title: Role of neuronal nitric oxide synthase in regulation of vascular and ductus arteriosus tone in the ovine fetus.
abstract: Nitric oxide (NO) is produced by NO synthase (NOS) and contributes to the regulation of vascular tone in the perinatal lung. Although the neuronal or type I NOS (NOS I) isoform has been identified in the fetal lung, it is not known whether NO produced by the NOS I isoform plays a role in fetal pulmonary vasoregulation. To study the potential contribution of NOS I in the regulation of basal fetal pulmonary vascular resistance (PVR), we studied the hemodynamic effects of a selective NOS I antagonist, 7-nitroindazole (7-NINA), and a nonselective NOS antagonist, N-nitro-L-arginine (L-NNA), in chronically prepared fetal lambs (mean age 128 +/- 3 days, term 147 days). Brief intrapulmonary infusions of 7-NINA (1 mg) increased basal PVR by 37% (P < 0.05). The maximum increase in PVR occurred within 20 min after infusion, and PVR remained elevated for up to 60 min. Treatment with 7-NINA also increased the pressure gradient between the pulmonary artery and aorta, suggesting constriction of the ductus arteriosus (DA). To test whether 7-NINA treatment selectively inhibits the NOS I isoform, we studied the effects of 7-NINA and L-NNA on acetylcholine-induced pulmonary vasodilation. The vasodilator response to acetylcholine remained intact after treatment with 7-NINA but was completely inhibited after L-NNA, suggesting minimal effects on endothelial or type III NOS after 7-NINA infusion. Western blot analysis detected NOS I protein in the fetal lung and great vessels including the DA. NOS I protein was detected in intact and endothelium-denuded vessels, suggesting that NOS I is present in the medial or adventitial layer. We conclude that 7-NINA, a selective NOS I antagonist, increases basal PVR, systemic arterial pressure, and DA tone in the late-gestation fetus and that NOS I protein is present in the fetal lung and great vessels. We speculate that NOS I may contribute to NO production in the regulation of basal vascular tone in the pulmonary and systemic circulations and the DA.
authors.affiliation: Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado 80218-1088, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Rairigh
authors.forename: L
authors.initials: L
authors.lastname: Storme
authors.forename: T A
authors.initials: TA
authors.lastname: Parker
authors.forename: T D
authors.initials: TD
authors.lastname: Le Cras
authors.forename: N
authors.initials: N
authors.lastname: Markham
authors.forename: M
authors.initials: M
authors.lastname: Jakkula
authors.forename: S H
authors.initials: SH
authors.lastname: Abman
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D004373:Ductus Arteriosus / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus / Q000378:metabolism / Q000502:physiology*; D005865:Gestational Age; D006439:Hemodynamics / Q000187:drug effects; D007191:Indazoles / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I; D019335:Nitroarginine / Q000494:pharmacology; D011652:Pulmonary Circulation / Q000187:drug effects; D012756:Sheep; D014664:Vasodilation / Q000187:drug effects; D014666:Vasomotor System / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D019335:Nitroarginine; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D000109:Acetylcholine; C080122:7-nitroindazole