We investigated the preventive and
therapeutic effects of the selective
endothelin ETA receptor antagonist
potassium(E)-N-[6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl]-2-phenylenthenesulfonamidate (
YM598) on the development of
pulmonary hypertension in
monocrotaline-induced pulmonary hypertensive and hypoxemic rats. In the prevention study,
oral administration of
YM598 (0.1 and 1 mg/kg) or
bosentan (30 mg/kg) for 4 weeks was started on the day following
monocrotaline (60 mg/kg) injection. In the therapeutic study,
oral administration of
YM598 (0.1, 0.3 and 1 mg/kg) for 2 weeks was started 3 weeks after
monocrotaline injection. In the prevention study, a marked increase in pulmonary arterial pressure and
right ventricular hypertrophy, a decrease in right cardiac function and
hypoxemia were observed. Histopathological examination indicated the presence of pulmonary remodeling, including medial wall thickening of the pulmonary microvasculature and alveolar disorders.
YM598 suppressed the increase in pulmonary arterial pressure,
right ventricular hypertrophy and systemic congestion, and improved the
hypoxemia, but
bosentan had only modest effects. Histopathological disorders were also ameliorated by
YM598. In the therapeutic study,
YM598 also ameliorated the
pulmonary hypertension and
hypoxemia in
monocrotaline-treated rats. These results suggest that
YM598 effectively prevented and reversed the development of
pulmonary hypertension, and reduced the pulmonary
vascular remodeling and parenchymal injury in
monocrotaline-treated rats.
YM598 also improved
hypoxemia which accompanied with the severe
pulmonary hypertension in these rats.