The effect of pregnancy on the response to the TxA₂/PGH₂ analogue U- 46619 in rabbits

We compared the hemodynamic actions of U-46619, a stable thromboxane A₂ (TxA₂) prostaglandin H₂ (PGH₂) analogue, in nonpregnant (NP) rabbits with those observed in late pregnant (P) rabbits. An intravenous injection of U- 46619 (10 μg) to each of eight NP chronically instrumented rabbits (mean body weight 3.4 kg) induced an immediate (1 min) and reversible fall of cardiac output (CO, 66%) and mean arterial pressure (MAP, 41%, both P < 0.01). P rabbits (n = 6, mean body weight 3.8 kg), however, responded with an elevation of MAP (5%, P < 0.02) upon intravenous injection of the drug (10 μg), while CO remained unchanged. The fall of CO in NP rabbits was associated with the temporary disappearance of a fraction of circulating platelets between the superior vena cava and the aortic arch. The number of platelets at 30 and 60 s after U-46619 was reduced (P < 0.05) by 14 and 20% respectively in the aortic blood, whereas caval platelet counts were unchanged until 90 s (-6%, P < 0.05). In contrast, intraaortic administration of this drug (10 μg) to NP rabbits resulted in neither thrombocytopenia nor hypotension. U-46619 (10-30 μg iv) caused no decrease in platelet count in the aorta of P rabbits. In vitro, U-46619-induced aggregation of platelets harvested from P rabbits was also blunted (P < 0.001). This could not be attributed to reduced affinity or number of platelet thromboxane receptors. The data indicate that U-46619 induces a fall of arterial pressure simultaneous with intravascular platelet aggregation. A relationship between the refractoriness of P rabbits to the hypotensive action of intravenous U- 46619 and the diminished aggregatory response of isolated platelets of P rabbits to this TxA₂/PGH₂ agonist is suggested.