Within minutes after delivery, pulmonary arterial pressure falls and blood flow increases in response to birth- related stimuli. Mechanisms contributing to the fall in PVR at birth include establishment of an air-liquid interface, rhythmic lung distension, increased 02 tension, and altered production of vasoactive substances. Physical stimuli, such as increased shear stress, ventilation and increased 02, cause pulmonary vasodilation in part by increasing production of vaosodilators (e.g., NO and PGI2). Pretreatment with the arginine analogue, nitro-L-arginine, blocks NOS activity and attenuates the decline in PVR after delivery of near term fetal lambs. These findings suggested that ~50% of the rise in pulmonary blood flow at birth may be directly related to the acute release of NO. Specific mechanisms that cause NO release at birth include the marked rise in shear stress, increased 02, and ventilation. Increased Pa02 triggers NO release, which augments vasodilation through cGMP/PKG-mediated K+ channel activation (66). Although the endothelial isoform of NOS (type III) has been presumed to be the major contributor of NO at birth, recent studies suggest that other isoforms (inducible (type II) and neuronal (type I)) may be important sources of NO release in utero and at birth as well. Although early studies were performed in term animals, NO also contributes to the rapid decrease in PVR at birth in premature lambs, at least as early as 112-115 days (0.7 term).
Other vasodilator products, including PGI2, also modulate changes in pulmonary vascular tone at birth. Rhythmic lung distension and shear stress stimulate both PGI2 and NO production in the late gestation fetus, but increased 02 tension triggers NO activity and overcomes the effects of prostaglandin inhibition at birth. In addition, the vasodilator effects of exogenous PGI2 are blocked by NOS inhibitors, suggesting that NO modulates activity in the perinatal lung. Adenosine release may also contribute to the fall in PVR at birth, but its actions may be partly through enhanced production of NO. Thus, although NO does not account for the entire fall in PVR at birth, NOS activity appears important in achieving postnatal adaptation of the lung circulation. Transgenic eNOS knock-out mice successfully make the transition at birth without evidence of PPHN (20). This finding suggests that eNOS"'" mice may have adaptive mechanisms, such as a compensatory vasodilator mechanisms (e.g., upregulation of other NOS isoforms or dilator prostaglandins) or less constrictor tone. Interestingly, these animals are more sensitive to the development of pulmonary hypertension at relatively mild decreases in Pa02 and have higher neonatal mortality when exposed to hypoxia after birth (unpublished observations). We speculate that isolated eNOS deficiency alone may not be sufficient for the failure of postnatal adaptation, but that decreased ability to produce NO in the setting of a perinatal stress (e.g., hypoxia, inflammation, hypertension, or upregulation of vasoconstrictors) may cause PPHN.
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