LOSARTAN PREVENTS THROMBOXANE-A(2) RECEPTOR-MEDIATED PULMONARY-HYPERTENSION

We investigated the possibility that the selective angiotensin II type 1 (AT1) receptor antagonist, losartan, interacts with thromboxane A2/endoperoxide (TxA2/PGH2) receptors. We measured 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 mug/kg) dose-dependently increased MPAP. The U-46619 (1.25 mug/kg)-evoked increase in MPAP (approximately 51 % ; p < 0.01) was dose-dependently inhibited by the TxA2/PGH2 receptor antagonist, SQ 29,548(approximately 94 and 102 % at 0.63 and 2.5 mg/kg, respectively ; both p < 0.05). Losartan also dose-dependently reduced this increase (approximately 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 (approximately 112 %) induced by an 8 fold higher dose of U-46619 (10 mug/kg) by approximately 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.