The aim of this study was to investigate the potential role of
endothelin (ET) in the development of chronic hypoxic
pulmonary hypertension. Pulmonary vascular reactivity to ET-1 was first examined in isolated perfused lungs from normoxic and chronically hypoxic rats in the presence of
bosentan, a new nonpeptide mixed antagonist of ETA and ETB receptors. The effect of chronic treatment with
bosentan was then examined in rats that were exposed to chronic
hypoxia and developed
pulmonary hypertension. In lungs from normoxic rats,
bosentan (10(-5) M) abolished the
vasodilator responses to ET-1 (10(-10) M) or to the ETB-selective agonist
IRL-1620 (10(-10) M) and attenuated the
vasoconstrictor responses to 10(-9) M ET-1 (from 8.7 +/- 0.7 to 1.8 +/- 0.3 mmHg, P < 0.01) or 10(-9) M
IRL-1620 (from 1.5 +/- 0.4 to 0.4 +/- 0.1 mmHg, P < 0.05). In lungs from chronically hypoxic rats, the pressor response to 3 x 10(-10) M ET-1 was abolished by
bosentan and partially reduced by the selective ETA antagonist
BQ-123. In conscious rats previously exposed to
hypoxia for 15 days, pretreatment with
bosentan (100 mg.kg-1.day-1 by gavage) for 3 days attenuated the increase in systemic arterial pressures and the concomitant decrease of cardiac output in response to an intravenous bolus of ET-1 (3 x 10(-10) M). In rats exposed to
hypoxia for 15 days and simultaneously treated with
bosentan, pulmonary arterial pressure was lower (P < 0.05) and
right ventricular hypertrophy was less severe (P < 0.01) than in control hypoxic rats treated with vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)