Maturation And Chronic Hypoxia Influence Alpha Adrenergic Function In The Pulmonary Vasculature Of Sheep

Purpose of Study: Lung blood flow is regulated to maximize gas exchange. This is controlled by various factors including autonomic nervous stimulation. Before birth, the fetal lung has high vascular resistance and low blood flowas all oxygen and nutrients are provided by the mother. In comparison, chronic hypoxia (CH) can cause structural and functional pathology, with increased pulmonary pressure and vascular remodeling. Modern medications focus on alleviating pulmonary hypertension (PH) by blocking smooth muscle contractility, but they do not fully reverse disease progression. This inability to cure PH in newborns and adults is partly because we do not understand the etiology of disease. Our aim is to understand this progression. Previous work from our group shows that CH does not affect norepinephrine induced pulmonary arterial contractility in fetus, but does influence cerebrovascular tone. We therefore tested the hypothesis that maturation and CH depress alpha adrenergic receptor (AR) dependent pulmonary arterial contractility. Methods Used: Pulmonary arteries were isolated from near term sheep fetuses (~140 days) and adult ewes maintained under normoxic (300m) or CH conditions (3800m) for 100 days. Wire myography was performed to assess the role of alpha-ARs, with rings being stimulated with cumulative doses of phenylephrine (PE), a selective alpha-AR agonist, ranging from 10-9 to 5 X 10-4 M. Summary of Results: PE caused arteries from adult normoxic animals to contract 69 +/- 5 % of that due to 124 mM potassium (%TKmax), with a Log EC50 of -6.9 +/- 0.22 M. Rings from adult CH animals had a similar magnitude, being 61 +/- 4 %TKmax. However, the Log EC50 was shifted, being -5.7 +/- 0.18 M. PE caused greater tone in arterial rings from normoxic fetuses, being 100 +/- 10 %TKmax. Yet, these arteries were less responsive than those of adult, with a Log EC50 of -6.1 +/- 0.25 M. Arteries from CH fetuses reacted similarly to normoxic controls with an EC50 of -5.7 +/- 0.20 M and tone being 90 +/- 6 %TKmax Conclusions: Our preliminary studies show the role of alpha-AR to pulmonary arterial contractility is influenced by postnatal development as well as CH. This suggests that alpha-ARs may be therapeutically relevant in the treatment of pulmonary hypertension.