McMillan, Michael Ross; (1998) The role of purine receptors in the control of pulmonary vascular reactivity in the normal and hypertensive newborn. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The porcine model of puhnonary development was used to investigate the role of purines and pyrimidines in the adaptation of the normal pulmonary circulation to extrauterine life. The effect of neonatal pulmonary hypertension (PHN) was studied by exposing animals to chronic hypobaric hypoxia (50.8kPa.). In vitro force measurements of isolated vessels demonstrated a P2Y]-purine receptor mediated endothelium-independent relaxation in precontracted newborn intrapulmonary arteries (IPA) , which increased with age and was not affected by PHN. ATP induced an endothelium-independent relaxation in intrapulmonary veins (IPV) which was unaffected by age. At resting tone, ATP induced a relaxation in IPA from neonatal piglets, developing a contractile response in the mature animal with a rank order of potency, uridine 5'-triphosphate > ATP >>,p-methyleneATP. However, in the porcine intrapulmonary vein (IPV) the order of potency was a,p-methyleneATP >> UTP > ATP. Desensitisation experiments indicated that in both IPA and IPV, ATP and UTP were acting at a different contractile receptor(s) than , (3-methyleneATP. PHN reduced the IPA contractile response to ATP and UTP. Radioligand binding on frozen lung sections demonstrated that [35S] dATPaS bound to a P2Y]-purine receptor but that UTPaS bound to a non-selective nucleotide-receptor binding site on the media of the IPA. The nomial transient increase in binding of both ligands at 3 days of age was reduced by PHN.Vessels studied from a small number of nonnal and pulmonary hypertensive children gave similar results to those in porcine vessels, except that the P2Y-relaxation of IPA was largely endothelium-dependent and that [35S] dATPaS bound selectively to a P2X-purine receptor on the media of the IPA from a nomial 8 year old child. In conclusion, the in vitro findings from the present study support the clinical impression that infusion of a purine will tend to cause vasodilatation of a high resistance pulmonary circulation such as that normally present at birth and found in PHN, and indicate a therapeutic potential for these compounds

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