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Vol. 50, Issue 1, 35-58, March 1998
Laboratory for Pregnancy and Newborn Research, Department of
Physiology, College of Veterinary Medicine, Cornell University, Ithaca,
New York
I. Introduction
II. Physiological Roles of the Ductus Arteriosus
A. The Fetal Circulation
B. The Neonatal Transitional Circulation
C. Closure of the Ductus Arteriosus
III. Factors Maintaining Ductal Patency In Utero
A. Prostaglandins
1. Dilator effects of prostaglandins.
2. Prostanoid receptors and signal transduction.
3. Local sources of prostaglandins.
4. Circulating prostaglandins.
5. Effects of prostaglandin H synthase inhibition in vivo and in
vitro.
6. Relative roles of local and circulating prostaglandin in fetal
life.
7. Prostaglandin H synthase isoforms.
B. Nitric Oxide
C. Carbon Monoxide
D. Other Relaxants of the Ductus Arteriosus
IV. Factors Mediating Contraction at Birth
A. Oxygen-Induced Contraction
1. Cytochrome a3 hypothesis.
2. Arachidonate hypothesis.
3. Endothelin/cytochrome P450 hypothesis.
4. Membrane hypothesis.
5. Characterizing an oxygen sensor.
B. Contractile Effects of prostaglandins
C. Elimination of Dilator Prostaglandins
1. Circulating prostaglandin E2.
2. Locally released prostaglandin.
D. Neural Vasoconstriction
E. Other Locally Released Vasoconstrictors
F. Myogenic Tone
G. Circulating Vasoconstrictors
V. Ontogeny of Pharmacological Responses
A. Altering Pharmacological Responses with Advancing Gestational
Age
B. The Effects of Corticosteroids on Pharmacological Responses
VI. Intracellular Control of Contractility
A. Control of Membrane Potential and Intracellular Calcium
B. Other Signal Transduction Systems
C. Contractile Proteins
VII. Ductal Remodeling
A. Anatomical Changes After Birth
B. Pharmacological Aspects of Remodeling
VIII. Integrated Model of Postnatal Ductal Contraction
IX. Clinical Significance
A. Patent Ductus Arteriosis
B. Ductus-Dependent Circulation
C. Prostaglandin H Synthase Inhibitors and Pregnancy
X. Experimental Models for Novel Therapeutics
A. In Vitro Comparisons of Drugs
B. In Vivo Comparisons of Drugs in the Fetus
C. In Vivo Comparisons of Drugs in the Neonate
XI. Scope for Novel Therapies
A. Patent Ductus Arteriosus
1. Prostanoid EP4 receptor antagonist.
2. Isoform specific prostaglandin H synthase inhibitor.
3. Potassium channel closing agents.
B. Ductus-Dependent Circulation
1. Prostanoid EP4 receptor agonist.
2. Potassium channel activators.
3. Nitric oxide donors.
4. ETA receptor antagonist.
C. Preterm Labor
1. Prostanoid EP3/FP receptor antagonists.
2. Prostaglandin H synthase-2 inhibitors.
3. Sulindac.
XII. Conclusions
Acknowledgments
References
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