Role of the nitric oxide-cgmp system in regulation of ductus
arteriosus tone in the ovine fetus.
Fox, Jonathan J., James W. Ziegler, D. Dunbar Ivy, Ann C. Halbower,
John P. Kinsella, Steven H. Abman.
Departments of Pediatrics, Sections of Cardiology, Neonatology and
Pulmonary Medicine, The Children's Hospital and the University of
Colorado School of Medicine, Denver, CO; and the Department of
Pediatrics, Pulmonary Medicine, University of New Mexico School of
Medicine, Albequerque, NM
APStracts 3:0298H, 1996.
Although endogenous nitric oxide (NO) modulates basal tone in the
pulmonary and systemic circulation of the fetus, little is known
about its role in regulating tone of the ductus arteriosus (DA). We
performed immunostaining of DA tissue from late gestation fetal lambs
using a specific monoclonal antibody to Type III endothelial nitric
oxide synthase (eNOS). Strong staining for eNOS was present in DA
endothelial cells but not smooth muscle cells. To study the
physiologic role of the NO-cGMP system in the DA in vivo, we measured
the hemodynamic effects of nitro-L-arginine (L-NA; 30 mg), a NOS
inhibitor, methylene blue (40 mg), a guanylate cyclase inhibitor, and
indomethacin (0.8 mg), a cyclooxygenase inhibitor in 10 chronically
prepared late gestation fetal lambs. Infusions were given over a ten
minute period into the main pulmonary artery (MPA). Left pulmonary
artery blood flow was measured in 6 animals and blood flow across the
DA was measured in 4 animals. L-NA increased MPA and aortic (Ao)
pressures (p<0.05 vs. baseline) but did not change the pressure
gradient between MPA and Ao. L-NA decreased DA flow and increased
resistance across the DA following infusion. Methylene blue increased
MPA pressure and increased the pressure gradient between MPA and Ao
from 0.3+0.2 (baseline) to 7.0+2.7 mmHg (p<0.05) 30 minutes
after the start of infusion, suggesting constriction of the DA.
Indomethacin increased MPA pressure and increased the pressure
gradient between MPA and Ao from 1.1+0.4 (baseline) to 6.3+1.5 mmHg
(p<0.05) 40 minutes after the start of infusion. Indomethacin
decreased DA flow 40 minutes after infusion and increased DA
resistance 70 minutes after infusion. We conclude that eNOS is
present in endothelial cells of the fetal DA, and that NOS inhibition
causes constriction of the DA in vivo. DA constriction following NOS
inhibition is less potent when compared to cyclooxygenase inhibition.
Methylene blue also constricts the DA, suggesting that guanylate
cyclase activity contributes to DA relaxation. We speculate that
although the NO-cGMP system modulates tone of the DA, its role in
modulating basal tone of the DA may be less than prostaglandins.
Received 29 March 1996; accepted in final form 5 June 1996.
APS Manuscript Number H300-6.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 25 July 1996