Maturational changes in ovine pulmonary vascular responses to inhaled nitric oxide

Abstract

Developmental changes in modulation of pulmonary vasomotor tone by endothelium-derived nitric oxide (EDNO) may reflect maturational differences in endothelial synthesis of and/or vascular smooth muscle response to nitric oxide. This study sought to determine whether pulmonary vascular sensitivity and responsiveness to nitric oxide change during newborn development, and whether this is related to changes in guanylate cyclase activity. Pulmonary artery dose-responses to inhaled nitric oxide (iNO, 0.25-100 parts per million) were measured in hypoxic, indomethacin-treated, isolated lungs from 1-day (1-d)- and 1-month (1-m)-old lambs. The lungs of 1-m-old lambs were ventilated with 4% (oxygen) O2, and lungs of 1-d-old lambs were ventilated with either 4% or 7% O2 in order to achieve similar stimuli or vasomotor tone. Cyclic guanosine monophosphate (cGMP) concentrations in the perfusate were measured at iNO concentrations of 0, 5, and 100 parts per million (ppm). Basal and stimulated pulmonary guanylate cyclase activity was also measured in lung extracts in vitro. The effects of iNO were similar in both 1-d groups, even though baseline hypoxic tone was significantly higher in 1-d lungs ventilated with 4% O2 than with 7% O2. Furthermore, both the 1-d 7% O2 and 1-d 4% O2 lungs exhibited greater responsiveness and sensitivity to iNO than 1-m lungs. Perfusate cGMP concentrations and soluble guanylate cyclase activity were higher under stimulated than basal conditions, but neither differed statistically between 1 d and 1 m. These data suggest that pulmonary vascular responsiveness and sensitivity to nitric oxide decrease with age, but the mechanisms underlying these maturational changes require further investigation.