Arrigoni, Francesca Irene; (2000) Relationship between aspects of the nitric oxide pathway and vascular responses in the developing lung. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The development of the pulmonary circulation is continuous from the fetal to the mature lung, with nitric oxide (NO) having a role as a major pulmonary vasodilator. Using a porcine model, the relationship of NO with pulmonary development was studied in lungs from 1 week pre-term to adulthood, and in hypoxia induced pulmonary hypertension, from birth and 3 days of age. The effects of breathing on the fetal and newborn lung were also investigated. Arterial and venous vasoactivity was studied using organ baths, with particular attention being paid to the NO pathway in the arteries. In addition, NO synthase (NOS) activity and protein expression were studied in lung homogenates using the citrulline assay and Western blotting. At all perinatal ages, vascular reactivity in the veins was greater than the arteries, with a minimal vasoactivity in the fetal arteries. Low contractility was created by the fetal arteries existing in an "un-dilated" state. Despite the basal release of NO, arterial relaxation to ACh was attenuated in the fetus in association with a low NOS activity. This did not correspond with a low NOS protein or the presence of endogenous inhibitors. At birth, arterial contractility improved, related to parturition and the onset of breathing. This was accompanied by an increased NOS activity and basal NO release. However, relaxation to ACh remained absent until 1 day of age. From 3-14 days of age, changes in arterial contractility were associated with structural development. ACh relaxation improved, not associated with a further increase in NOS activity, but perhaps an increasing contribution of other endothelium dependent relaxing factors. The enhanced vascular contractility following hypoxia induced pulmonary hypertension from birth corresponded with a change in smooth muscle cell structure. ACh induced relaxation was abolished in association with the alteration of the activities of the NOS isoforms and the production of NO from the smooth muscle. Thus lung development in the fetus/newbom, postnatal and pulmonary hypertensive pig exists as distinct phases, in which NO has a role.

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