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OtherCARDIOVASCULAR PHARMACOLOGY

The Orally Active ETA Receptor Antagonist (+)-(S)-2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl-propionic acid (LU 135252) Prevents the Development of Pulmonary Hypertension and Endothelial Metabolic Dysfunction in Monocrotaline-Treated Rats

Stéphane Prié, Tack Ki Leung, Peter Cernacek, James W. Ryan and Jocelyn Dupuis
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1312-1318;
Stéphane Prié
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Tack Ki Leung
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Peter Cernacek
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James W. Ryan
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Jocelyn Dupuis
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Abstract

Pulmonary hypertension is associated with endothelial dysfunction that may mediate or contribute to the disease process; among those abnormalities is an increase in circulating endothelin-1 levels. We investigated the effect of the orally active endothelin A receptor antagonist LU 135252 (LU) on the development of monocrotaline (MCT)-induced pulmonary hypertension and endothelial metabolic dysfunction. Rats were assigned to four groups by receiving a single dose of MCT or saline, followed by once-daily gavage with LU (50 mg/kg) or saline for 3 weeks. Plasma immunoreactive endothelin-1 levels doubled after MCT and were unaffected by LU therapy. The MCT-induced increase in right ventricular systolic pressure (72.5 ± 15.9 mmHg) and hypertrophy (right ventricle/[left ventricle plus septum weight]; 0.58 ± 0.08) were reduced by LU to 42.7 ± 8.5 mmHg (P < .01) and 0.42 ± 0.05 (P < .01), respectively. LU, however, did not modify MCT-induced pulmonary artery medial hypertrophy. Pulmonary vascular endothelial metabolic activity was evaluated in isolated lungs by measuring endothelium-bound angiotensin-converting enzyme activity using a synthetic angiotensin-converting enzyme substrate,3H-benzoyl-phenylalanly-glycyl-proline. MCT reduced fractional 3H-benzoyl-phenylalanly-glycyl-proline hydrolysis (0.488 ± 0.051, P < .01) which was normalized by LU therapy (0.563 ± 0.050). LU treatment alone had no significant effect on any of these parameters. We conclude that the endothelin A antagonist LU reduces MCT-induced pulmonary hypertension and right ventricular hypertrophy and restores endothelial metabolic function. These results support the development of endothelin antagonists for the treatment of pulmonary hypertension and associated endothelial metabolic abnormalities.

Footnotes

  • Send reprint requests to: Dr. Jocelyn Dupuis, Montreal Heart Institute, 5000 Bélanger St. East, Montreal, Quebec, Canada H1T 1C8.

  • ↵1 This work was supported by the Medical Research Council of Canada, the Fonds de la recherche en santé du Québec, the Quebec Heart and Stroke Foundation and the Fonds de recherche de l’Institut de Cardiologie de Montréal.

  • Abbreviations:
    PH
    pulmonary hypertension
    MCT
    monocrotaline
    LU or LU 135252
    (+)-(S)-2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl-propionic acid
    ET-1
    endothelin-1
    ETA
    endothelin A receptor
    ETB
    endothelin B receptor
    BPGP
    benzoyl-phenylalanly-glycyl-proline
    ACE
    angiotensin-converting enzyme
    RV
    right ventricle
    LV + S
    left ventricle plus septum
    • Received January 24, 1997.
    • Accepted May 29, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherCARDIOVASCULAR PHARMACOLOGY

The Orally Active ETA Receptor Antagonist (+)-(S)-2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl-propionic acid (LU 135252) Prevents the Development of Pulmonary Hypertension and Endothelial Metabolic Dysfunction in Monocrotaline-Treated Rats

Stéphane Prié, Tack Ki Leung, Peter Cernacek, James W. Ryan and Jocelyn Dupuis
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1312-1318;

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OtherCARDIOVASCULAR PHARMACOLOGY

The Orally Active ETA Receptor Antagonist (+)-(S)-2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl-propionic acid (LU 135252) Prevents the Development of Pulmonary Hypertension and Endothelial Metabolic Dysfunction in Monocrotaline-Treated Rats

Stéphane Prié, Tack Ki Leung, Peter Cernacek, James W. Ryan and Jocelyn Dupuis
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1312-1318;
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