[Losartan prevents pulmonary hypertension induced by a thromboxane A2 analog].
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 micrograms/kg) dose-dependently increased MPAP. The U-46619 (1.25 micrograms/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 micrograms/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.
Bertolino
F
F
Division des maladies cardiovasculaires II, centre de recherche Pierre-Fabre, Castres.
Valentin
J P
JP
Maffre
M
M
Jover
B
B
Bessac
A M
AM
John
G W
GW
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D019808:Losartan; D011450:Prostaglandin Endoperoxides, Synthetic / Q000009:adverse effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D013928:Thromboxane A2 / Q000009:adverse effects / Q000031:analogs & derivatives*; D014662:Vasoconstrictor Agents / Q000009:adverse effects
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D011450:Prostaglandin Endoperoxides, Synthetic; D013777:Tetrazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019808:Losartan
Le losartan prévient l'hypertension pulmonaire induite par un analogue du thromboxane A2.