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(Circulation Research. 2001;88:721.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Role of Inducible Nitric Oxide Synthase in the Pulmonary Vascular Response to Birth-Related Stimuli in the Ovine Fetus

Robyn L. Rairigh, Thomas A. Parker, D. Dunbar Ivy, John P. Kinsella, I-Da Fan, Steven H. Abman

From the Pediatric Heart Lung Center and the Sections of Neonatology (R.L.R., T.A.P., J.P.K.), Cardiology (D.D.I.), and Pulmonary and Critical Care Medicine (S.H.A.), Department of Pediatrics, University of Colorado School of Medicine, Denver, Colo.

Correspondence to Steven H. Abman, MD, Pulmonary Medicine, B395, The Children’s Hospital, 1056 E Nineteenth Ave, Denver, CO 80218-1088. E-mail steven.abman{at}UCHSC.edu

Abstract—To determine whether type II nitric oxide synthase (NOS II) contributes to the NO-mediated fall in pulmonary vascular resistance (PVR) at birth, we studied the effects of selective NOS II antagonists N-(3-aminomethyl) benzylacetamidine dihydrochloride (1400W) and aminoguanidine (AG) and a nonselective NOS antagonist, nitro-L-arginine (L-NA), during mechanical ventilation with low FIO₂ (<10%), high FIO₂ (100%), and inhaled NO (20 ppm) in 23 near-term fetal lambs. Intrapulmonary infusions of AG, 1400W, and L-NA increased basal PVR before delivery (P<0.05). In control animals, ventilation with low and high FIO₂ decreased PVR by 62% and 85%, respectively. Treatment with AG and 1400W attenuated the fall in PVR by 50% during ventilation with low and high FIO₂ (control versus treatment, P<0.05 for each intervention). L-NA treatment attenuated the fall in PVR during ventilation with low and high FIO₂ to a similar degree as the NOS II antagonists. To test the selectivity of the NOS II antagonists, we studied the effects of acetylcholine and inhaled NO in each study group. Acetylcholine-induced pulmonary vasodilation remained intact after treatment with selective NOS II antagonists but not after treatment with nonselective NOS blockade with L-NA. In contrast, the response to inhaled NO was similar between treatment groups. We conclude that selective NOS II inhibition is as effective as nonselective NOS blockade in attenuating pulmonary vasodilation at birth and speculate that NOS II activity contributes to NO-mediated pulmonary vasodilation at birth. We additionally speculate that stimulation of the airway epithelium by rhythmic distension and increased FIO₂ may activate NOS II release at birth.

Key Words: pulmonary circulation • pulmonary hypertension • nitric oxide • nitric oxide synthase • persistent pulmonary hypertension of the newborn

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