Prevention of thromboxane A₂ receptor-mediated pulmonary hypertension by a nonpeptide angiotensin II type 1 receptor antagonist

Losartan is a potent, nonpeptide, angiotensin II type 1 receptor antagonist. We investigated the possibility that losartan may interact with thromboxane A₂ (TxA₂)/prostaglandin H₂ (PGH₂) receptors. We measured changes in mean systemic (MS) and pulmonary (MP) arterial pressures (AP) as well as in hematocrit induced by the TxA₂ analog, U-46619 (9, 11-dideoxy- 9α,11α-methanoepoxy PGF(2α), during pharmacological blockade of either TxA₂/PGH₂ receptors or the renin-angiotensin system. In anesthetized, open chest rats, U-46619 dose dependently increased MPAP whereas MSAP presented a biphasic evolution. The U-46619 (1.25 μg/kg)-increased MPAP (52.4 ± 12.1%; P < .005) was dose dependently inhibited by the TxA₂/PGH₂ receptor antagonist, SQ 29,548 {[1S-[1α,2α(5z),3α,4α]]-7-[3-[[2-[(phenylamino)- carbonyl]hydrazino]methyl]-7-oxabiacyclo[2.2.1]hept-2-yl]-5-heptenoic acid} (10.6 ± 2 and 2.1 ± 1.4% at 0.63 and 2.5 mg/kg, respectively; both P < .05 vs. U-46619 in control rats). Losartan dose dependently reduced this increase (45.5 ± 5.8 and 11.9 ± 1.8% at 2.5 and 10 mg/kg, respectively; P = N.S. and P < .05 vs. U-46619 in control rats) whereas chronic suppression of angiotensin II generation by the converting-enzyme inhibitor enalapril (10 mg/kg/day per os for 4-5 days) did not affect this response. None of these treatments significantly reduced the U-46619-associated increase in MSAP. Moreover, the angiotensin II-evoked increases in MSAP and MPAP were suppressed by pretreatment with losartan but not with SQ 29,548. U-46619 (1.25 μg/kg) administration was associated with a 4.6 ± 1.5% increase in hematocrit, corresponding to a calculated decrease in plasma volume of 8.3 ± 2.5%. The U-46619-induced increase in hematocrit was prevented by SQ 29,548 and dose dependently inhibited by losartan, but was not affected by chronic enalapril. Furthermore, losartan at doses of 10 and 40 mg/kg also dose dependently prevented the increases in both MPAP and hematocrit induced by an 8-fold higher dose of U-46619 (10 μg/kg). Selective activation of TxA₂/PGH₂ receptors by the TxA₂ analog, U-46619, induced pulmonary hypertension and plasma exudation independently of the involvement of angiotensin II. These responses were specifically attenuated by the angiotensin II type 1 receptor antagonist, losartan, suggesting that this compound may act as a TxA₂/PGH₂ receptor antagonist.