Role of inducible nitric oxide synthase in the pulmonary vascular response to birth-related stimuli in the ovine fetus.
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 FIO(2) (<10%), high FIO(2) (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 FIO(2) 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 FIO(2) (control versus treatment, P<0.05 for each intervention). L-NA treatment attenuated the fall in PVR during ventilation with low and high FIO(2) 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 FIO(2) may activate NOS II release at birth.
Rairigh
R L
RL
Pediatric Heart Lung Center and the Sections of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado, USA.
Parker
T A
TA
Ivy
D D
DD
Kinsella
J P
JP
Fan
I D
ID
Abman
S H
SH
D000109:Acetylcholine / Q000494:pharmacology; D000280:Administration, Inhalation; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005333:Fetus; D006146:Guanidines / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D007743:Labor, Obstetric / Q000502:physiology*; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000196:embryology; D009569:Nitric Oxide / Q000008:administration & dosage; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology*; D052247:Nitric Oxide Synthase Type II; D019335:Nitroarginine / Q000494:pharmacology; D010100:Oxygen / Q000008:administration & dosage; D011247:Pregnancy; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D012121:Respiration, Artificial; D012756:Sheep; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D000578:Amidines; D001596:Benzylamines; D004791:Enzyme Inhibitors; D006146:Guanidines; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D014665:Vasodilator Agents; D019335:Nitroarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D000109:Acetylcholine; D010100:Oxygen; C004479:pimagedine