Abstract
Endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen, is produced from its precursor, preproendothelin-1 (ppET-1), by ET converting enzyme (ECE-1) activity. In the fetal lung, the effects of ET-1 are also dependent upon stimulation of ET A and B receptors, which mediate vasoconstriction and vasodilation, respectively. Past studies have suggested that ET-1 contributes to high pulmonary vascular resistance (PVR) in an experimental model of perinatal pulmonary hypertension due to chronic ligation of the ductus arteriosus (DA). Physiologic studies in this model have demonstrated altered ET A and ET B activities after DA ligation, but little is known about mechanisms contributing to these changes in ET-1 activity. To further study the role of ET-1 in pulmonary hypertension after DA ligation, we studied lung mRNA expression of ppET-1, ECE-1, and the ET A and ET B receptors in normal and hypertensive fetal lambs. Total RNA was isolated from whole lung tissue in normal late gestation fetuses (135±3 days; 147 days = term) and from animals with pulmonary hypertension after DA ligation for 8 days(134±4 days). DA ligation increased right ventricular hypertrophy(0.56±0.02 vs 0.85±0.05, right ventricle / left ventricle + septum, p<0.05). Northern blot analysis was performed using cDNA probes and was normalized to the signal for 18s rRNA. We found a 71±24% increase in steady state ppET-1 mRNA (p<0.05) and a 62±5% decrease in ET B mRNA expression in DA ligation (p<0.05). ECE-1 and ET A receptor mRNA expression did not change. We conclude that chronic intrauterine pulmonary hypertension from DA ligation increases steady state ppET-1 mRNA and decreases ET B receptor mRNA without changing ECE-1 mRNA or ET A receptor mRNA expression. These findings suggest that both increased ET-1 production and decreased ET B receptor expression favor increased vasoconstrictor tone and contribute to high PVR in experimental neonatal pulmonary hypertension.
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