LE LOSARTAN PREVIENT L'HYPERTENSION PULMONAIRE INDUITE PAR UN ANALOGUE DU THROMBOXANE A₂

We investigated the possibility that the selective angiotensin II type 1 (AT₁) receptor antagonist, losartan, interacts with thromboxane A₂/endoperoxide (TxA₂/PGH₂) receptors. We mearured changes in mean pulmonary arterial pressure (MPAP) induced by the stable TxA₂ analogue, U-46619, during blockade of either TxA₂/PGH₂ or AT₁ receptors, in anesthetized, open chest rats (n = 4-8 per group). U-46619 (1.25 and 10 μg/kg) dose-dependently increased MPAP. The U-46619 (1.25 μg/kg)-evoked increase in MPAP (~51%; p < 0.01) was dose-dependently inhibited by the TxA₂/PGH₂ receptor antagonist, SQ 29,548 (~94 ard 102% at 0.63 and 2.5 mg/kg, respectively; both p < 0.05). Losartan also dose-dependently reduced this increase (~11 and 65% at 2.5 and 10 mg/kg, respectively; p = NS and p < 0.05, respectively). Furthermore, losartan dose-dependently prevented the increase in MPAP (~112%) induced by an 8 fold higher dose of U-46619 (10 μg/kg) by ~9 and 75% at doses of 10 and 40 mg/kg, respectively; p = NS and p < 0.05, respectively. Thus, selective activation of TxA₂/PGH₂ receptors by the TxA₂ analogue, U-46619, induced pulmonary hypertension, which was specifically inhibited by the TxA₂/PGH₂ receptor antagonist, SQ 29,548 and the AT₁ receptor antagonist, losartan, suggesting that the latter compound exerts antagonist activity at TxA₂/PGH₂ receptors.