CHRONIC PULMONARY-HYPERTENSION IN-UTERO IMPAIRS ENDOTHELIUM-DEPENDENTVASODILATION

To determine whether endothelium-dependent pulmonary vasodilation is s electively impaired by chronic intrauterine pulmonary hypertension, we compared the hemodynamic effects of an endothelium-dependent agonist, acetylcholine (ACh), with an endotheliumin-dependent agonist, atrial natriuretic peptide (ANP), before, during, and after development of pu lmonary hypertension in five late-gestation fetal lambs. Pulmonary hyp ertension was produced over 9-12 days by progressive inflation of a va scular occluder around the ductus arteriosus. Age-matched fetal lambs (n = 5) without occluders served as controls. Mean pulmonary arterial pressure increased from 44 +/- 2 (baseline) to 65 +/- 4 Torr after 10- 12 days of inflation (P < 0.05). Left lung pulmonary vascular resistan ce (PVR) increased from 0.52 +/- 0.06 to 0.72 +/- 0.11 Torr.ml(-1) min over 10 days (P < 0.05). O-2 saturation remained at > 40% during the study period. Although brief intrapulmonary infusions of ACh (1.5 mu g over 15 min) lowered left lung PVR by 29 +/- 8% before ductus arterio sus compression, ACh-induced pulmonary vasodilation was absent after 9 -12 days of pulmonary hypertension. In contrast, the vasodilator respo nse to ANP remained intact throughout the study period. ACh- and ANP-i nduced vasodilation did not change with time in control animals. In fi ve hypertensive animals delivered by cesarean section, inhaled NO (20 ppm) reduced left lung PVR from levels achieved during ventilation wit h 100% O-2 alone (0.61 +/- 0.31 to 0.24 +/- 0.007 Torr.ml(-1) min), in creased arterial O-2 saturation from 51 +/- 14 to 84 +/- 13%, and incr eased arterial PO2 from 29 +/- 11 to 106 +/- 34 Torr. We conclude that , in the hypertensive fetal lung, endothelium-dependent vasodilation i s preferentially impaired, whereas vasodilation to direct-acting smoot h muscle guanosine 3',5'-cyclic monophosphate agonists ANP and inhaled NO remains intact. We speculate that impaired endothelium-derived rel axing factor/NO activity, as well as vascular remodeling or altered sm ooth muscle cell function, contributes to the failure of postnatal ada ptation in this model of pulmonary hypertension.