. Muscarinic receptor activation affects pulmonary artery contractility in sheep: the impact of maturation and chronic hypoxia on endothelium-dependent and endothelium-independent function. High Alt Med Biol. 17:122-132, 2015.-Muscarinic receptor activation in the pulmonary vasculature can cause endothelium-dependent vasodilation and smooth muscle-dependent vasoconstriction. Chronic hypoxia (CH) can modify both of these responses. This study aimed to assess the combined influence of CH and maturation on endothelium-dependent and endothelium-independent muscarinic-induced vasoreactivity. This was accomplished by performing wire myography on endothelium-intact or endothelium-disrupted pulmonary arterial rings isolated from normoxic or CH fetal and adult sheep. In endothelium-intact arteries, vasodilation was evaluated using cumulative bradykinin doses in phenylephrine and carbachol precontracted pulmonary arterial segments; and vasoconstriction was examined using cumulative doses of carbachol following bradykinin predilation. Effects of nonselective (atropine) and selective M1 (pirenzepine), M2 (AFDX116), and M3 (4-DAMP and Dau5884) muscarinic receptor antagonists were assessed in disrupted arteries. In normoxic arteries, bradykinin relaxation was twofold greater in the adult compared to fetus, while carbachol contraction was fourfold greater. In adult arteries, CH increased bradykinin relaxation and carbachol contraction. In vessels with intact endothelium, maturation and CH augmented maximal response and efficacy for carbachol constriction and bradykinin relaxation. Approximately 50%-80% of adult normoxic and CH endothelium-disrupted arteries contracted to acetylcholine, while *50% of fetal normoxic and *10% of CH arteries responded. Atropine reduced carbachol-induced contraction in all vessels. Adult normoxic vessels were most responsive to M3 antagonism, fetal to M2 antagonism, while M1 inhibition had no effect. Overall, muscarinic-induced pulmonary arterial contraction is partially endothelium dependent and appears to develop after birth. Fetuses are more reliant on M3 receptors while M2 receptors predominate in adults, whereas CH augments muscarinic-dependent pulmonary vasoconstriction in both.
Muscarinic acetylcholine receptor (mAChR)‐ arterial relaxation is often used to test for a functional endothelium, but some show it can cause constriction. The present studies tested the hypothesis that mAChR activation contracts pulmonary arteries (PA) with intact endothelium and examined age and altitude effects on mAChR activation. This hypothesis was tested by performing wire myography on endothelium intact as well as denuded PA from chronic hypoxic (CH) term‐fetal and adult sheep that lived at 3,200 m for >100 days or normoxic sheep that lived at 720 m. Dose‐dependent contraction to carbachol (CCH; 1nM‐100 μM), a mAChR agonist and bradykinin (BK; 10 pM‐1 μM) were examined in phenylephrine preconstricted PA (PE; 10 μM). CCH caused a dose‐dependent contraction of PA from adult sheep, while fetal PA contracted to a lesser extent. BK (1 μM) relaxed CCH constricted PA, showing the endothelium was functional. Chronic hypoxia suppressed mAChR‐ contraction of denuded PA in fetuses and adults. M2 receptors dominated in fetus, while M3 receptors were central in adult, suggesting a developmental isoform switch. Because parasympathetic nerve activation contracts airways through mAChR activation potentially there is co‐constriction of associated PA. This mAChR contraction of PA may provide a novel mechanism that matches ventilation to perfusion in the lung. Grant Funding Source: Supported by NSF MRI923559, NIH HD‐69746, P01HD31226,R01HD3807,P20MD6988,LLUSOM, Macpherson Society
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