Role of inducible nitric oxide synthase in the pulmonary vascular responseto 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 st udied the effects of selective NOS II antagonists N-(3-aminomethyl) benzyla cetamidine dihydrochloride (1400W) and aminoguanidine (AG) and a nonselecti ve NOS antagonist, nitro-L-arginine (L-NA), during mechanical ventilation w ith low FIO2 (<10%), high FIO2 (100%), and inhaled NO (20 ppm) in 23 near-t erm fetal lambs. Intrapulmonary infusions of AG, 1400W, and L-NA increased basal PVR before delivery (P<0.05). In control animals, ventilation with lo w and high Fro, 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-N A 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 selectivit y of the NOS II antagonists, we studied the effects of acetylcholine and in haled NO in each study group. Acetylcholine-induced pulmonary vasodilation remained intact after treatment with selective NOS II antagonists but not a fter treatment with nonselective NOS blockade with L-NA, In contrast, the r esponse to inhaled NO was similar between treatment groups. We conclude tha t selective NOS II inhibition is as effective as nonselective NOS blockade in attenuating pulmonary vasodilation at birth and speculate that NOS II ac tivity contributes to NO-mediated pulmonary vasodilation at birth. We addit ionally speculate that stimulation of the airway epithelium by rhythmic dis tension and increased Fro, may activate NOS II release at birth.