Chronic
hypoxia (10% O2 for 2-3 weeks) causes
pulmonary hypertension and
vascular remodeling in the rat. To study the role of thromboxase A2 in chronic hypoxic
pulmonary hypertension, the hemodynamic effects of
intravenous administration of a
thromboxane analogue (
STA2) were measured in chronic hypoxic (H) and normoxic (N) Sprague-Dawley rats. During
anesthesia baseline pulmonary arterial pressure (PAP) was higher in H rats (34.6 +/- 1.0 mmHg) than in N rats (18.4 +/- 1.2 mmHg). Intravenous
STA2 (0.3 microgram) acutely increased pulmonary artery pressure by 74% +/- 11% (25 +/- 4 mmHg) in H rats and by 47% +/- 2% (9 +/- 1 mmHg) in N rats, which indicates that both the absolute and relative acute pulmonary vasoconstriction caused by
STA2 were greater in H rats. The changes in systemic arterial pressure caused by
STA2 were smaller than the changes in pulmonary arterial pressure both in H rats (11% +/- 3%) and in N rats (17% +/- 3%). Lungs were isolated and perfused with saline, and the vasoconstrictive response to 0.05 microgram of
STA2 in lungs (14.5 +/- 2.4 mmHg) from H rats was greater than the response to 0.1 microgram of
STA2 (5.6 +/- 1.3 mmHg) in lungs from N rats. To examine whether blockade of
calcium channels could suppress the
vasoconstrictor response to
STA2, the effects of the
calcium channel blocker nicardipine hydrochloride on vasoconstriction caused by
STA2 were measured in H and N rats. In vivo, the blockade of
calcium channels suppressed the increase in pulmonary artery pressure caused by
STA2. This suppression was greater in H rats (56% +/- 11%) than in N rats (25% +/- 4%). Similar results were obtained with isolated perfused lungs. Blockade of
calcium channels suppressed the vasoconstriction caused by
STA2 and this suppression was greater in H rats than in N rats. The finding that
thromboxane A2 induced greater vasoconstriction in H rats than in N rats indicates that
thromboxane A2 may play an important role in
pulmonary hypertension, and suggests that blockade
thromboxane A2 may benefit some patients with primary and secondary
pulmonary hypertension. Furthermore, the finding that suppression of
thromboxane-induced vasoconstriction by blockade of
calcium channels was greater in H rats than in N rats indicates that such treatment may also benefit some patients.