ROLE OF NITRIC-OXIDE AND CGMP SYSTEM IN REGULATION OF DUCTUS-ARTERIOSUS TONE IS OVINE FETUS

Although endogenous nitric oxide (NO) modulates basal tone in the feta l pulmonary and systemic circulations, little is known about its role in regulating ductus arteriosus (DA) tone. Immunostaining of DA tissue from late-gestation fetal Iambs demonstrated strong staining for endo thelial NO synthase (eNOS) in DA endothelium. To study the physiologic al role of the NO and guanosine 3',5'-cyclic monophosphate (cGMP) syst em in the DA in vivo, we measured the hemodynamic effects of N-G-nitro -L-arginine (L-NNA; 30 mg), a NOS inhibitor, methylene blue (40 mg), a guanylate cyclase inhibitor, and indomethacin (0.8 mg), a cyclooxggen ase inhibitor in 10 chronically prepared late-gestation fetal lambs. L -NNA increased main pulmonary artery (MPA) and aortic pressures (P < 0 .05 vs. baseline) but did not change the pressure gradient between the MPA and the aorta. L-NNA caused a small decrease in DA flow and a sli ght rise in resistance across the DA. Methylene blue increased both MP A pressure and the pressure gradient between the MPA and the aorta fro m 0.3 +/- 0.2 (baseline) to 7.0 +/- 2.7 mmHg (P < 0.05). Indomethacin increased both MPA pressure and the pressure gradient between the MPA and the aorta from 1.1 +/- 0.4 (baseline) to 6.3 +/- 1.5 mmHg (P < 0.0 5) after 40 min. Indomethacin decreased DA flow and increased DA resis tance. We conclude that eNOS is in fetal DA endothelial cells and that NOS inhibition causes constriction of the DA in vivo. DA constriction after NOS inhibition is minimal, especially in comparison with cycloo xygenase inhibition. Methylene blue also constricts the DA, suggesting that guanylate cyclase activity contributes to DA relaxation. We spec ulate that, although the NO and cGMP system modulates DA tone, prostag landins may play a greater role.