ROLE OF INDUCIBLE NITRIC-OXIDE SYNTHASE IN REGULATION OF PULMONARY VASCULAR TONE IN THE LATE-GESTATION OVINE FETUS

Nitric oxide (NO) produced by NO synthase (NOS) modulates fetal pulmon ary vascular tone and contributes to the fall in pulmonary vascular re sistance (PVR) at birth. Although the inducible (type II) NOS isoform is present in human and rat fetal lungs, it is uncertain whether type II NOS activity contributes to vascular NO production in the fetal lun g. To determine whether type II NOS is present in the ovine fetal lung and to study the potential contribution of type II NOS on the regulat ion of basal PVR in the fetus, we measured the hemodynamic effects of three selective type II NOS antagonists: aminoguanidine (AG), 2-amino- 5,6-dihydro-6-methyl-4H-1,3 thiazine (AMT), and S-ethylisothiourea (EI T). Studies were performed after at least 72 h of recovery from surger y in 19 chronically prepared fetal lambs (133+/-3 d; 147 d, term), Bri ef intrapulmonary infusions of AG (140 mg), AMT (0.12 mg), and EIT (0. 12 mg) increased basal PVR by 82, 69, and 77%, respectively (P < 0.05) . The maximum increase in PVR occurred within 20 min, but often persis ted up to 80 min, These agents also increased mean aortic pressure but did not alter the pressure gradient between the pulmonary artery and aorta, suggesting little effect on tone of the ductus arteriosus. Acet ylcholine-induced pulmonary vasodilation remained intact after treatme nt with selective type II NOS antagonists, but not after treatment wit h the nonselective NOS blocker, nitro-L-arginine. Using Northern blot analysis with poly(A)(+) RNA, we demonstrated the presence of two mRNA transcripts for type II NOS (4.1 and 2.6 kb) in the fetal lung. We co nclude that the type II NOS isoform is present in the ovine fetal lung , and that selective type II NOS antagonists increase PVR and systemic arterial pressure in the late-gestation fetus. We speculate that type II NOS may play a physiological role in the modulation of vascular to ne in the developing fetal lung.