Abstract
Muscarinic acetylcholine receptor (mAChR)‐dependent arterial relaxation is often used to test for a functional endothelium, where inability to relax is indicative of endothelial damage. The present studies test the hypothesis that mAChR activation can contract pulmonary arteries (PA) with intact endothelium from chronically hypoxic sheep. The hypothesis was tested in PA isolated from term‐fetal sheep, ~10 days old newborns, and in adult ewes that lived at 3,200 meters for <100 days, which provides a chronic hypoxic insult. Dose‐dependent vasoreactivity to carbachol, a mAChR agonist and bradykinin (BK) were examined in PA pre‐constricted with 10 μM phenylephrine (PE). Carbachol caused robust dose‐dependent contraction of PA from adult sheep, fetal PA contracted somewhat, and PA from newborns relaxed. Bradykinin (1 μM) relaxed carbachol treated PA, indicating the endothelium was functional. Bradykinin caused dose‐dependent relaxation of PE‐constricted newborn and adult arteries to a similar extent, while fetal arteries relaxed somewhat. Carbachol (100 μM) contracted BK‐relaxed arteries from fetal and adult, but not newborn sheep. mAChR‐dependent contraction may therefore provide a novel mechanism to match ventilation to perfusion in the lung. Targeted therapies could increase lung perfusion and improve oxygenation in patients with pulmonary vascular disease. NIH P01HD031226, R01HD003807 (LDL)
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