Chronic hypoxia suppresses muscarinic‐induced contractility in ovine pulmonary arteries (1089.17)

Abstract

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