Nitric oxide alterations following acute ductal constriction in the fetal lamb: a role for superoxide

Jong‐Hau Hsu1,2, Peter Oishi1, Dean A. Wiseman3, Yali Hou3, Omar Chikovani1, Sanjeev A. Datar1, Enikö Sajti1, Michael Johengen1, Cynthia Harmon1, Stephen M. Black3, Jeffrey R. Fineman4,1
1‡Department of Pediatrics and
2Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; and
3Vascular Biology Center, Medical College of Georgia, Augusta, Georgia
4Cardiovascular Research Institute, University of California, San Francisco, California

Tóm tắt

Acute partial compression of the fetal ductus arteriosus (DA) results in an initial abrupt increase in pulmonary blood flow (PBF), which is followed by a significant reduction in PBF to baseline values over the ensuing 2–4 h. We have previously demonstrated that this potent vasoconstricting response is due, in part, to an endothelin-1 (ET-1)-mediated decrease in nitric oxide synthase (NOS) activity. In addition, in vitro data demonstrate that ET-1 increases superoxide levels in pulmonary arterial smooth muscle cells and that oxidative stress alters NOS activity. Therefore, the objectives of this study were to determine the potential role of superoxide in the alterations of hemodynamics and NOS activity following acute ductal constriction in the late-gestation fetal lamb. Eighteen anesthetized near-term fetal lambs were instrumented, and a lung biopsy was performed. After a 48-h recovery, acute constriction of the DA was performed by inflating a vascular occluder. Polyethylene glycol-superoxide dismutase (PEG-SOD; 1,000–1,500 units/kg, n = 7) or PEG-alone (vehicle control group, n = 5) was injected into the pulmonary artery before ductal constriction. Six animals had a sham operation. In PEG-alone-treated lambs, acute ductal constriction rapidly decreased pulmonary vascular resistance (PVR) by 88%. However, by 4 h, PVR returned to preconstriction baseline. This vasoconstriction was associated with an increase in lung superoxide levels (82%), a decrease in total NOS activity (50%), and an increase in P-eNOS-Thr495 (52%) ( P < 0.05). PEG-SOD prevented the increase of superoxide after ductal constriction, attenuated the vasoconstriction, preserved NOS activity, and increased P-eNOS Ser1177 (307%, P < 0.05). Sham procedure induced no changes. These data suggest that an acute decrease in NOS activity that is mediated, in part, by increased superoxide levels, and alterations in the phosphorylation status of the endothelial NOS isoform, underlie the pulmonary vascular response to acute ductal constriction.

Từ khóa


Tài liệu tham khảo

10.1152/ajpheart.1989.257.2.H626

10.1172/JCI114091

10.1074/jbc.M211926200

10.1203/00006450-200001000-00018

10.1016/j.vph.2006.08.005

10.1203/00006450-199812000-00001

10.1016/S0006-291X(05)80808-3

10.1203/00006450-200102000-00009

10.1074/jbc.M802269200

10.1152/ajprenal.2001.280.2.F193

10.1097/01.hjh.0000226199.51805.88

10.1152/jappl.1996.81.6.2481

10.1203/00006450-199603000-00010

10.1002/jcb.1094

10.1152/ajpheart.2001.280.2.H777

10.1203/00006450-198903000-00005

10.1152/ajpheart.00417.2001

10.1016/S0008-6363(99)00161-3

10.2174/157016105774329408

10.1074/jbc.C100084200

10.1146/annurev.physiol.64.081501.155952

10.1152/ajplung.1997.272.5.L1005

10.1203/00006450-199904010-00018

10.1203/00006450-199903000-00022

10.1161/01.RES.63.5.944

10.1016/S0095-5108(18)30903-5

10.1152/ajplung.1997.272.5.L1013

10.3109/10623320109090806

10.1152/ajplung.2001.281.5.L1058

10.1161/hh1601.094983

10.1203/00006450-198903000-00006

10.1152/ajplung.00459.2005

10.1152/ajpcell.00509.2005

10.1038/ajh.2007.14