Regulation of the perinatal pulmonary circulation is a complex phenomenon involving the production of several metabolites of arachidonic acid. In particular, the production of pulmonary vasoconstricting leukotrienes and the pulmonary vasodilating prostaglandin, PGI2, are now established. The mechanisms involved in the production of these and other relevant vasoactive substances have been sparsely investigated. Fragmentary information is available which now allows us to propose a hypothesis linking the events leading to the establishment of normal pulmonary blood flow after birth. The common pathways proposed are the secondary production, and subsequent pulmonary vasodilating effects, of PGI2 and platelet activating factor (PAF). PGI2 is a clearly established pulmonary vasodilator and is produced by the lung in the immediate postnatal period. Established information, mainly from the in vitro studies with adult vascular tissue, indicates that PGI2 and PAF production can be induced by bradykinin and angiotensin II (AII). Because bradykinin is released with the onset of ventilation, we plan to study the role of bradykinin in stimulating PGI2 and PAF production. Although bradykinin may affect the pulmonary circulation through PGI2 or PAF production, it also causes the release of EDRF, and could even act directly. Similarly, although O2 releases bradykinin, and could produce its effect solely by this mechanism, it also could have a direct effect. Because AII concentrations also increase after the onset of ventilation, we also plan to study the possible role of AII in stimulating PGI2 and PAF production. The studies proposed here will address all those issues by selective use of antagonists or synthesis inhibitors of PGI2, PAF, and EDRF in association with the infusion of the stimulators (BK, AII), or during carefully controlled fetal ventilation. All studies will be performed in chronically prepared fetal sheep.
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