NO and prostaglandin interactions during hemodynamic stress in the fetal ovine pulmonary circulation.

Nitric oxide (NO) and prostacyclin (PGI(2)) are potent fetal pulmonary vasodilators, but their relative roles and interactions in the regulation of the perinatal pulmonary circulation are poorly understood. We compared the separate and combined effects of nitric oxide synthase (NOS) and cyclooxygenase (COX) inhibition during acute hemodynamic stress caused by brief mechanical compression of the ductus arteriosus (DA) in chronically prepared fetal lambs. Nitro-L-arginine (L-NNA; NOS antagonist), meclofenamate (Mec; COX inhibitor), combined drugs (L-NNA-Mec), or saline (control) was infused into the left pulmonary artery (LPA) before DA compression. In controls, DA compression decreased pulmonary vascular resistance (PVR) by 43% (P < 0.01). L-NNA, but not Mec, treatment completely blocked vasodilation and caused a paradoxical increase in PVR (+31%; P < 0.05). The effects of L-NNA-Mec and L-NNA on PVR were similar. To determine if the vasodilator effect of PGI(2) is partly mediated by NO release, we studied PGI(2)-induced vasodilation before and after NOS inhibition. L-NNA treatment blocked the PGI(2)-induced rise in LPA blood flow by 73% (P < 0.001). We conclude that NO has a greater role than PGs in fetal pulmonary vasoregulation during acute hemodynamic stress and that PGI(2)-induced pulmonary vasodilation is largely mediated by NO release in the fetal lung.

[1]  Qiang Liu,et al.  Development of intrinsic tone in isolated pulmonary arterioles. , 1999, American journal of physiology. Lung cellular and molecular physiology.

[2]  L. Storme,et al.  In Vivo Evidence for a Myogenic Response in the Fetal Pulmonary Circulation , 1999, Pediatric Research.

[3]  P. Hardy,et al.  A major role for prostacyclin in nitric oxide-induced ocular vasorelaxation in the piglet. , 1998, Circulation research.

[4]  D. Pelligrino,et al.  Cyclic nucleotide crosstalk and the regulation of cerebral vasodilation , 1998, Progress in Neurobiology.

[5]  J. Gordon,et al.  Relative Effects of Cyclooxygenase and Nitric Oxide Synthase Inhibition on Vascular Resistances in Neonatal Lamb Lungs , 1997, Pediatric Research.

[6]  H. Vapaatalo,et al.  Nitric oxide as a regulator of prostacyclin synthesis in cultured rat heart endothelial cells. , 1997, Arzneimittel-Forschung.

[7]  S. Diamond,et al.  Does elevated nitric oxide production enhance the release of prostacyclin from shear stressed aortic endothelial cells? , 1997, Biochemical and biophysical research communications.

[8]  M. Gimbrone,et al.  Identification of vascular endothelial genes differentially responsive to fluid mechanical stimuli: cyclooxygenase-2, manganese superoxide dismutase, and endothelial cell nitric oxide synthase are selectively up-regulated by steady laminar shear stress. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[9]  J. Tarbell,et al.  Shear stress-induced release of PGE2 and PGI2 by vascular smooth muscle cells. , 1996, Biochemical and biophysical research communications.

[10]  M. Currie,et al.  Nitric oxide-mediated cyclooxygenase activation. A key event in the antiplatelet effects of nitrovasodilators. , 1996, The Journal of clinical investigation.

[11]  J. Roberts,et al.  Nitric oxide produced by endothelial cells increases production of eicosanoids through activation of prostaglandin H synthase. , 1995, Circulation research.

[12]  L. Sautebin,et al.  Nitric oxide modulates prostacyclin biosynthesis in the lung of endotoxin-treated rats. , 1994, European journal of pharmacology.

[13]  J. Belik.  Myogenic Response in Large Pulmonary Arteries and Its Ontogenesis , 1994, Pediatric Research.

[14]  P. S. Wilson,et al.  Effect of nitric oxide and cyclooxygenase products on vascular resistance in dog and rat lungs. , 1993, Journal of applied physiology.

[15]  M. Heymann,et al.  EDRF inhibition attenuates the increase in pulmonary blood flow due to oxygen ventilation in fetal lambs. , 1992, Journal of applied physiology.

[16]  K. Decker,et al.  Regulation by prostaglandin E2 of cytokine-elicited nitric oxide synthesis in rat liver macrophages. , 1992, Biological chemistry Hoppe-Seyler.

[17]  D. Cornfield,et al.  Effects of birth-related stimuli on L-arginine-dependent pulmonary vasodilation in ovine fetus. , 1992, The American journal of physiology.

[18]  M. Heymann,et al.  Prostaglandin Inhibition Prevents the Fall in Pulmonary Vascular Resistance as a Result of Rhythmic Distension of the Lungs in Fetal Lambs , 1991, Pediatric Research.

[19]  Jon M. Fukuto,et al.  Shear Stress‐Induced Release of Nitric Oxide From Endothelial Cells Grown on Beads , 1991, Hypertension.

[20]  S. Abman,et al.  Role of endothelium-derived relaxing factor during transition of pulmonary circulation at birth. , 1990, The American journal of physiology.

[21]  F. Accurso,et al.  Acute effects of partial compression of ductus arteriosus on fetal pulmonary circulation. , 1989, The American journal of physiology.

[22]  J. N. Evans,et al.  Stretch-induced contraction in pulmonary arteries. , 1988, The American journal of physiology.

[23]  N. Flavahan,et al.  Prostacyclin releases endothelium‐derived relaxing factor and potentiates its action in coronary arteries of the pig , 1988, British journal of pharmacology.

[24]  P. Vanhoutte,et al.  Flow-induced release of endothelium-derived relaxing factor. , 1986, The American journal of physiology.

[25]  L V McIntire,et al.  Flow effects on prostacyclin production by cultured human endothelial cells. , 1985, Science.

[26]  M. Tod,et al.  Perinatal pulmonary responses to arachidonic acid during normoxia and hypoxia. , 1984, Journal of applied physiology: respiratory, environmental and exercise physiology.

[27]  R. Green,et al.  The Onset of Breathing at Birth Stimulates Pulmonary Vascular Prostacyclin Synthesis , 1984, Pediatric Research.

[28]  J. Newell,et al.  Pulmonary prostacyclin production with increased flow and sympathetic stimulation. , 1983, Journal of applied physiology: respiratory, environmental and exercise physiology.

[29]  C. Leffler,et al.  Effect of indomethacin on pulmonary vascular response to ventilation of fetal goats. , 1978, The American journal of physiology.

[30]  M. Heymann,et al.  Gestational Changes in Pulmonary Vascular Responses in Fetal Lambs in Utero , 1976, Circulation research.

[31]  M. Heymann,et al.  Formalin infiltration of the ductus arteriosus. A method for palliation of infants with selected congenital cardiac lesions. , 1975, The New England journal of medicine.

[32]  F. Adams,et al.  Effect of Lung Expansion on the Fetal Lamb Circulation , 1966, Acta paediatrica Scandinavica.

[33]  F. Accurso,et al.  Sustained fetal pulmonary vasodilation with prolonged atrial natriuretic factor and GMP infusions. , 1991, The American journal of physiology.

[34]  F. Accurso,et al.  Time-dependent response of fetal pulmonary blood flow to an increase in fetal oxygen tension. , 1986, Respiration physiology.

[35]  N. Haneda,et al.  [Formalin infiltration of the ductus arteriosus in ductus dependent cardiac anomalies (author's transl)]. , 1982, Kyobu geka. The Japanese journal of thoracic surgery.