Effects of
sitaxsentan (
TBC11251), an orally active, highly selective antagonist of
endothelin A receptors, were examined on the development and maintenance of
pulmonary hypertension, pulmonary
vascular remodeling, and
cardiac hypertrophy in the rat. The pulmonary
vasoconstrictor response to acute
hypoxia (10% O(2)for 90 min) was prevented with
sitaxsentan (5 mg/kg infused iv 10 min prior to the onset of
hypoxia) while
BQ-788 (a specific
endothelin B receptor antagonist) was without effect. The same dose of
sitaxsentan delivered iv 50 min after the onset of
hypoxia reversed the established pulmonary vasoconstriction. In a 2-week model of
hypoxia using 10% O(2), treatment with
sitaxsentan (15 mg/kg per day in
drinking water) attenuated
pulmonary hypertension and the associated
right ventricular hypertrophy, and prevented the remodeling of small pulmonary arteries (50-100 microM) without affecting systemic arterial blood pressure or heart rate. Institution of
sitaxsentan treatment (15 and 30 mg/kg per day in
drinking water) for 4 weeks after 2 weeks of untreated
hypoxia produced a significant, dose dependent reversal of the established
pulmonary hypertension, right
heart hypertrophy, and pulmonary
vascular remodeling despite continued hypoxic exposure.
Sitaxsentan blocked increased plasma
endothelin levels in the prevention protocol but did not affect the established elevated levels in the intervention study.
Sitaxsentan dose dependently (10 and 50 mg/kg per day in the
drinking water) attenuated right ventricular systolic pressure, right
heart hypertrophy, and pulmonary
vascular remodeling observed 3 weeks after a single
subcutaneous injection of
monocrotaline. These findings support the hypothesis that
endothelin-1 plays a significant role in the development of
pulmonary hypertension, pulmonary
vascular remodeling, and the associated
cardiac hypertrophy, and further suggest that specific
endothelin-A receptor blockade may be useful in the treatment of
pulmonary hypertension of diverse etiologies.