Acetylcholine receptor-mediated contractility of ovine pulmonary arteries: Changes with maturation and chronic hypoxia

Muscarinic acetylcholine (ACh) receptor (mAChR) activation relaxes arteries through endothelium‐dependent NO signaling pathways and endothelium removal from most systemic arteries alleviates ACh mediated relaxation. However, Ach induces “paradoxical” contractility in endothelium disrupted pulmonary arteries (PA), through mAChR activation in multiple species including human. Chronic hypoxia (CH) disrupts vascular endothelium, producing loss of endothelium‐dependent PA relaxation. Given the intimacy between endothelial and myocyte function the hypothesis that CH reduces ACh‐dependent PA contractility was tested by performing wire‐myography of endothelium‐denuded PA rings from normoxic fetal and adult animals. The data show that Ach (100 μM) contracted arteries pre‐contracted with 125 mM KCl and this contractility was reduced by CH in adult PA and ablated in fetus. In CH adult, the mAChR agonist carbachol (CCh, 10 μM) caused contraction while 1 μM atropine (mAChR antagonist) blocked Ach and CCh contractility. Consistent with mAChR activation, In situ confocal microscopy approaches show Ach caused cytosolic Ca 2+ increases in PA myocytes of CH adult. In conclusion, this study provides evidence for CH induced loss of mAChR PA contractility, a process that likely helps match ventilation to perfusion, especially as ACh causes bronchoconstriction. (Support from NIH, NSF and UM)