Gestational resistance to the pulmonary vasoconstrictor effect of the TxA₂ mimetic U-46619: Possible mechanism

Pregnancy is associated with the reduction of vascular sensitivity to vasoconstrictor compounds. We have examined whether pregnancy in rabbits induces hyposensitivity of the pulmonary vascular system to U-46619. Anesthetized, mechanically ventilated nonpregnant (NP; n = 7) and late- pregnant (P; n = 7) rabbits were studied. The intravenous injection of 0.03, 0.1, and 0.3 μg/kg U-46619 led to a dose-dependent elevation of mean pulmonary arterial pressure (MPAP) in NP rabbits from a baseline value of 15 ± 1 to 22 ± 1 mgHg. There was no significant MPAP response to intravenous administration of U-46619 in P rabbits. The pulmonary arterial pressure response of isolated, ventilated, and buffer-perfused lungs of P rabbits was also blunted (P < 0.001 vs. NP). Pulmonary arterial membrane binding of [¹²⁵I]BOP, another thromboxane (Tx)A₂ analog, indicated 48 ± 16 fmol receptors/mg protein in P rabbits and 193 ± 48 fmol receptors/mg protein in NP samples (P < 0.025). Receptor affinity [1/dissociation constant (K(D))] was also lower in the tissue of P rabbits (P < 0.01 vs. NP). The urinary excretion of the stable TxA₂ metabolite 11-dehydro-TxB₂ was lower in P than in NP rabbits (P < 0.02), which made homologous desensitization an unlikely explanation for the changes of vascular TxA₂ receptors. These results show that, in late gestation, rabbit pulmonary vascular sensitivity to U-46619 is reduced simultaneously with, and as a possible consequence of, downregulation of specific receptors.