Supplemental
oxygen and
alkalosis are the most effective treatments used to lower pulmonary arterial pressure in children with pulmonary hypertensive disorders. However, their mechanisms of action are unknown.
Endothelium-derived nitric oxide (EDNO) is an important mediator of pulmonary vascular tone and produces potent pulmonary vasodilation during
pulmonary hypertension. In vitro evidence suggests that EDNO may mediate the vasodilating effects of
oxygen. To investigate whether EDNO synthesis mediates the pulmonary vasodilation produced by
hyperoxia [normocarbic ventilation with 100%
oxygen, arterial
oxygen tension > 450 torr (60 kPa)] or
alkalosis (
hyperventilation with 21%
oxygen, pH > 7.55) in vivo, eight intact newborn lambs were studied during similar degrees of
pulmonary hypertension induced either by the infusion of
U46619 (a
thromboxane A2 mimic) or
N omega-nitro-L-arginine (an inhibitor of EDNO synthesis). The lambs were sedated, paralyzed, and mechanically ventilated.
Meclofenamic acid was infused to inhibit
prostaglandin synthesis. During
pulmonary hypertension induced by
U46619, pulmonary arterial pressure and pulmonary vascular resistance were significantly decreased by
acetylcholine (an EDNO-dependent
vasodilator) (23.1 +/- 3.4% and 43.3 +/- 14.5%, respectively),
hyperoxia (26.8 +/- 7.8% and 32.9 +/- 10.6%), and
alkalosis (32.1 +/- 10.3% and 36.1 +/- 17.0%) (p < 0.05). During
pulmonary hypertension induced by
N omega-nitro-L-arginine, the decreases in pulmonary arterial pressure and pulmonary vascular resistance produced by
acetylcholine (9.6 +/- 6.4% and 23.9 +/- 14.1%, respectively) were significantly attenuated (p < 0.05), but the decreases produced by
hyperoxia or
alkalosis were unchanged. Therefore,
hyperoxia and
alkalosis can produce pulmonary vasodilation independent of EDNO synthesis in the intact newborn lamb.