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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL040473-02
Application #
3357684
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1988-06-01
Project End
1993-05-31
Budget Start
1989-06-01
Budget End
1990-05-31
Support Year
2
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Takahashi, Y; de Vroomen, M; Gournay, V et al. (1999) Mechanisms of adrenomedullin-induced increase of pulmonary blood flow in fetal sheep. Pediatr Res 45:276-81
Heymann, M A (1999) Control of the pulmonary circulation in the fetus and during the transitional period to air breathing. Eur J Obstet Gynecol Reprod Biol 84:127-32
De Vroomen, M; Takahashi, Y; Roman, C et al. (1998) Calcitonin gene-related peptide increases pulmonary blood flow in fetal sheep. Am J Physiol 274:H277-82
Roberts Jr, J D; Fineman, J R; Morin 3rd, F C et al. (1997) Inhaled nitric oxide and persistent pulmonary hypertension of the newborn. The Inhaled Nitric Oxide Study Group. N Engl J Med 336:605-10
Bootstaylor, B S; Roman, C; Parer, J T et al. (1997) Fetal and maternal hemodynamic and metabolic effects of maternal nitroglycerin infusions in sheep. Am J Obstet Gynecol 176:644-50
Glasgow, R E; Buga, G M; Ignarro, L J et al. (1997) Endothelium-derived relaxing factor as a mediator of bradykinin-induced perinatal pulmonary vasodilatation in fetal sheep. Reprod Fertil Dev 9:213-6
de Vroomen, M; Takahashi, Y; Gournay, V et al. (1997) Adrenomedullin increases pulmonary blood flow in fetal sheep. Pediatr Res 41:493-7
Bogaert, G A; Kogan, B A; Mevorach, R A et al. (1996) Exogenous endothelin-1 causes renal vasodilation in the fetal lamb. J Urol 156:847-53
Winters, J W; Wong, J; Van Dyke, D et al. (1996) Endothelin receptor blockade does not alter the increase in pulmonary blood flow due to oxygen ventilation in fetal lambs. Pediatr Res 40:152-7
Wong, J; Fineman, J R; Heymann, M A (1994) The role of endothelin and endothelin receptor subtypes in regulation of fetal pulmonary vascular tone. Pediatr Res 35:664-70

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