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-9 alpha, 11 alpha-methanoepoxy PGF2 alpha, 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-446619 (1.25 micrograms/kg)-increased MPAP (52.4 +/- 12.1%; P < .005) was dose dependently inhibited by the TxA2/PGH2 receptor antagonist, SQ 29,548 ([1S-[1 alpha,2 alpha (5z),3 alpha, 4 alpha]]-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.(ABSTRACT TRUNCATED AT 250 WORDS)
Bertolino
F
F
Division of Cardiovascular Diseases II, Centre de Recherche Pierre Fabre, Castres, France.
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*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004656:Enalapril / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D006400:Hematocrit; D006834:Hydrazines / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D007093:Imidazoles; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D013777:Tetrazoles; D000804:Angiotensin II; D013928:Thromboxane A2; D004656:Enalapril; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D019808:Losartan