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1 Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA
2 Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA
3 Department of Pediatrics, University of Wisconsin School of Medicine, Madison, WI, USA
* To whom correspondence should be addressed. E-mail: rbland{at}stanford.edu.
Chronic lung injury from prolonged mechanical ventilation after premature birth inhibits the normal postnatal decrease in pulmonary vascular resistance (PVR) and leads to structural abnormalities of the lung circulation in newborn sheep. Compared to normal lambs born at term, chronically ventilated preterm lambs have increased pulmonary arterial smooth muscle and elastin, fewer lung microvessels, and reduced abundance of endothelial nitric oxide synthase (eNOS). These abnormalities may contribute to impaired respiratory gas exchange that often exists in infants with chronic lung disease (CLD). Nitric oxide inhalation (iNO) reduces PVR in human infants and lambs with persistent pulmonary hypertension (PPHN). We wondered if iNO might have a similar effect in lambs with CLD. We therefore studied the effect of iNO on PVR in lambs that were delivered prematurely at ~125 d gestation (term = 147 d) and mechanically ventilated for 3 weeks. All of the lambs had chronically implanted catheters for measurement of pulmonary vascular pressures and blood flow. During week 2 of mechanical ventilation, iNO at 15 ppm for 1 h decreased PVR by ~20% in 12 lambs with evolving CLD. When the same study was repeated in 8 lambs at the end of week 3, iNO had no significant effect on PVR. To see if this loss of iNO effect on PVR might reflect dysfunction of lung vascular smooth muscle, we infused 8-bromo-cGMP, 150 (µg/kg)/min iv for 15-30 min in 4 of these lambs at the end of week 3. PVR consistently decreased by 30-35%. Lung immunohistochemistry and immunoblot analysis of excised pulmonary arteries from lambs with CLD, compared to control term lambs, showed decreased soluble guanylate cyclase (sGC). These results suggest that loss of pulmonary vascular responsiveness to iNO in preterm lambs with CLD results from impaired signaling, possibly related to deficient or defective activation of sGC, the intermediary enzyme through which iNO induces increased vascular smooth muscle cell cGMP and resultant vasodilation.
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