Loading…
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
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...
Saved in:
Published in: | The Journal of pharmacology and experimental therapeutics 1997-09, Vol.282 (3), p.1312 |
---|---|
Main Authors: | , , , , |
Format: | Article |
Language: | English |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | 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, 3 H-benzoyl-phenylalanly-glycyl-proline. MCT reduced fractional 3 H-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. |
---|---|
ISSN: | 0022-3565 1521-0103 |