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Bronchial epithelium-associated pulmonary arterial muscle relaxation in the rat is absent in the fetus and suppressed by postnatal hypoxia

Canadian Institutes of Health Research Group in Lung Development, Lung Biology, and Integrative Biology Programmes, Hospital for Sick Children Research Institute; Clinical Integrative Biology, Sunnybrook and Women's Research Institute; and Departments of Paediatrics and Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

Submitted 16 August 2004 ; accepted in final form 22 October 2004

We recently reported the existence of a bronchial epithelium-derived relaxing factor (BrEpRF) capable of reducing pulmonary arterial smooth muscle force generation in the newborn rat. We reasoned in this study that BrEpRF has physiological significance in the control of pulmonary vascular tone. We hypothesized that the release and/or activity of this factor can be stimulated and is suppressed prenatally or under hypoxic conditions postnatally. Therefore, we evaluated the pathways stimulated by the BrEpRF in fetal and newborn rat intrapulmonary arteries mounted with their adjacent bronchi in a wire myograph under both normoxic and hypoxic conditions. Under normoxic conditions, BrEpRF release/activation was observed in newborn vessels following methacholine stimulation of M₂ muscarinic receptors, which was mediated via a nitric oxide (NO)-dependent mechanism involving the phosphatidylinositol 3-kinase pathway. Hypoxia suppressed the BrEpRF-dependent modulation of basal and methacholine-induced pulmonary arterial muscle tone in newborn vessels without altering endothelium-dependent or -independent NO-mediated relaxation. In fetal pulmonary arteries studied under normoxic conditions, BrEpRF neither was active under basal conditions nor could it be stimulated with methacholine. We conclude that release/activation of the BrEpRF occurs by an oxygen-dependent mechanism in the newborn and is suppressed during late fetal life. These results suggest that the BrEpRF may be involved in postnatal adaptation of the pulmonary circulation and that its suppression may contribute to hypoxic pulmonary vasoconstriction.

muscarinic receptors; pulmonary vascular resistance; nitric oxide; nitric oxide synthase; phosphatidylinositol 3-kinase

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