Endothelial (type III) nitric oxide synthase (eNOS) is developmentally regulated and modulates fetal pulmonary vascular resistance (PVR). Although inducible (type II) NOS (iNOS) has been detected in human and rat fetal lungs, its role in the developing lung is unknown. To study the potential contribution of iNOS in regulation of fetal PVR, we measured the hemodynamic efects of 3 selective inhibitors of iNOS, 2-amino -5,6- dihydro-6-methyl-4H-1,3-thiazine (AMT), S- ethylisothiourea (EIT), and aminoguanidine (AG) in 11 chronically-prepared fetal lambs (mean age, 134 days; term, 147 days). At surgery, catheters were placed in the left pulmonary artery for selective drug infusion, and in the main pulmonary artery, aorta, left atrium and amniotic cavity for pressure measurements. An ultrasonic flow transducer was placed on the LPA to measure blood flow. After at least 48 hours recovery from surgery, AMT (0.16 mg), EIT (0.16 mg) and AG (140 mg) were infused into the LPA over 10 minutes. Each agent increased PVR, which persisted for up to 60 minutes after infusion. Table Acetylcholine-induced vasodilation (30 ugm) was not different before and after AMT treatment (% change in PVR from baseline before (37±5%) and after(33±10%; p=NS), suggesting minimal eNOS inhibition. We conclude that selective iNOS antagonists increase PVR in the late-gestation fetus. We speculate that these effects are largely due to iNOS inhibition, and that iNOS may modulate vascular tone in the developing pulmonary circulation.

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