct effect on extracellular fluid partition. In anesthetized open-chest rats, U-46619 (1.25 and 20 μg/kg iv) dose dependently increased mean pulmonary arterial pressure and hematocrit, whereas mean systemic arterial pressure was raised only at the low dose of agonist. The increase in hematocrit (13.2 ± 2.9% at 20 μg/kg; P < 0.05) still occurred in bilaterally nephrectomized rats and in binephrectomized plus splenectomized rats (11.6 ± 2.7 and 12.2 ± 4.6%, respectively; both P = NS vs. U-46619 in control rats), corresponding to a calculated decrease in plasma volume of 22.1 ± 4.5, 19.6 ± 4.0, and 19.2 ± 5.8%, respectively. Plasma protein concentration increased less than hematocrit, and the coefficient of reflection was significantly lower in these groups, suggesting protein extravasation. Additional experiments showed that U-46619 (1.25 and 10 μg/kg iv) dose dependently increased the vascular leak of albumin mainly in lung, kidneys, and spleen but not in brain, liver, mesentery, and cardiac and skeletal muscles. Protreatment with the TxA₂ receptor antagonist SQ-29,548 (2.5 mg/kg iv bolus plus 2.5 mg · kg^-1 · h^-1 as maintenance) abolished all effects of U-46619, including the increase in mean pulmonary arterial pressure, hematocrit, plasma protein concentration, and albumin extravasation and the decrease in mean systemic arterial pressure, plasma volume, and coefficient of reflection. Thus the TxA₂ analogue U-46619 increased hematocrit and reduced plasma volume through an increase in microvascular permeability in specific organs. This fluid shift, evoked by TxA₂ receptor activation, probably resulted from homodynamic changes at the microvascular level and/or changes in microvascular permeability in target tissues.